Hypertrophic Osteoarthropathy Treatment & Management

Updated: Jan 13, 2021
  • Author: Vishnuteja Devalla, MD; Chief Editor: Herbert S Diamond, MD  more...
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Treatment

Medical Care

Primary hypertrophic osteoarthropathy

So far, no medical treatment has been suggested to alleviate primary or idiopathic hypertrophic osteoarthropathy (HOA; pachydermoperiostosis [PDP]). Medical care is palliative and includes nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, tamoxifen, retinoids, and risedronate  to alleviate the painful polyarthritis/osteoarthropathy. [8]

Colchicine may be helpful for the pain due to subperiosteal new bone formation. Colchicine inhibits neutrophil chemotaxis and tissue edema; thereby improving joint symptoms, pachyderma, and folliculitis.

Corticosteroids and bisphosphonates, which work by inhibition of osteoclasts and antiresorptive effects, have been tried with promising results for rheumatologic manifestations of HOA. Isolated reports suggest that pamidronate, [100]  zoledronic acid, [101, 102, 103]  and octreotide [104]  may help relieve bone pain in some cases. Retinoids, by decreasing procollagen messenger RNA in fibroblasts, has produced improvements in pachyderma, seborrhea, acne, folliculitis, and cutis vertices gyrate.

Botulinum toxin A (BTX-A) injection is a simple procedure that may be of value in providing temporary cosmetic improvement of leonine facies. [69]  For correction of gross disfigurement, plastic and reconstructive surgery may be indicated. Otherwise, reassurance is all that is required. Prognosis for survival is excellent but the effect on function depends on the degree of bone and joint involvement. [12]

Secondary hypertrophic osteoarthropathy

Treatment for secondary HOA is classified into 2 categories: (1) treatment of the underlying cause (eg, surgical resection, chemotherapy, radiotherapy, for cancer, surgery for cardiac anomalies, antibiotics for infection) and (2) symptomatic treatments (eg, NSAIDs, bisphosphonates, octreotide, vagotomy).

Treatment of the underlying disorder is the approach most widely reported to be effective. In one study, for example, the clinical manifestations and bone scintigram findings of HOA improved in half of the patients on treatment of lung cancer. [21]  Treatment of Pneumocystis pneumonia, pulmonary pseudotumor, and pulmonary tuberculosis have been reported to result in resolution of associated HOA, as has corticosteroid treatment of inflammatory interstitial lung disease with associated HOA. [105]

In cases in which primary therapy is not possible, several symptomatic treatment modalities are suggested, with various degree of success. [8] NSAIDs may be helpful for the painful osteoarthropathy [106, 107] In 2006, a case study by Kozak et al described clinical improvement of HOA in a 65-year-old woman with recurrent non–small cell lung cancer (NSCLC) and adrenal metastasis who was treated with the cyclo-oxygenase 2 (COX-2) inhibitor rofecoxib. COX-2 is an enzyme that is involved in the formation of prostaglandins, and urinary levels of prostaglandin E2 (PGE2)  have been shown to correlate with the pain level in patients with HOA. [8]  Similarly, Yuan et al reported resolution of symptoms of HOA and normalization of elevated levels of circulating PGE2 in patients who received a 3-month course of the COX-2 inhibitor etoricoxib (an agent that is not approved for use in the United States). [108]   

Other NSAIDs, including ketorolac and indomethacin, have also been reported in various case series to be effective at relieving HOA pain. In humans, PGE has been found to induce periostitis and overt HOA symptoms. Letts et al reported 5 cases of infants developing limb pain and swelling in association with periostitis after chronic infusion of PGE for congenital duct-dependent heart disease; in these cases, periostitis gradually improved once PGE was discontinued. Although involvement of PGE in the pathogenesis of HOA is still unclear, successful use of NSAIDs to relieve HOA pain symptoms warrants further investigation. [8]

In 2016, a systematic review of the effectiveness and safety of anti-inflammatory and analgesic agents for the symptomatic management of cystic fibrosis–related HOA in adults and children found no randomized controlled trials to evaluate these agents. Thus, no conclusions could be reached and clinicians were advised to balance potential benefit against the possible risk of complications in each case. [106]  However, a 2017 systematic review of NSAIDs for treatment of primary HOA concluded that these drugs are effective in improving arthralgia or arthritis symptoms in the majority of these patients, and recommended NSAID use for this indication. [107]

Given the evidence supporting a role of vascular endothelial growth factor (VEGF) in HOA and the pathogenesis theory of pulmonary shunting of vascular growth factors, a logical proposed treatment involves the use of VEGF inhibitors. According to Atkinson et al, VEGF may partly mediate clubbing by providing a persistent positive autocrine and paracrine loop to drive cellular and stromal changes including angiogenesis resulting in increased microvessel density, new bone formation, and edema. [109]

Furthermore, both VEGF plasma levels and tissue expression have been reported in almost all of the diseases associated with HOA and has been found to correlate with disease activity. The anti-VEGF antibody bevacizumab, which is approved for use in adjuvant therapy for NSCL, may be investigated for use in alleviating pain symptoms in patients with HOA secondary to NSCLC. As anti-VEGF monoclonal antibodies such as bevacizumab and VEGF pathway inhibitors (several drugs are in different phases of clinical trials) become more frequently used in the clinical practice of various cancers, more knowledge about the pathogenesis of HOA may be revealed in the near future. [110, 111]

Promising results in treatment of HOA have also been reported with octreotide. Case reports describe pain relief in patients with HOA secondary to squamous cell carcinoma and to Fallot tetralogy with pulmonary artery atresia. The success of this treatment may be due to the similarities of HOA to acromegaly; octreotide as a somatostatin analog has a well-established role in controlling the growth and secretions from pituitary adenomas, particularly in acromegaly and neuroendocrine tumors. Of note, octreotide also has an inhibitory effect on the production of VEGF and endothelial proliferation. [104, 8]

Bisphosphonates such as zoledronic acid and pamidronate are also effective for pain relief. [101, 102] Generally, these agents promote osteoclast apoptosis by inhibiting the activity of farnesyl pyrophosphate synthase. Their mechanisms also involve inhibiting osteocyte apoptosis and targeting monocytes/macrophages. In addition, bisphosphonates may also have antitumor, anti-inflammatory, anti-angiogenic effects and reduce VEGF in patients with metastatic solid tumors. [80]  

Case reports describe the successful use of the bisphosphonate pamidronate in HOA secondary to neoplasms, cystic fibrosis, and cyanotic congenital heart disease. [8, 100] Only scarce data are available on managing HOA-associated pain with zoledronic acid. [80, 103, 100]  However, zoledronic acid is a more potent bisphosphonate, with demonstrated 40-fold to 850-fold greater potency than pamidronate, and may be even more effective and longer lasting than pamidronate for management of the bone and joint pain associated with HOA, irrespective of the underlying disorders. [80]  However, use of bisphosphonates to treat hypertrophic osteoarthropathy–associated musculoskeletal pain is currently off-label. [80]

Gefinitib, an orally active selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, provided clinical antitumor activity, with disappearance of periostitis in a case of HOA secondary to advanced lung adenocarcinoma. [8, 112]

Reduction of the serum estrogen level or tissue sensitivity to circulating sex steroids might become a therapeutic strategy for HOA. Tamoxifen has been reported to improve arthralgia, sweating of hands, and gynecomastia.

Infliximab is a monoclonal antibody that binds to tumor necrosis factor alpha (TNF-alpha), an inflammatory cytokine that is found in high levels in HOA and is involved on the production of other inflammatory mediators, which increases osteoclastogenesis. A case report describes improvement of HOA symptoms with infliximab. [53]

Neurogenic therapy for HOA was proposed in 1976 by Readon et al. They reported falls in the thermographic index along with subjective improvement on combined adrenergic blockade with propranolol and phenoxybenzamine. [8]

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Surgical Care

Hypertrophic osteoarthropathy (HOA) secondary to cancer improves and in many cases resolves with treatment of the primary tumor. As early as 1976, Atkinson et al reported that chemotherapy for Hodgkin lymphoma also led to complete resolution of HOA symptoms. By 1991 and 1992, 2 reported cases of resolution of HOA following surgical resection of lung tumor were noted. Similarly in 2009, Poanta et al reported complete resolution of hypertrophic osteoarthropathy symptoms following pneumonectomy for squamous cell lung cancer. [77] Other treatment modalities of primary causes leading to alleviation of HOA symptoms include cytoreduction of tumor by radiofrequency ablation and lung transplantation for cystic fibrosis. [8]

In most lung cancer patients, digital clubbing resolves after effective surgical treatment of the tumor. [110] Joint and bone pains also resolve quickly after tumor resection, which confirms its paraneoplastic nature. [113]

Outside of primary pulmonary processes, treatment of primary liver disease, heart disease, and esophageal tumors has also been reported to alleviate symptoms of hypertrophic osteoarthropathy. In 1987, Huaux et al reported the first case of a liver graft alleviating symptoms of hypertrophic osteoarthropathy associated with end-stage cholestatic cirrhosis related to non-Wilsonian copper overload. [114] Since then, full liver transplantation has also led to resolution of hepatic hypertrophic osteoarthropathy. [8]

Correction of cyanotic heart malformation has also been found to be effective in relieving HOA symptoms. In 1982, Frand et al reported two cases in which surgical correction of cyanotic heart disease led to complete clinical and radiological resolution of HOA. [115]

Multiple case reports describe patients with hypertrophic osteoarthropathy secondary to esophageal leiomyoma or esophageal squamous cell carcinoma whose hypertrophic osteoarthropathy symptoms resolved with total esophagectomy. Pallecaros et al also reported that total esophagogastrectomy of a patient with crippling hypertrophic osteoarthropathy secondary to an inflammatory fibroid polyp led to resolution of pain. However, the author noted that vagotomy unavoidable during esophagogastrectomy, may have led to the resolution of the patient's hypertrophic osteoarthropathy.

In patients with secondary hypertrophic osteoarthropathy, tumor resection results in spontaneous improvement within 2-4 weeks. In fact, hypertrophic osteoarthropathy may disappear completely by 3-6 months. [51] Thus, in cases where the primary cause can be treated, symptoms of hypertrophic osteoarthropathy most likely improves or resolves. The challenge lies in symptomatic treatment of hypertrophic osteoarthropathy when the primary cause cannot be eliminated. [8]

In patients with primary hypertrophic osteoarthropathy, plastic surgery may be necessary to remove excess facial skin. The treatment of pachydermia is usually centered on improving the cosmetic appearance through plastic surgery. Surgical management of pachydermia includes bilateral blepharoplasties, tarsal wedge resections, excision of skin furrows, and facial rhytidectomy and scalp-reduction techniques. [69] More recently, forehead lifting and direct excision of the dermal folds have been described. A reported case described an approach using endotines in combination with mask subperiosteal and lateral SMASectomy facelifts.

A patient with the rare condition of PDP with secondary ptosis and floppy eyelid was successfully treated with a combination of levator advancement and an upper eyelid tarsal strip. [99]

Vagotomy

In the 1950s, thoracic surgeon Geoffrey Flavell discovered that unilateral vagotomy on the side of the lung cancer lead to symptomatic relief of hypertrophic osteoarthropathy symptoms in some severe cases. Flavell observed that patients with failed dissection, inoperable tumor, or disseminated disease had complete resolution of pain with dissection of the vagus nerve. In 1962 and 1964, Yacoub further supported Flavell’s hypothesis with a report of clinical and radiologic regression of HOA following vagotomy in 2 patients with severe HOA.

Despite varying success with vagotomy, the vagal mechanism has largely been deemed implausible given that it does not fit with physiological mechanisms accepted in current practices. Nevertheless, in 2007 Ooi et al revived the vagus nerve hypothesis with their report of a 50-year-old woman with disabling hypertrophic osteoarthropathy and inoperable lung cancer who experienced effective pain relief after video-assisted thoracoscopic truncal vagotomy. [116] Vagotomy improved the associated articular pain and swelling, and she regained full mobility.

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