eMedicine Specialties > Rheumatology > Metabolic and Bone Disease

Hypertrophic Osteoarthropathy

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine; Henri-Andre Menard, MD, Professor of Medicine, Director of Rheumatology, Department of Medicine, Division of Rheumatology, McGill University Health Center and McGill University; Director, The McGill Arthritis Center; Senior Physician, Shriner's Hospital for Crippled Children, Montreal

Updated: Nov 7, 2008

Introduction

Background

Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by excessive proliferation of skin and bone at the distal parts of extremities and by digital clubbing and periostosis of the tubular bones.¹ Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers.² In approximately 1890, both Bamberger³ and Marie⁴ reported the association of clubbing and arthritis with chronic pulmonary and cardiac diseases. Primary hypertrophic osteoarthropathy occurs without any underlying cause, is usually familial, and usually has a chronic course. Secondary hypertrophic osteoarthropathy is associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease and often has a more rapid course.

Interestingly, some patients with primary hypertrophic osteoarthropathy eventually develop diseases (eg, patent ductus arteriosus, Crohn disease, myelofibrosis) that are otherwise known to be underlying causes of secondary hypertrophic osteoarthropathy, many years after the onset of the osteoarthropathy.⁵

Clubbed digits

The clubbed portions of the fingers and toes consist of excessive collagen fiber deposition and accumulation of interstitial edema. Perivascular infiltrates of lymphocytes and vascular hyperplasia are responsible for thickening of the vessel walls. Electron microscopy reveals Weibel-Palade bodies and prominent Golgi complexes, confirming structural vessel wall damage.⁶ Vast numbers of arteriovenous anastomoses may also be seen in the nail bed.⁷

Periosteum

Subperiosteal, cancellous, and new bone formation exists along the distal diaphysis of tubular bones, progressing proximally over time. Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum.⁸ As this mineralizes, a new layer of bone is formed, and, eventually, the distal long bones may become sheathed with a cuff of new bone.⁹ These pathologic changes occur at the distal ends of the metacarpus, metatarsus, tibia, fibula, radius, ulna, femur, humerus, and clavicle. The tibia is almost invariably involved.^8,10

Bone

Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic.¹¹ Hypertrophy or bony overgrowth predominates in patients with lung cancer and hypertrophic pulmonary osteoarthropathy (HPOA), whereas acroosteolysis predominates in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy.¹² The type of bone remodeling process depends on the age when clubbing develops.¹¹ If clubbing appears in childhood, osteolysis is more prominent; however, if it develops after puberty, hypertrophic changes take place. Pineda et al hypothesize that a putative circulating growth factor destroys immature bone.¹¹

Synovium

Pathophysiology

The etiology of hypertrophic osteoarthropathy is unknown. The pathological hallmark is neoangiogenesis and edema and osteoblast proliferation in distal tubular bones that leads to subperiosteal new-bone formation. One explanation involves tumor production and the release of a factor that promotes features of hypertrophic osteoarthropathy into the circulation. One candidate is vascular endothelial growth factor (VEGF). Two case reports have independently noted elevated circulating concentrations of VEGF and evidence of tumor production of VEGF associated with lung cancer.

Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement. VEGF is a platelet-derived factor; its action is induced by hypoxia. It is a potent angiogenic and permeability-enhancing factor, as well as a bone-forming agent. Diverse types of cancer growths produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is known to occur in diseases associated with hypertrophic osteoarthropathy, such as mesothelioma, Graves disease, and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy.

Interestingly, the anatomic distribution of vagal nerve fibers correlates to the area of clubbing. Vagotomy and sympatholytic drugs have been reported to reverse or to improve hypertrophic osteoarthropathy, suggesting a role for reflex vagal stimulation.¹⁷ Bazaar and Yun proposed that sympathetic override of the normal protective function of vagal innervation is the basis of hypertrophic osteoarthropathy.¹⁸ Sympathetic activity has been noted to induce cytokine changes consistent with inflammation.

Among these, epinephrine has been shown to induce production of interleukin-11 (IL-11) in human osteoblasts. Recombinant IL-11 has been shown to cause reversible symmetric periostitis in the extremities. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. Removal of the associated lung neoplasm or correction of a cyanotic heart malformation has similar effects, suggesting that alteration of lung function plays an important role.¹⁹

Paraneoplastic growth factors;¹⁹ neurologic, hormonal,²⁰ and immune mechanisms;¹⁴ and vascular thrombi caused by platelets and antiphospholipid antibodies²¹ have all been proposed as possible etiologies.⁸ A popular current theory involves the interaction between activated platelets and the endothelium.^19,21,22 Hypertrophic osteoarthropathy can be associated with pregnancy and aging secondary to platelet abnormalities, hormonal disturbances, and cytokine dysfunction.

Most illnesses associated with hypertrophic osteoarthropathy involve alterations of lung function in which intrapulmonary shunting of blood may be prominent. For example, in patients with patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt, hypertrophic osteoarthropathy is evident only in the limbs that receive unsaturated blood. Hypertrophic osteoarthropathy has been induced in dogs by surgically producing right-to-left shunts.^23,24 Hence, hypertrophic osteoarthropathy has been suggested to be due to factors that are normally removed or inactivated in the lung.²²

Normally, platelets are fragmented in the pulmonary microvasculature before they reach the general circulation. Patients with cyanotic heart diseases have large circulating platelets with abnormal and, at times, bizarre morphology. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves.^25,21

Having escaped fragmentation in the lung microvasculature and reached the systemic circulation, their impaction at distal sites may lead to local endothelial cell activation through the release of growth factors (ie, platelet-derived growth factor, transforming growth factor, VEGF) stored in the platelet alpha-granules. This initiates finger clubbing by inducing connective-tissue matrix synthesis.^21,22 VEGF receptors are expressed in subperiosteal bone-forming cells. In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated von Willebrand factor antigen (vWF:Ag) levels in persons with primary hypertrophic osteoarthropathy and in persons with hypertrophic osteoarthropathy secondary to cyanotic heart disease.²¹

Frequency

United States

No systematic prevalence studies have been performed for secondary hypertrophic osteoarthropathy, but hypertrophic osteoarthropathy is associated with many illnesses. Primary hypertrophic osteoarthropathy is a rare condition. A hereditary sex-linked (male) predisposition exists, but the exact type of inheritance is unknown.²⁶

International

Hypertrophic osteoarthropathy likely has the same incidence and prevalence around the world.

Mortality/Morbidity

The mortality and morbidity of hypertrophic osteoarthropathy vary with the associated illness.

Race

Hypertrophic osteoarthropathy affects persons of all races.

Sex

Primary hypertrophic osteoarthropathy has a male-to-female ratio of 9:1.²⁶ Secondary hypertrophic osteoarthropathy has the same sex ratio as the associated illnesses.

Age

Primary hypertrophic osteoarthropathy has a bimodal peak of onset that occurs in patients younger than 1 year and in patients who are around puberty, ie, approximately age 15 years.²⁶

Clinical

History

The clinical presentation of hypertrophic osteoarthropathy (HOA) varies according to the rapidity of onset and the evolution of the underlying disease.

• In primary hypertrophic osteoarthropathy or in the slowly progressing chronic secondary forms, hypertrophic osteoarthropathy is insidious and essentially asymptomatic.
  • Such patients rarely voluntarily report symptoms because the clubbing and skin manifestations (see Physical) have progressively become part of the patient's body image over many years, and the patient usually considers them more or less normal.
  • Because patients initially seek medical help for minor pains in the shoulders and hands or recurrent swelling of a mechanical nature in the knees (hydrarthrosis) or ankles (osteoarthritis), they are sometimes surprised by the physician’s interest in their fingers.
• When hypertrophic osteoarthropathy occurs in the presence of neoplastic or inflammatory pulmonary conditions, the patient reports pain and swelling in joints and long bones.
  • These rheumatic symptoms have a mechanical diurnal pattern, but they are definitely signs of inflammation, even if the synovial fluid is noninflammatory.
  • This picture can precede the appearance of constitutional symptoms (eg, fatigue, fever, weight loss) or respiratory symptoms (eg, cough, hemoptysis, chest pain, dyspnea) by several months.

Physical

• Clubbing
  • Clubbing usually progresses through 4 phases.⁸
    1. Fluctuation and softening of the nail bed, with a rocking sensation upon palpation due to increased edema and soft tissue
    2. Loss of the normal 15° angle (Lovibond angle²⁷ ) between the nail and cuticle
    3. Accentuation of the convexity of the nails and clubbed appearance of the fingertips, with warmth and sweating
    4. Shiny or glossy change in the nail and adjacent skin, with disappearance of the normal creases and appearance of longitudinal striation of the nail
  • Clubbing can be classified into 3 topographical groups.^28,29
    • Symmetrical: All the fingers and toes are involved (see Image 1).
    • Unilateral: The fingers or toes of 1 hand or foot are involved.
    • Unidigital: Only 1 finger or toe is involved.
  • Clubbing can also be classified into 3 color groups (personal observations).
    • Normal skin color: This is an insidious onset of mildly symptomatic clubbing, evolving over years, that is usually associated with chronic low-grade inflammatory and infectious diseases or primary hypertrophic osteoarthropathy.
    • Red skin color: This is of recent onset with rapid progression and fairly severe bone and joint symptoms that are usually associated with malignant diseases or chronic severe infections, such as miliary tuberculosis.
    • Blue skin color: This is chronic clubbing associated with cyanotic cardiopulmonary conditions.
  • Four clinical signs can be used to describe clubbing.
    • The profile sign: On lateral views, a loss of the normal 15° angle between the nail bed and the cuticle is visible. The hyponychial angle can also be measured.
    • The nail sign (rocking): The base of the nail bed can be palpated for sponginess.
    • The apposition sign: The distal interphalangeal (DIP) joints and the nail bed of the right and left index finger are placed in apposition. Normally, an oblong diamond-shaped aperture is visible between the 2 juxtaposed nail beds. With clubbing, this space is obliterated.
    • The digital index: The circumference of each finger at the nail bed and DIP joint are measured. The mean ratio of the nail bed circumference to the DIP joint circumference should be less than 1. Alternatively, the ratio of each finger's nail bed and DIP joint can be added. If the sum is greater than 10, clubbing is present; if the sum is greater than 11, advanced clubbing is present.^30,22
• Bone and joint symptoms
  • Periostosis may be asymptomatic or may cause a severe burning and deep-seated pain in the distal extremities. This pain is aggravated with dependency and relieved with elevation.⁸ In some cases, dysesthesia of the fingers is present, with accompanying heat, sweating, clumsiness, and stiffness of the hands.⁸ Adults with primary hypertrophic osteoarthropathy are asymptomatic.²⁶
  • Joint symptoms range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles.⁸ The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints, eg, knees, ankles, and wrists (see Image 2).³¹ Arthrocentesis reveals a very thick noninflammatory fluid, with a cell count of less than 500 cells/µL.¹⁴ The effusions are more likely a sympathetic reaction to nearby periostosis.
• Cutaneous symptoms
  • They are more prominent in, but not exclusive to, primary hypertrophic osteoarthropathy.
  • Cutaneous gland dysfunction occurs, resulting in acne, hyperhydrosis, or seborrhea.²⁶
  • Hypertrophy of soft tissues occurs, resulting in coarse facial features, cylindrical calves (elephant feet), ptosis of the lids, and cutis verticis gyrata or prominent frontal cerebroid wrinkles.

Causes

Clubbing and hypertrophic osteoarthropathy likely represent different stages of the same disease process. Hypertrophic osteoarthropathy can be classified as either primary or secondary.

• Primary hypertrophic osteoarthropathy
  • Pachydermoperiostosis,²⁶ also called Touraine-Solente-Golé syndrome, involves digital clubbing, periostosis (revealed by radiography), and coarse facial features. It has a hereditary predisposition (although less than a third of patients have a relative who is affected) with a male predominance (male-to-female ratio of 9:1). Disease onset has a bimodal peak, with one in the first year of life and one at puberty. The activity of the illness is limited to the growth period, with adults becoming asymptomatic. Long-standing clubbing and a positive family history suggest primary hypertrophic osteoarthropathy, but excluding any associated illness is still of utmost importance. Clinical features involve the skeleton and the skin. Associated abnormalities include cranial suture defects, gynecomastia, female hair distribution, striae, bone marrow failure, and hypertrophic gastropathy.^32,8
  • Most patients with congenital and familial clubbing are asymptomatic and have relatives with the same disorder. This syndrome may reflect incomplete expression of pachydermoperiostosis.³³ A case report in Germany described a family with a variant form of primary hypertrophic osteoarthropathy restricted to the lower extremities without digital clubbing or cutaneous changes. Three family members had pain, swelling, and hyperhidrosis in both feet. Radiographs showed destruction and osteoproliferative changes of the metatarsal bones with periosteal hyperostosis close to the talus. All known infectious, neurologic, metabolic, and malignant diseases that affect the bone and joints were excluded.
  • Goldbloom syndrome is a rare, idiopathic, diffuse, painful, hypertrophic periostosis occurring transiently in children. Clubbing and skin involvement are usually absent. The clinical picture consists of a high fever with weight loss and severe bone pain in the mandibles and long bones. It is accompanied by a major acute-phase reaction and polyclonal hypergammaglobulinemia.³⁴ The syndrome spontaneously resolves in 4-8 weeks, and radiographic and bone scan abnormalities return to normal within the next few years. Long-term follow-up shows normal growth thereafter, without permanent sequelae.
• Secondary hypertrophic osteoarthropathy
  • This is also called Pierre Marie-Bamberger syndrome. In adulthood, 90% of generalized hypertrophic osteoarthropathy is associated with an intrathoracic infectious or neoplastic condition (see Image 4).¹⁰ Features include clubbing, skin hypertrophy, thickening of tubular bones, periostosis, and effusions of large joints. The disease progresses more rapidly than primary hypertrophic osteoarthropathy. The underlying disease usually appears first. However, hypertrophic osteoarthropathy occasionally precedes symptoms of the underlying disorder by more than a year.^35,8 Among pulmonary neoplasms, hypertrophic osteoarthropathy is most commonly found with non–small cell lung carcinoma.³⁶
  • In childhood, generalized hypertrophic osteoarthropathy is associated with pulmonary infections,³⁷ cystic fibrosis,³¹ congenital cyanotic heart disease,^38,39 and osteosarcoma with lung metastasis.⁸ Case reports have described an association with biliary atresia.^40,41 Cyanotic heart disease is the prototype of hypertrophic osteoarthropathy because almost all patients have clubbing and more than a third of patients have the full-blown syndrome.³⁹
  • Localized clubbing, similar to unilateral digital clubbing, has been described in association with local vascular lesions such as aneurysms; arteriovenous fistulas; and venous abnormalities of the arm, axilla, and thoracic outlet.^28,29 Other causes of localized hypertrophic osteoarthropathy include hemiplegia, patent ductus arteriosus with pulmonary hypertension, infected arterial grafts, endothelial infections, and extensive endothelial injury of a limb.²⁹ In patients with patent ductus arteriosus, pulmonary hypertension causes right-to-left shunting of blood, which may cause hypertrophic osteoarthropathy of the toes and fingers on the left side.^29,22 Unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet.²⁹
  • Thomas first described thyroid acropachy in 1933.⁴² It is a rare condition associated with prior or active Graves disease. Thyroid acropachy is characterized by the triad of (1) clubbing; (2) noninflammatory swelling of the soft tissues of the hands and feet; and (3) asymptomatic, asymmetrical, exuberant, periosteal proliferation preferentially affecting the diaphysis of the metacarpal and metatarsal bones.⁴³ It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid.³¹
• Pulmonary
  • Chronic respiratory diseases include cystic fibrosis, pulmonary fibrosis, chronic obstructive lung disease, and chronic infections.
  • Lung cancer (primary or metastatic) can include arteriovenous malformations and mesothelioma.
• Cardiac - Congenital cyanotic heart disease and infective endocarditis
• Hepatic - Cirrhosis, hepatocellular carcinoma, and primary liver rhabdomyosarcoma
• Intestinal - Crohn disease, ulcerative colitis, chronic infections, laxative abuse, polyposis, and malignant tumors
• Mediastinal - Esophageal carcinoma, thymoma, and achalasia
• Miscellaneous - Graves disease, thalassemia, diverse malignancies, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, metastatic phyllodes tumor of breast, epithelioid hemangioendothelioma, nasopharyngeal carcinoma with lung metastasis, thymic carcinoma, renal cell carcinoma with lung metastasis, Osler-Weber-Rendu syndrome, and deep infections such as vascular graft infection and perianal abscess (Primary hypertrophic osteoarthropathy and POEMS syndrome overlap; both conditions are associated with digital clubbing, pachyderma, hyperhidrosis, gynecomastia, and bone proliferation.)

Differential Diagnoses

Other Problems to Be Considered

Inflammatory arthropathy may be incorrectly diagnosed in cases of malignant lung tumors, in which painful arthropathy can be the presenting feature of hypertrophic osteoarthropathy (HOA). Hypertrophic osteoarthropathy is more likely when the following factors are present: pain that extends beyond the joint into the adjacent bone, an absence of rheumatoid factor, and noninflammatory synovial fluid.

Acromegaly may be suggested in cases of exuberant skin hypertrophy and enlarged hands and feet. Normal growth hormone levels and the absence of both prognathism and enlarged sella turcica exclude acromegaly.

Fingertip changes due to other conditions that may be confused with hypertrophic osteoarthropathy include spooning of nails secondary to iron deficiency anemia, calcific deposits in distal digital pads of patients with scleroderma, and sarcoid involvement of the digit.

Diseases associated with periostitis with predominant location of periostitis should be included in the differential diagnoses, as follows:

• Hypertrophic osteoarthropathy - Distal diaphysis of long bones and metacarpal joints
• Psoriatic onycho-pachydermo periostitis - Terminal phalanx
• Psoriatic arthritis - Phalanges of fingers and toes
• Reactive arthritis - Phalanges of fingers and toes
• Athletic overuse (running, jumping) - Upper and lower extremities
• Ossifying fasciitis - Variable
• Periostitis ossificans - Variable
• Polyarteritis nodosa - Lower extremities
• Systemic lupus erythematosus - Variable
• Facial infections - Mandible, orbita
• Florid reactive periostitis - Phalanges of hands and feet
• Osteoblastoma - Variable
• Bizarre parosteal osteochondromatous proliferation (Nora tumor) - Bones of the hands and feet
• Chondrosarcoma - Variable
• Treatment with IL-11 - Clavicle, long bones
• Osteomyelitis - Variable
• Chronic leg ulcers - Tibia
• Synovitis-acne-pustulosis-hyperostosis (SAPHO) syndrome - Variable

Pretibial edema may be due to thrombophlebitis, venous stasis, or pretibial myxedema and may mimic periostosis.

The importance of recognizing hypertrophic osteoarthropathy cannot be overstated. A previously healthy individual with any manifestation of the syndrome should undergo a thorough evaluation for an underlying illness. Direct special attention toward the chest.

Workup

Laboratory Studies

• The erythrocyte sedimentation rate may be elevated in persons with pachydermoperiostosis and is often elevated in those with secondary hypertrophic osteoarthropathy (HOA).⁸
• Serum alkaline phosphatase levels may be elevated secondary to periosteal new bone formation.⁸
• If an effusion is present, the synovial fluid is noninflammatory (cell count <500/µL), with a predominantly lymphocytic and monocytic infiltrate.^14,16

Imaging Studies

• Plain radiographs show 2 types of changes, bone formation with hypertrophy and bone dissolution with acroosteolysis.¹¹
  • Periosteal thickening occurs along the shafts of long and short bones, initially appearing in the distal diaphyseal regions of the long bones. Periosteal changes are seen as a continuous thin line of sclerotic new bone separated from the cortex by a radiolucent space. Over time, the periosteal new bone thickens and fuses with the cortex, and the process extends proximally to the diaphysis and metaphysis. These changes are most commonly observed in the tibia, radius, ulna, fibula, and femur. Primary hypertrophic osteoarthropathy is distinguished by more exuberant periosteal new bone formation that extends to the epiphyseal regions.⁸
  • Acroosteolysis may be seen in the distal tufts in patients with long-standing hypertrophic osteoarthropathy.
• Radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. These findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies (see Images 1-3).^8,31
• Angiography findings may demonstrate hypervascularization of the finger pads.^44,13

Other Tests

• An evaluation for the primary condition is warranted in patients with possible secondary hypertrophic osteoarthropathy; for example, search for an intrathoracic malignancy or infection.

Treatment

Medical Care

• The only effective treatment for secondary hypertrophic osteoarthropathy (HOA) is treatment of the underlying condition, ie, surgery for cardiac anomalies or cancer and antibiotics for infections. Although removal of the primary tumor usually resolves this syndrome, effective treatment in patients with advanced lung cancer has not been established.
• Recently, an orally active selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) provided clinical antitumor activity in a case report in Tokyo.
  • A 71-year-old male smoker with cough presented with clubbed fingers. A transbronchial lung biopsy (stage T2N3M1-IV) on a cavity lesion in the left lower lobe showed the features of adenocarcinoma, while bone scintigraphy revealed bilaterally symmetrical abnormal uptakes in the lower extremities, suggesting secondary hypertrophic osteoarthropathy.
  • The serum level of growth hormone was increased to 1.42 ng/mL. Chemotherapy (cisplatin, vinorelbine) was not effective. Gefitinib, as a second-line therapy, induced disappearance of the abnormal accumulation on bone scintigraphy and decrease of the cavity in the lung and of serum growth hormone. The presented case suggests that the EGFR inhibitor might be a promising option for the treatment of hypertrophic osteoarthropathy with advanced lung adenocarcinoma.⁴⁵
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful for the painful osteoarthropathy in controlling the symptoms.
• In those with primary hypertrophic osteoarthropathy, propranolol may be useful for hyperhydrosis, but the drug does not alter the natural course of the disorder. By adulthood, patients with primary hypertrophic osteoarthropathy are asymptomatic.
• VEGF inhibitors such as octreotide have also been shown to have improved hypertrophic osteoarthropathy–related symptoms.
  • A 34-year-old man was admitted with bilateral leg pain. He had tetralogy of Fallot with pulmonary artery atresia. Surgical interventions had been performed in the past, with only transient success. The patient was rejected for cardiopulmonary transplantation. He had grade III dyspnea. In the last 2 months, progressive, severe pain along both legs and ankles developed, which had not responded to usual analgesics and impeded his sleep.
  • After informed consent had been obtained, subcutaneous octreotide 100 µg twice daily was added. After 3-4 days, complete pain relief was achieved and the other drugs could be withdrawn. No adverse events were recorded.
  • After 2 weeks, octreotide was tapered to 100 µg/d and the patient was discharged. After about 1 week, the pain reappeared and the patient was readmitted. His poor cardiorespiratory status was then rapidly deteriorating. Octreotide was increased to 100 µg twice daily, but, owing to untreatable dyspnea, multiple other palliative measures were needed, including morphine administration (thus precluding the evaluation of a specific response to octreotide), and the patient finally died.⁴⁶
• Bisphosphonates such as zoledronic acid and pamidronate are also effective for pain relief in hypertrophic osteoarthropathy.⁴⁷ Bisphosphonates not only inhibit osteoclast activity, but some, including pamidronate, inhibit VEGF expression. One case report described a patient with hypertrophic osteoarthropathy of the lower extremities that developed secondary to congenital cyanotic heart disease. The major clinical manifestation was debilitating bilateral leg pain, which completely resolved following a single administration of 60 mg pamidronate.⁴⁸

Surgical Care

• In patients with primary hypertrophic osteoarthropathy, plastic surgery may be necessary to remove excess facial skin.
• 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.

Medication

No drug effectively treats hypertrophic osteoarthropathy (HOA). Drugs such as NSAIDs may be used for symptomatic relief. Beta-blockers may be used for the treatment of hyperhidrosis of primary hypertrophic osteoarthropathy.

Nonsteroidal anti-inflammatory drugs

These agents have analgesic, anti-inflammatory, and antipyretic activities. The main mechanism of action is inhibition of COX activity and prostaglandin synthesis. These agents may also have other mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. NSAIDs such as ibuprofen, naproxen, indomethacin, piroxicam, diclofenac, and others are reasonable alternatives.

Ibuprofen (Ibuprin, Motrin)

DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. Most common toxicities are nausea, dyspepsia, peptic ulcer disease, and renal and central nervous system toxicity.

Dosing

Adult

400-800 mg PO tid/qid; not to exceed 3.2 g/d

Pediatric

20-70 mg/kg/d PO divided tid/qid; start at lower end of dosing range and titrate; not to exceed 2.4 g/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of ACE inhibitors, beta-blockers, and other antihypertensive agents; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease (unless prophylaxis is adequate), renal insufficiency, anticoagulation or coagulopathy, or aspirin-sensitive asthma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Most common toxicities include GI manifestations (eg, nausea, abdominal pain, peptic ulcer disease) and renal insufficiency; category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Naproxen (Naprosyn, Naprelan, Anaprox, Aleve)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of COX, which is responsible for prostaglandin synthesis.

Dosing

Adult

250-500 mg PO bid; may increase to 1.5 g/d

Pediatric

10-20 mg/kg/d PO divided bid

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of ACE inhibitors, beta-blockers, and other antihypertensive agents; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease (unless prophylaxis is adequate), renal insufficiency, anticoagulation or coagulopathy, or aspirin-sensitive asthma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Most common toxicities include GI manifestations (eg, nausea, abdominal pain, peptic ulcer disease) and renal insufficiency; category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Celecoxib (Celebrex)

Inhibits primarily COX-2, which is considered an inducible isoenzyme induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek lowest effective dose for each patient.

Dosing

Adult

200 mg PO qd

Pediatric

Not established

Interactions

Coadministration with fluconazole may cause increased plasma concentrations because of inhibition of celecoxib metabolism; coadministration with rifampin may decrease celecoxib plasma concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, and conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; may mask usual signs of infection; caution in presence of existing controlled infections; evaluate therapy when symptoms or lab results suggest liver dysfunction

Adrenergic beta-blockers

Beta-blockers are useful for treating hyperhidrosis, which may occur in primary hypertrophic osteoarthropathy.

Propranolol (Inderal, Betachron E-R)

Opposes multisystemic effects of excessive adrenergic tone.

Dosing

Adult

Adults are asymptomatic; use is unnecessary

Pediatric

0.5 mg/kg/d PO divided bid/qid; increase gradually q3-7d; dosage range is 2-4 mg/kg/d divided bid; not to exceed 2 mg/kg/d

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia, cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Beta-blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely

Follow-up

Further Inpatient Care

Hypertrophic osteoarthropathy (HOA) itself does not require inpatient care; however, inpatient care may be required for associated conditions.

Further Outpatient Care

With specific curative treatment for the associated conditions, hypertrophic osteoarthropathy may remit with only analgesic and anti-inflammatory supportive treatment. Similarly, the symptomatic recurrences of hypertrophic osteoarthropathy in persons with cystic fibrosis are usually associated with pulmonary superinfections and can be controlled and prevented with appropriate curative or prophylactic antibiotic therapy.

Inpatient & Outpatient Medications

Any of the classic NSAIDs or the newer COX-2 inhibitors can be used at their usual dose as needed. These drugs do not influence the evolution of hypertrophic osteoarthropathy, but they are useful to control symptoms. Other analgesic medications (eg, acetaminophen, opioid analgesics) may be used.

Complications

The only complication of hypertrophic osteoarthropathy is secondary osteoarthritis observed in patients with long-standing hypertrophic osteoarthropathy.

Prognosis

At times, hypertrophic osteoarthropathy may be an ominous syndrome, but it does not add significantly to the mortality or morbidity of the associated diseases.

Patient Education

Patients first diagnosed with hypertrophic osteoarthropathy should be reassured regarding its good prognosis as a musculoskeletal condition. That being established, they should be informed of its significance and the need for further investigation to rule out any treatable associated disease. These investigations are guided by results from thorough clinical evaluations, including questions specifically targeting intrathoracic diseases.

Miscellaneous

Medicolegal Pitfalls

Because 90% of hypertrophic osteoarthropathy (HOA) cases are a paraneoplastic or parainfectious syndrome that can precede the diagnosis of the primary disease, a medicolegal pitfall may be encountered if the primary condition is missed. Because the diagnosis is essentially clinical in nature, the physician is expected to perform a systematic history and physical examination, including a screening examination of the musculoskeletal system, even in asymptomatic people. Thus, a good clinical practice is to always write in the clinical notes that physical examination findings are normal, eg, "The musculoskeletal examination findings are normal. No clubbing."

Multimedia

Media file 1: Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This is symmetrical clubbing; it involves all the fingers and toes.

Media file 2: Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints (eg, knees, ankles, wrists).

Media file 3: For hypertrophic osteoarthropathy diagnosis, radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. These findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies.

Media file 4: In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition.

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Keywords

hypertrophic osteoarthropathy, primary hypertrophic osteoarthropathy, primary HOA, HOA, secondary HOA clubbing, Hippocratic fingers, clubbed digits, pachydermoperiostosis, acroosteolysis, Touraine-Solente-Golé syndrome, Goldbloom's syndrome, Goldbloom syndrome, Pierre Marie-Bamberger's disease, Pierre Marie-Bamberger disease, osteoarthropathie hypertrophiante pneumique, hypertrophic pulmonary osteoarthropathy, HPOA, acropachy, hyperhidrosis, digital clubbing, periostosis, intrathoracic malignancy, intrathoracic infection, cyanotic cardiac disease, cyanotic heart disease, congenital clubbing, familial clubbing, osteosarcoma, thyroid acropachy, Crohn disease, Crohn's disease, polyposis, thymoma, achalasia, Graves disease, Graves' disease, thalassemia, POEMS syndrome

Contributor Information and Disclosures

Author

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Richa Dhawan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology
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Coauthor(s)

Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine
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Henri-Andre Menard, MD, Professor of Medicine, Director of Rheumatology, Department of Medicine, Division of Rheumatology, McGill University Health Center and McGill University; Director, The McGill Arthritis Center; Senior Physician, Shriner's Hospital for Crippled Children, Montreal
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