Hypertrophic Osteoarthropathy

Etiology

HOA is associated with many internal diseases, mainly pulmonary and cardiac. Still, it has also been described as associated with gastrointestinal and endocrine diseases, 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

PHO and secondary hypertrophic osteoarthropathy (SHO) 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 considered 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, and chronic inflammation ultimately result in the stimulation and release of VEGF, which 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 (ie, 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 or lung neoplasm, it significantly decreased VEGF, and drastic resolution of skeletal abnormalities resulted.[1] VEGF stimulates angiogenesis, increases capillary permeability, and promotes stimulation and migration of osteoblasts, new bone formation, and edema, all accounting 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 prostaglandin E2 (PGE2) in the pulmonary vasculature. Impaired inactivation due to bypassing 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, stimulates bone formation, and activates endothelial cells, which increase the 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 collagen fiber deposition 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. 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, differentiating 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 2-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 dermal and glandular hypertrophy. Dermal hypertrophy results in coarsening facial features and furrowing 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 discovered due to tenderness on palpation of the affected area. Joint effusions may be detected in larger joints, especially the knees and wrists. Effusions of smaller joints may be harder to appreciate due to swelling in the surrounding soft tissue.[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, nonpitting, 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.[1][5][1]

Synovial fluid is thick and viscous, tends to clot, and has no inflammatory cells.[7] Plain films of extremities may show tissue and bony abnormalities even in asymptomatic patients. Clubbing is recognizable by 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 nonspecific and may also present in other conditions where there is periosteal proliferation. F-fluorodeoxyglucose positron emission tomography and 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, cyclooxygenase-2 (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, and 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.

Dermal changes of coarse, thickened skin may raise the question of acromegaly and should merit consideration in the differential diagnosis of HOA. One should also 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, 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, and 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 an exclusion diagnosis, 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.