Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by a combination of clinical findings of severe disabling arthralgia and arthritis, digital clubbing, and periostosis of tubular bones, with or without synovial effusion.
With fibrovascular proliferation at the heart of the pathogenesis, it can occur as a primary familial autosomal dominant condition called pachydermoperiostosis. Much more commonly, it occurs as a secondary manifestation of pulmonary or extrapulmonary chronic diseases and malignancies. Hypertrophic osteoarthropathy associated with pulmonary pathology is also known as hypertrophic pulmonary osteoarthropathy (HPOA).
Pierre Marie and Eugen von Bamberger first described the syndrome in 1890 and 1891. For this reason, secondary hypertrophic osteoarthropathy is also referred to as Pierre Marie- Bamberger syndrome. Marie first coined the term hypertrophic pulmonary osteoarthropathy, referring to the more prevalent association with pulmonary diseases like lung carcinoma, cystic fibrosis, or pulmonary tuberculosis. Ninety-five to 97% of reported cases of hypertrophic osteoarthropathy are of secondary origin.
The causes of secondary hypertrophic osteoarthropathy can be broadly divided into generalized with the symmetrical involvement of multiple bones and localized disease. The majority of generalized disease is of pulmonary origin; hence the name hypertrophic pulmonary osteoarthropathy (HPOA). There are, however, several diseases of extrapulmonary origin that can cause generalized secondary hypertrophic osteoarthropathy.
Causes of Generalized Pleuro-Pulmonary HPOA
Causes of Generalized Extra-Pulmonary HPOA
Causes of Localized HPOA
No racial or sexual predominance is seen. The common age of presentation is 55 to 75 years.
Ninety percent of reported hypertrophic osteoarthropathy is associated with malignancy. Non-small cell lung cancer (NSCLC), specifically adenocarcinoma, is the most common cause of secondary hypertrophic osteoarthropathy, reported as between 0.7% and 17%. Although lower in absolute incidence, a higher percentage of pleural tumors result in hypertrophic osteoarthropathy (22% of solitary fibrous tumor of pleura compared to 5 % of NSCLC).
The etiopathogenesis of secondary hypertrophic osteoarthropathy has been largely attributed to either a neurogenic pathway or a vascular pathway triggered by circulating growth factors. The vascular pathway can be classified into two subtypes: (1) hypersecretion of vasoactive agents by the tumor itself or hypoxemia and (2) the mechanical release of vasoactive agents in systemic circulation due to arteriovenous shunting within the pulmonary circulation.
A neural reflex triggered by the affected organs with vagal innervation results in vasodilatation and increased blood circulation to the extremities, leading to the clinical manifestations. Chemical and surgical vagotomy have achieved symptom suppression with varying level of success.
Alternatively, a hypoxemia-driven surge of circulating growth factors, like platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), or prostaglandin E2 (PGE2) have also been proven to incite the triad of changes, including clubbing, effusion of small joints, and periostosis of tubular bones. The function of PDGF includes stimulation of endothelial, smooth muscle proliferation, vascular permeability, and chemotaxis of neutrophils. Similar to PDGF, VEGF is also derived from platelets and stimulates angiogenesis. Newly formed immature vessel walls tend to be more permeable. At the tissue level, VEGF induces vasodilatation, vascular hyperplasia, interstitial edema and collagen deposition. Connective tissue proliferation in the outer margin of bones elevates the periosteum and deposits new osteogenic matrix underneath. In addition, VEGF also has a direct effect on osteoblasts and osteoclasts. Silveri et al., as well as multiple other studies, demonstrate overexpression of PDGF and VEGF in hypertrophic osteoarthropathy patients in comparison to healthy subjects. When concurrent with malignancies, removal of primary tumors also results in a decline of these levels. In the presence of pathological intracardiac or intrapulmonary shunt, the megakaryocytic precursor of platelets bypass fragmentation in the pulmonary circulation and enter into systemic circulation instead. This aberrant entry of circulating factors in systemic circulation in the presence of pulmonary shunt was first hypothesized by Dickenson and Martin in 1987. The release of PDGF from entrapped platelet fragments at the capillary level promotes hypervascularization as well as fibroblast activity. Paraneoplastic hypersecretion of VEGF by bronchogenic carcinoma as well as pleural fibrous tumor also results in a similar surge of their function.
Genomic studies also support a role of prostaglandin E2 in the pathogenesis of primary hypertrophic osteoarthropathy. Families with primary hypertrophic osteoarthropathy often carry homozygous and compound heterozygous mutations in 15 hydroxyprostaglandin dehydrogenase encoding gene HPGD, which is the key enzyme for platelet degradation. There is a resultant high circulating level of PGE2 and its metabolite PGEM. However, PGE2 is presumed to have more of an indirect role in secondary hypertrophic osteoarthropathy, acting as a facilitator to VEGF expression, particularly in bones and joints.
Patients with congenital cyanotic heart diseases of myriad forms, have a common histological feature of a pleomorphic platelet population, of giant macrothrombocytes with aberrant volume distribution curves. They also tend to have glomerular enlargement with entrapped megakaryocytic nuclei, as well as a high circulating level of von Willebrand factor antigen. All these experimental models allude to activation of platelets and endothelial cells as the primary histologic mechanism with subsequent release of growth factors as a secondary step, leading to the common clinical manifestations.
A somewhat different, but well-demonstrated, pathology is seen in vascular graft infection-associated hypertrophic osteoarthropathy, where the bacteria adherent to graft releases certain endotoxins and vasoactive agents.
Structural damage to vessel integrity is confirmed by certain electron microscopic findings including the presence of Weibel–Palade bodies, prominences of Golgi complexes, activated endothelia, reduplicated capillary basement membranes, and perivascular infiltrate. Even at the level of joints, synovial cell proliferation is minimal, but pathologic changes are dominated by arterial wall thickening with deposition of electron-dense material.
Affected patients can present at any point in a continuum of symptom complexes, from asymptomatic to a classic triad of clubbing, periostosis, and synovial effusions.
Characteristically, malignancy patients complain of a deep-seated burning sensation of digits in early forms to the excruciating pain of lower extremity long bones, aggravated in a dependent position in later stages. Bone and joint pain often mislead to a diagnosis of inflammatory arthritis. Often the classical history suggests a poor response to opioid agents and encouraging response to NSAIDs. Joint involvements are typically bilaterally symmetrical and are characterized by effusion without inflammatory cellular infiltrate or synovial membrane hypertrophy. Symptoms related to the primary organ dysfunction are also often the diagnostic cues including new onset cough, hemoptysis, weight loss in lung malignancies, exophthalmos and myxedema in Graves disease, stigmata of chronic liver disease, or biliary disease.
Physical examination reveals some characteristic findings. Clubbing with "drumstick" appearance of the nailbeds are identifiable by meticulous digital exam. Convex nail with shiny overlying skin and loss of normal crease renders the characteristic appearance to both fingers and toes, although toes are more difficult to appreciate due to normal splaying of toe tips.
Clubbing may be the only clinical manifestation, although secondary hypertrophic osteoarthropathy may present with cylindrical swelling of the legs known as "elephant" legs. Thickening of long bones may be evident in nonmuscular locations like ankles and wrists.
Large joint effusion is more common in knee and wrists. Arthrocentesis yields a pauci-inflammatory fluid with less than 500 WBC, but with a tendency to clot spontaneously. Effusions are considered to be a sympathetic response to periostosis in the vicinity.
Clinical diagnosis is often challenging as the symptom complex on presentation can be very similar to connective tissue diseases. To complicate things further, there are reports of HPOA associated with lung malignancy which presented with elevated ANA and anti-Sm antibody levels. There are reported cases of positive ANCA serology as well. There are no specific serological markers of HOA. However, there is indirect evidence of increased circulating bone formation markers like bone alkaline phosphatase, osteocalcin or amino-terminal propeptide of type 1 procollagen. With a limited scope of this marker in routine clinical practice, diagnosis of HPOA is often delayed although HPOA appears early in the course of lung malignancy.
Imaging is the mainstay of diagnosis. Symmetrical periostosis, in the absence of cortical destruction or fracture, is the hallmark of radiological findings. It characteristically involves shafts of tubular bones, initially limited to diaphysis (epiphyseal involvement is more common in primary HOA). With progression, metaphysis is also involved. There is an initial monolayer circumferential widening without transformation of bone shape, followed by multilayered, laminated, centripetal thickening with an irregular appearance in advanced stages. Tibia, fibula, radius, and ulna are most commonly affected, followed by phalanges.
Long-standing clubbing can cause osseous resorption at terminal phalanges. In addition, tuftal overgrowth is seen in malignancy-associated HOA, first in toes and then in fingers.
MR imaging usually shows a low to intermediate signal intensity on T1 and T2 weighted images, highlighting periosteal elevation and reaction. MRI also helps in identifying synovial effusions.
There are reports of diagnosis of hypertrophic pulmonary osteoarthropathy based on PET scan findings of irregular bilateral periosteal new bone formation with increased fluorodeoxyglucose (FDG) uptake. For the same reason, there is a possibility of an erroneous diagnosis of metastatic disease based on FDG avidity.
Bone scintigraphy with technetium 99m (99mTc) methylene diphosphonate (MDP) is the gold standard and is a more sensitive test. In fact, early suspicion based on radiograph should prompt a radionuclide bone scan along with a search for primary etiology with thoracic imaging.
Enhanced tracer uptake in a symmetric distribution along cortical margins of tubular bones in the bone scan, is described by “double stripe" or "tramline" sign. Digital clubbing also results in prominent tracer uptake. There is an immense utility of radionuclide scan as a marker of treatment response, as scintigraphic findings do resolve with successful treatment of underlying etiology.
Prognosis and treatment of secondary hypertrophic osteoarthropathy are understandably related to the primary etiology. Treatment strategy can be broadly classified as follows:
Ipsilateral vagus nerve dissection resulting in symptom relief in HPOA in inoperable cases of primary lung malignancy was reported by Geoffrey Flavell in the 1950s and was later reconfirmed by Yacoub et al. in 1962. It was never universally adopted and lost favor subsequently, as the humoral theory of pathogenesis gained prominence. Less invasive targets for symptom control, therefore, appeared justified. However, the approach was revisited in 2006 by Ooi et al. in a patient with inoperable lung malignancy where HOA symptom control was successfully achieved by video-assisted thoracoscopic surgery (VATS) assisted truncal vagotomy.
A combination regimen of adrenergic antagonists with propranolol and phenoxybenzamine was reported to achieve symptom suppression in hypertrophic osteoarthropathy associated with small cell carcinoma lung, as reported by Readon et al. in 1976. The treatment response was objectively measured by improvement in the thermographic index as well as the functional ability, including ring size and grip strength.
Letts et al. published a case series of five infants with arthritis and periostitis following PGE2 infusion for patent ductus arteriosus. That aligned with subsequent reports of a robust response of hypertrophic osteoarthropathy symptoms to NSAIDs like indomethacin and ketorolac and COX-2 inhibitors like rofecoxib. In contrast, opioid analgesics were not nearly as effective. A PGE2-induced mechanism of hypertrophic osteoarthropathy was suggested, as rofecoxib suppressed cyclooxygenase 2 which is an inducer of the prostaglandin E2 pathway.
Johnson et al. first reported successful treatment of hypertrophic osteoarthropathy with 200 mcg of octreotide daily in a patient with squamous cell carcinoma lung. Angel Moreno Maroto et al. also reported pain relief with octreotide in a patient with cyanotic heart disease from Tetralogy of Fallot and pulmonary artery atresia. Apart from inhibition of endothelial proliferation through VEGF, octreotide also has a well-demonstrated role in inhibition of nociceptive neurons.
There have been several case reports of intravenous pamidronate and zoledronic acid achieving symptomatic relief of hypertrophic osteoarthropathy in bronchogenic carcinoma, as well as in metastatic breast carcinoma and cyanotic congenital heart disease. Therapeutic response was noted in terms of symptom suppression as well as the radiographic resolution of periostitis in the bone scan. The mechanism of action of the bisphosphonates traces them to a proven inhibition of circulating VEGF levels in plasma.
VEGF circulating levels, as well as tissue expression, are enhanced in almost all cases of hypertrophic osteoarthropathy, irrespective of the primary etiology. It is only rational therefore that specific inhibitors of VEGF should inhibit the final common pathway and achieve symptom suppression. Therapeutic trials of combining Bevacizumab with conventional chemotherapy regimen in non-small cell lung cancer is underway. Similarly, isolated case reports from Japan suggest the reduction of periostitis in advanced lung malignancy, with use of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.
Differential diagnosis based on radiological signs of multifocal periosteal reactions include thyroid acropathy, primary hypertrophic osteoarthropathy, hematological malignancy, Hypervitaminosis A, and a rare autosomal dominant disease entity named Camurati Engelmann disease or progressive diaphyseal dysplasia. Voriconazole has been reported to cause periostitis that often mimics findings typical of hypertrophic osteoarthropathy. Inflammatory arthropathy, connective tissue diseases, and vasculitis-related arthropathy often can be the initial diagnosis before the actual diagnosis of hypertrophic osteoarthropathy is established.
In summary, secondary hypertrophic osteoarthropathy should be actively entertained in the differential of bone and joint pain and new-onset clubbing in a patient with known malignancy, chronic lung disease, liver disease, or cyanotic heart disease. Reciprocally, a new diagnosis of hypertrophic osteoarthropathy based on clubbing, periostitis, and arthropathy should always trigger a search for a primary cause. As opposed to inflammatory arthritis, both the joint and the adjacent bone are involved. Rheumatoid factor is absent usually, and if the synovial fluid is aspirated, it is noninflammatory. A technetium bone scan is the diagnostic imaging of choice. Treatment is best achieved by definitive treatment of the primary pathology wherever possible. Where the primary disease is noncurative, symptom suppression is achieved at varying degrees with bisphosphonates, COX-2 inhibitors, octreotide, and certain anticancer chemotherapies that target fibroblastic growth factors.