Continuing Education Activity

Hypertrophic osteoarthropathy (HOA), consists of the presence of digital clubbing, increased periosteal activity of the tubular bones, arthralgias, and joint effusion and is characterized by abnormal proliferation of the skin, soft tissues, and osseous tissues in the distal parts of extremities. There are two forms of the disease - primary and secondary. Primary HOA (PHO), also called pachydermoperiostosis, comprises of digital clubbing, periostosis, and pachydermia and is a rare genetic disease, while secondary hypertrophic osteoarthropathy is associated with a variety of pulmonary, cardiac, and other conditions. This activity reviews the etiology, presentation, evaluation, and management of hypertrophic osteoarthropathy and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Describe the pathophysiology and progression of hypertrophic osteoarthropathy.
• Review the components of a proper evaluation and assessment of a patient presenting with hypertrophic osteoarthropathy, including any indicated imaging studies.
• Summarize the management options available for hypertrophic osteoarthropathy.
• Explain the importance of improving coordination among the interprofessional team to enhance care for patients affected by hypertrophic osteoarthropathy.

Introduction

Hypertrophic osteoarthropathy (HOA), consists of the presence of digital clubbing, increased periosteal activity of the tubular bones, arthralgias, and joint effusion and is characterized by abnormal proliferation of the skin, soft tissues, and osseous tissues in the distal parts of extremities.[1][2]  There are two forms of the disease - primary and secondary. Primary HOA (PHO), also called pachydermoperiostosis, comprises of digital clubbing, periostosis, and pachydermia and is a rare genetic disease, while secondary hypertrophic osteoarthropathy is associated with a variety of pulmonary, cardiac and other conditions.

Clubbing is among the oldest signs in clinical medicine, first described in a man with curved fingernails and empyema by Hippocrates (460 BC - 370 BC).[1] Friedreich was the first to scientifically describe primary hypertrophic osteoarthropathy in 1868 as "hyperostosis of the entire skeleton" in two affected brothers. Touraine, Solente, and Gole in 1935 distinguished PHO as the primary form of HOA and distinct from HOA associated with an underlying disease like pulmonary or cardiac disease.[3]

Etiology

Hypertrophic osteoarthropathy is associated with a plethora of internal diseases, mainly pulmonary and cardiac. Still, it has also been described to occur in association with gastrointestinal and endocrine diseases, and this is known as secondary hypertrophic osteoarthropathy. Lung cancer, particularly non-small cell variety, is the most common association, and this association is considered a paraneoplastic rheumatic syndrome. PHO, on the other hand, is a genetic disease and has no known etiology.[1]

Epidemiology

The precise incidence and prevalence of PHO are unknown.[3] The age of disease onset has a bimodal distribution, the initial peak being in the first year of life and the other during puberty. Males are affected predominantly. Research has described both autosomal dominant and recessive inheritance.[4]

Pathophysiology

Primary and secondary hypertrophic osteoarthropathy possess similar clinical and pathologic features, suggesting they may share similar pathogenicity.[3] Digital clubbing and HOA are considered to be different stages of the same clinical spectrum, with clubbing thought to be the first manifestation before periostosis occurs. However, Callemeyn et al. propose that idiopathic clubbing and HOA be regarded as distinct entities because the underlying etiologies differ.[1] 

Pathologic examination of digital clubbing in both primary and secondary forms reveals increased capillary density, capillary dilation, edema, and hyperplasia of fibroblasts and vascular smooth muscle. Increased vascular endothelial growth factor (VEGF) has been implicated as a pathophysiological mechanism. Abnormal vascularization, hypoxia, chronic inflammation ultimately result in the stimulation and release of VEGF, and these are implicated in some of the conditions associated with SHO.[5] Researchers postulate that clubbing primarily affects the upper extremities because the distance to the distal upper extremities is shorter than the distal lower extremities. It is unclear why increased VEGF levels seem to affect the capillaries of terminal phalanges exclusively.

Abnormal vascularization is believed to derive from abnormal fragmentation of megakaryocytes into platelets.[3] Typically, this process occurs in the pulmonary circulation when megakaryocytes and platelet clumps get trapped within the pulmonary circulation. In conditions where these aggregates can bypass the pulmonary capillary beds, such as left-to-right shunts, malformations in existing vasculature (i.e., hepatopulmonary syndrome), or aberrant vessel formation (bronchogenic neoplasms), these aggregates interact with endothelial cells in the peripheral circulation, causing hypoxia and release of inflammatory and growth-promoting factors. This set of conditions is of particular significance given that excessive levels have been identified in patients with PHO and SHO. Furthermore, upon removal of the underlying etiology in patients with SHO secondary to either cyanotic heart disease and lung neoplasm, it significantly decreased VEGF, and drastic resolution of skeletal abnormalities resulted.[1] VEGF stimulates angiogenesis, increases capillary permeability, promotes stimulation and migration of osteoblasts, new bone formation, and edema, all of which account for the characteristic findings in HOA.

In PHO, genomic studies have identified mutations in the 15-hydroxyprostaglandin-dehydrogenase encoding gene (HPGD). HPGD is the enzyme responsible for the breakdown of PGE2 in the pulmonary vasculature. Impaired inactivation due to bypassing of this vasculature or inadequate breakdown of PGE2 by 15-hydroxyprostaglandin hydrogenase leads to higher levels of this prostaglandin. PGE2 induces transcription of VEGF in osteoblasts and stimulates bone formation, activates endothelial cells which increase transcription of VEGF and promote local angiogenesis. These may explain the changes seen in PHO.[1]

Histopathology

The bullous deformity of the digits is due to excessive deposition of collagen fibers and interstitial edema. Histologically, in addition to these changes, there is an increased number of arteriovenous anastomoses, small vessel dilation, vascular hyperplasia, and vessel wall thickening with perivascular lymphocytic infiltration.

The presence of Weibel-Palade bodies, perivascular infiltrate, endothelial activation, and thickened, reduplicated capillary basal membranes confirm structural damage to the vessels on electron microscopy.[6]

History and Physical

Digital clubbing is present in almost all cases and is the most common finding in PHO. It may be the only manifestation in mild or early cases. A physical exam is pertinent to the diagnosis of clubbing is detected on physical examination, and the bulbous deformity of the fingertips is distinctive. The nail becomes progressively convex, and there is soft tissue deposition at the base of the nail, which results in the distinctive bulbous or "drumstick" appearance of the fingertips and sometimes the tips of the toes. The skin at the base of the nail becomes shiny and thin, and the normal creases in the fingertips disappear. On palpation, because of the increased edema and soft tissue, the rocking of the nail bed may be appreciated.

Objectively, clubbing can be diagnosed using the Lovibond profile sign, which differentiates clubbing from pseudo-clubbing. Lovibond sign is positive for clubbing if there is an increase in the angle between the proximal nail fold and the nail as it leaves the nail bed to greater than 180 degrees. An increased Lovibond angle results in Schamroth sign, the obliteration of the diamond-shaped window formed by opposing dorsal surfaces of two-terminal phalanges. The accuracy of Schamroth's sign is unclear. A phalangeal depth ratio may also be used and is diagnostic when the distal phalangeal depth to interphalangeal depth ratio is greater than 1.

Skin involvement comprises of dermal and glandular hypertrophy. Dermal hypertrophy results in coarsening of facial features and furrowing of the skin on the face and scalp (cutis verticis gyrata).[1] There may also be non-pitting, cylindrical soft tissue swelling of both legs resulting in "elephant legs." Thickening of tubular bones may be seen at ankles and wrists since muscles do not cover these areas. Glandular hypertrophy affects sebaceous and sweat glands in the skin and results in seborrhea, blepharoptosis, acne, and hyperhidrosis.[3]

Periostosis may be asymptomatic or may be discovered due to tenderness on palpation of the affected area. Joint effusions may be detected in larger joints, especially in the knees and wrists. Effusions of smaller joints may be harder to appreciate due to surrounding soft tissue swelling.[6]

Evaluation

There are no serologic tests for the diagnosis of PHO. The physical findings of digital clubbing with associated dermal changes (coarsening of facial features, non-pitting, cylindrical soft tissue swelling of both legs) and thickening of tubular bones may lead one to suspect the diagnosis of hypertrophic osteoarthropathy. HOA's secondary causes should be ruled out, particularly lung cancer, since HOA is often a paraneoplastic rheumatic syndrome. A chest X-ray can screen for intrathoracic abnormality in cases of isolated clubbing. If clubbing is unilateral, it is often vascular or neurologic in origin, and angiography should be considered.[5][1]

Synovial fluid is thick and viscous with a tendency to clot and is without any inflammatory cells.[7]

Plain films of extremities may show tissue and bony abnormalities even in asymptomatic patients. Clubbing is recognizable by the presence of various degrees of bulbous deformity of the soft tissues located at the distal end of the fingers and abnormal curvature of the nails. In those with long-standing clubbing, acro-osteolysis and rarely overgrowth of tufts may appear. New bone formation tends to be most evident in the subperiosteal region of the distal diaphysis of bones of the forearms and legs. Periostitis causes increased circumference of bone without changing its shape. Multiple layers of new bone are deposited, resulting in "onion skin" like lesions in affected bones. Reports also exist of ossification of ligaments and interosseous membranes.[5]

Radionuclide bone scanning may be useful in the early diagnosis of the disease by demonstrating periosteal involvement. Even though sensitive, the findings on the bone scan are non-specific and may also present in other conditions where there is periosteal proliferation. F-fluorodeoxyglucose positron emission tomography in combination with CT scan may show evidence of periostitis and uptake of excess tracer in internal organs, indicating a possible etiology in cases of secondary HOA.[8]

Treatment / Management

Treatment of secondary hypertrophic osteoarthropathy is the treatment of the underlying disease. Regression of hypertrophic osteoarthropathy has been observed after removing lung tumors, correcting congenital heart malformations, and treating infective endocarditis. There are also reports of regression of symptoms in cystic fibrosis after lung transplant. If no etiology is found and clubbing is determined to be primary, symptomatic treatment may commence. Given the accepted pathophysiology of PGE2 driven overproduction of VEGF, COX-2 inhibitors are the treatment of choice. In those with refractory bone pain, bisphosphonates have been effective. In those with HOA with cyanotic congenital heart disease or pulmonary malignancy, octreotide has been used to relieve pain as well.[5]

Differential Diagnosis

Clubbing is the physical sign that alerts the clinician to the possibility of hypertrophic osteoarthropathy, and this should be distinguished from pseudo-clubbing (seen in secondary hyperparathyroidism associated with chronic kidney disease, scleroderma, sarcoidosis). The angle between and is the nail plate, and the proximal nail-fold (Lovibond angle) is less than 180 degrees in pseudoclubbing, while this angle is greater than 180 degrees in true clubbing. Pseudoclubbing may be asymmetrical, while clubbing tends to be symmetrical. Acro-osteolysis is the classic radiological finding in pseudoclubbing, while an overgrowth of phalangeal tufts presents in clubbing. However, there may be an overlap in these findings between clubbing and pseudoclubbing.

The dermal changes of coarse, thickened skin may raise the question of acromegaly and should merit consideration in the differential diagnosis of HOA, and one should look for prognathism, radiological changes of enlarged sella turcica, and elevated growth hormone levels.

Thyroid acropachy may also present with digital clubbing and swelling with periosteal proliferation. It is usually associated with thyroid dermopathy, which may be easily confused with HOA.

Patients with POEMS syndrome may also display clubbing, hyperhidrosis, and skin thickening. Interestingly, both POEMS syndrome and HOA usually have high levels of circulating VEGF. A periostotic reaction may present in trauma, multifocal osteomyelitis, hypervitaminosis A, fluorosis, leukemia, juvenile idiopathic arthritis, psoriatic arthritis, polyostotic bone tumors, sickle cell dactylitis.[1][9]  There are also a few reports of voriconazole-induced nodular periostitis in patients status post-renal transplant. All these are considerations in the differential diagnosis of PHO.[10]

The diagnosis of PHO is a diagnosis of exclusion, and a thorough workup for secondary causes, particularly lung malignancy, should be considered in all patients with HOA.

Prognosis

PHO is a self-limiting illness, and the disease becomes stationary or resolves spontaneously after the active phase during adolescence years. The prognosis in SHO, on the other hand, is related to underlying disease but worse clinical outcomes have been reported in cystic fibrosis, tuberculosis, idiopathic pulmonary fibrosis, extrinsic allergic alveolitis, and asbestosis. Its prognostic value in malignancies has not been studied.[1]

Complications

The complications of hypertrophic osteoarthropathy itself are limited to pain and loss of range of motion from edema and periostitis.

Deterrence and Patient Education

Patients under evaluation for hypertrophic osteoarthropathy must be prepared to give a detailed past medical and family history. Other than preventing underlying disease through an overall healthy lifestyle, there are no known preventative measures to educate patients on at this time.

Enhancing Healthcare Team Outcomes

Patients with hypertrophic osteoarthropathy may present to the primary caregiver, nurse practitioner, or the internist. It is important for the healthcare professional to know that the cause may be an underlying malignancy. Thus, a thorough history and physical exam are necessary. A chest x-ray may reveal a lung lesion. Depending on the findings, an appropriate referral is necessary. 

HOA is a poor prognostic indicator in certain diseases and may justify more aggressive therapy for specific conditions such as stage I non-small cell lung cancer.[1]

An interprofessional team is the best approach to addressing HOA (both PHO and SHO). This team includes physicians, specialists, and specialty-trained nursing staff, working and communicating together to achieve optimal care and patient outcomes. [Level V]