Hypertrophic Osteoarthropathy 

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

Overview

Practice Essentials

Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by clubbing of the digits, periostitis of the long (tubular) bones, and arthritis.[1]  It is also known as pachydermoperiostosis (PDP).

HOA can be primary (hereditary or idiopathic) or secondary. Secondary HOA, which accounts for about 80% of HOA cases,[2] is associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease and often has a more rapid course. As a paraneoplastic syndrome, it most commonly occurs with pleural or pulmonary tumors; however, other tumors (eg, nasopharyngeal carcinoma and esophageal cancer) may also be involved.[3]  

An evaluation for the primary condition is warranted in patients with possible secondary HOA; for example, a search for an intrathoracic malignancy or chronic infection. See Workup.

Therapy for HOA consists of treatment of the primary cause and symptomatic treatment. Examples of treatment of the primary cause include the following:

  • Oncologic therapy for cancer (eg, surgical resection of tumor, chemotherapy, radiotherapy)
  • Surgical correction of cardiac anomalies
  • Antibiotics for infection 

Symptomatic treatments include the following:

  • NSAIDs
  • Bisphosphonates
  •  Octreotide
  • Vagotomy

See Treatment.

Background

The clinical triad of digital clubbing, arthralgias, and ossifying periostitis that characterizes hypertrophic osteoarthropathy (HOA) has been recognized since the late 1800s and was previously known as hypertrophic pulmonary osteoarthropathy (HPOA). Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers.[4] Observations made in modern times by Eugen von Bamberger (1889)[5]  and Pierre Marie (1890)[6]  led to the term Marie–Bamberger disease.[7]  Work by other investigators led to identification of various causes of this digital anomaly, which can be the first manifestation of a severe organic disease such as chronic pulmonary and cardiac diseases,[8]  

HOA is classified either as primary (hereditary or idiopathic) or secondary. Primary hypertrophic osteoarthropathy (PHO; also termed primary pachydermoperiostosis or Touraine-Solente-Gole syndrome) was initially described by Friedreich in 1868 and then by Touraine et al in 1935, who recognized its familiar features and proposed the following classification[9, 10] :

  • Complete - Pachydermia, digital clubbing, and periostosis
  • Incomplete - No pachydermia
  • Forme fruste  - Prominent pachydermia with few skeletal manifestations

In some cases, the diagnosis of HOA as primary can be challenged with the development of a disease that is known to be associated with secondary HOA. This may occur as late as 6-20 years after the appearance of HOA.[11, 12]

Clubbed digits

Clubbing is characterized by elevation of the nail and widening of the distal phalanx caused by swelling of the subungual capillary bed resulting from increased collagen deposition, interstitial inflammation with edema, and proliferation of the capillaries themselves.[13] 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.[14] Vast numbers of arteriovenous anastomoses may also be seen in the nail bed.[15]

Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic.[16]  Hypertrophy or bony overgrowth predominates in patients with HOA secondary to lung cancer, whereas acro-osteolysis predominates in patients with HOA secondary to cyanotic congenital heart disease.[17] The type of bone remodeling process depends on the age when clubbing develops.[16] 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.[16]

Periosteum

The pathologic hallmark of HOA is neoangiogenesis, edema, and osteoblast proliferation in distal tubular bones that lead to subperiosteal new-bone formation. Subperiosteal new bone formation exists along the distal diaphysis of tubular bones, progressing proximally over time. The irregular periosteal proliferation affects predominantly the distal ends of long bones, including the epiphysis in 80-97% of patients. Usually the metacarpals, metatarsals, tibia, fibula, radius, ulna, femur, humerus, and clavicle are involved. The tibia is almost invariably involved.[18, 19, 20] Involvement of the epiphysis distinguishes it from the secondary form, which typically spares the epiphysis.

Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum.[18] 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.[21]

Synovium

Synovial involvement may occur with subperiosteal changes.[18] Thickening of the subsynovial blood vessels and mild lining-layer hyperplasia may occur.[22, 18] The edematous synovium becomes mildly infiltrated with lymphocytes, plasma cells, and occasional polymorphonuclear leukocytes, but the results of immunohistologic studies are negative. Electron-dense subendothelial deposits are present in vessel walls.[23, 24, 25] In a study of a patient with primary HOA and chronic arthritis, Lauter et al found multilayered basement laminae around small subsynovial blood vessels consistent with the late stages of vascular injury.[25] Synovial fluid is usually noninflammatory with low leukocyte counts and few neutrophils.[23, 25]

Skin

Skin changes are more evident in primary HOA and are caused by dysregulation of mesenchymal cells.[26] Characteristic cutaneous manifestations include pachydermia (ie, thickening of facial skin resulting in leonine faces) over the scalp, cutis verticis gyrata, and bilateral ptosis over the eyes resulting in blepharoptosis.[27] These changes yield a characteristic “bulldog” appearance.[28]

Other dermatologic manifestations are acne, eczema, seborrhea, and palmoplantar hyperhidrosis. The skin of the hands and feet are also thickened, but usually not folded.

Pathophysiology

The development of hypertrophic osteoarthropathy (HOA) has been linked to several mechanisms, including excessive collagen deposition, endothelial hyperplasia, edema, and new bone formation.[29]  It has been hypothesized that these mechanisims are driven by paraneoplastic growth factors,[30]  such as prostaglandin E and other cytokines; and neurologic, hormonal,[31]  and immune mechanisms.[32, 18]  All, or at least many, likely contribute to its development in different clinical situations. A popular current theory involves the interaction between activated platelets and the endothelium, which is discussed further below.[30, 32, 33]  Primary and secondary HOA have distinct pathophysiologies despite similar clinical presentations.

Primary HOA has been linked to mutations in two genes, 15-hydroxyprostaglandin dehydrogenase (HPDG) [34] , and solute carrier organic anion transporter family, member 2A1 (SLCO2A1).[35]  Both autosomal dominant inheritance with incomplete penetrance and recessive inheritance have been reported.[2]  The mutations of HPDG and SLCO2A1 lead to elevation of prostaglandin E2 (PGE2) with decrease in the level of its metabolites. Under normal conditions, PGE2 is degraded into unstable 13, 14-dihydro-15-keto PGE2 and then into stable 13, 14-dihydro-15-keto PGA2, with 15-PGDH as a key enzyme in the catabolic pathway.[36]  Increased PGE2 levels have been shown to stimulate activity of both osteoclast and osteoblast, which may contribute to the skeletal manifestations of primary HOA, including periostosis and acro-osteolysis.[37, 38]

Kozak et al tested the hypothesis that elevated systemic levels of PGE2 in patients with lung cancer contributes to digital clubbing. This study found that the median urinary level of the metabolite of prostaglandin E2 was 2.3-fold higher in patients with clubbing than in patients without clubbing.[39]

Secondary HOA, on the other hand, is most often associated with an underlying pulmonary disease, mainly bronchogenic carcinoma. HOA has been observed in up to 17% of bronchogenic carcinoma patients.[40]  Secondary HOA can also be associated with non-pulmonary conditions, including cardiovascular, gastrointestinal, hepatobilliary, and endocrine diseases[40]

Several other pathophysiologic mechanisms have also been observed in HOA. The most important of these mechanisms involve circulating signaling molecules and growth factors that are normally cleared from the blood by the pulmonary endothelium.[22]  

Normally, megakaryoctes released from bone marrow into the general circulation travel to the pulmonary microvasculature, where they fragment into platelets.[41] If that fails to occur, the platelet precursors can become trapped in the peripheral vasculature, where they release platelet-derived growth factor and vascular endothelial growth factor, which promote vascularity.[42]  This has been demonstrated in patients with cyanotic heart diseases, in which large circulating platelets with abnormal, and at times bizarre, morphology have been found. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves.[43, 32]

To date, several physiologic and anatomic processes have been defined in which these large particles reach the fingertip capillaries and impact release of growth factors. Megakaryocytes or megakaryocyte fragments have been observed bypassing the lung capillary network (eg, in patients with right-to-left intracardiac shunts, carcinoma of the bronchus, anatomic malformation of the vasculature, patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt) and forming large platelet clumps on the left side of the heart or in large arteries (eg, subacute bacterial endocarditis, subclavian aneurysm), or chronic platelet excess (eg, in chronic inflammatory bowel disease).[44]

For the reasons above, cyanotic heart diseases are an excellent model for studying HOA pathogenesis because more than one third of patients with lifelong clubbing secondary to cyanotic heart disease eventually display the full HOA syndrome.[45] HOA caused by intrapulmonary shunting of blood becomes evident only in the limbs that receive unsaturated blood, for example, in patients with patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt.

The growth factors released by megakaryocytes or megakaryocyte fragments impacted at distal sites include bradykinin, slow-reacting substance of anaphylaxis, transforming growth factor–β1 (TGF-β1), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) stored in the platelet alpha granules. Those are all angiogenic, with trophic effects on capillary beds. In addition, they all enhance the activity of osteoblasts and fibroblasts. This initiates finger clubbing by inducing connective-tissue matrix synthesis periostosis.[32, 33]

Increased circulating growth factor levels thus would explain all of the features of HOA. PDGF and VEGF are thought to contribute significantly to the development of HOA. VEGF is a platelet-derived factor whose action is induced by hypoxia. It is a potent angiogenic and permeability-enhancing factor, as well as a bone-forming agent. VEGF receptors are expressed in subperiosteal bone-forming cells. Both PDGF and VEGF induce vascular hyperplasia, new bone formation, and edema.[46]

In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated von Willebrand factor antigen (vWF:Ag) levels in persons with primary HOA and in persons with HOA secondary to cyanotic heart disease.[32] vWF:Ag is a surrogate marker of endothelial activation and damage, as shown by the fact that high plasma levels of vWF:Ag are also found in the vasculitides, myocardial infarction, diabetic microangiopathy, and scleroderma.[32] Thus, a common pathogenetic pathway for HOA possibly involves localized activation of endothelial cells by an abnormal platelet population. Macrothrombocyte and endothelial cell activation can also be present in cases of HOA associated with other disease entities such as liver cirrhosis, in which a prominent intrapulmonary shunting of blood occurs.[33]

Stimulation of fibroblasts by PDGF, epidermal growth factor (EGF) and TGF-β along with overexpression of VEGF have also been linked to the extensive myelofibrosis seen in a few cases of pachydermoperiostosis.[47]

A second proposed mechanism for the development of hypertrophic pulmonary osteoarthropathy is a vagally-mediated alteration in limb perfusion. 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 HOA, suggesting a role for reflex vagal stimulation.[48] Bazaar et al proposed that sympathetic override of the normal protective function of vagal innervation is the basis of HOA.[49] Sympathetic activity has been noted to induce cytokine changes consistent with inflammation.

Among these, epinephrine has been shown to induce production of interleukin (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. Reversal of those conditions with removal of the associated lung neoplasm or correction of a cyanotic heart malformation suggests that alteration of lung function plays an important role.[30]

A third mechanism is the possibility of ectopic production of hormonelike substances (such as VEGF) by tumor or inflammatory tissue, resulting in excessive circulating levels of angiogenic substances that would cause capillary bed hypertrophy and periosteal reaction, as noted earlier. Elevated circulating concentrations of VEGF and evidence of tumor production of VEGF have been found in lung cancer.[50] Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement. Increased levels of VEGF and IL-6 caused by the genetic mutation of K-ras might play a role in the pathogenesis of HOA with lung cancer.[51]

Diverse types of cancers produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is also known to occur in non-neoplastic diseases associated with HOA, such as Graves disease and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy. In HOA related to vascular prosthesis infection, Alonso-Bartolome et al suggested involvement of the humoral pathway giving rise to graft infection–associated HOA syndrome by endotoxin or vasoactive compound activated or released by bacteria adherent to the graft.[8]

Chronic activation of macrophages secondary to pulmonary pathologies may lead to digital clubbing by continual production of profibrotic tissue repair factors (eg, growth factors, fibrogenic cytokines, angiogenic factors, remodelling collagenases). These factors act systemically, but their effect is greatest at those parts of the vasculature which are most sensitive to these actions, such as the nail beds. Hypoxia also triggers the activation of macrophages.[52]

The role of different cytokines and cell receptors, including IL-6 and the osteoprotegerin or RANKL (receptor activator of nuclear factor kappa-Β ligand) system have been described on the development of the disease. Higher serum levels of IL-6 and RANKL are associated with increased values in markers of bone resorption (degradation products of C-terminal telopeptides of type-I collagen and urinary hydroxyproline/creatinine ratio) and reduced serum levels of bone alkaline phosphatase, a marker of bone formation, suggesting that HOA is characterized by increased bone resorption, probably mediated by IL-6 and RANKL.[53, 54]

Studies in patients with PDP or PHO evidenced increased plasma levels of several substances, such as endothelin-1, β-thromboglobulin, platelet-derived factor, von Willebrand factor, and vascular endothelial factor, among others, which could have a role in disease progression and periosteal proliferation.[54]

The pathogenesis underlying the higher risk of HOA in males, as proposed by Bianchi et al, relates to the high levels of nuclear steroid receptors, increased cytosolic estrogen receptors, and absence of detectable progesterone and androgen cytosolic receptors in HOA. Those suggest increased tissue sensitivity to different circulating sex steroids, which could enhance tissue epidermal growth factor or transforming growth factor alpha production and use.[53]

HOA can be associated with pregnancy and aging secondary to platelet abnormalities, hormonal disturbances, and cytokine dysfunction.

Enhanced Wnt genetic signaling contributes to the development of pachydermia skin changes in primary HOA by enhancing dermal fibroblast functions.[26]

Epidemiology

Frequency

Primary hypertrophic osteoarthropathy (HOA) is a rare condition. The precise incidence of this syndrome is unknown. According to one study, it has an estimated prevalence of 0.16%.[55]

 No systematic prevalence studies have been performed for secondary HOA, but cases are associated with many illnesses. According to Rassam et al, HOA occurred in about 3% (9 of 280) of consecutive lung cancer cases seen between 1970-1975. Other literature has described higher rates in primary lung cancer, ranging from about 4% to 32%.[8]

In a study of consecutive patients with congenital cardiac disease, Martínez-Lavín et al identified HOA in 10 of 32 patients (31%).[56] HOA associated with respiratory failure is reported to be present in 2–7% of patients.

Mortality/morbidity

Primary HOA has a self-limiting course, with progression stopping at the end of adolescence. There is no cure for the skeletal abnormalities.[12] The mortality and morbidity of secondary HOA vary with the associated illness. Secondary osteoarthritis may complicate long-standing HOA.

Race-, sex-, and age-related demographics

HOA affects persons of all races. Primary HOA has a marked predominance in males, with a male-to-female ratio of 9:1.[57] It has an autosomal dominant pattern of inheritance, with mainly variable expression and incomplete penetrance and familial aggregation in 25-38% of cases.[10, 28] Recessive autosomal inheritance and X-linked mutations may also occur, but those cases may differ in severity and prevalence of clinical features.[2] Secondary osteoarthropathy has the same sex ratio as the associated illnesses.

Primary HOA has a bimodal peak of onset: the first is before age 1 year and the second is at around the age of puberty (ie, approximately 15 years).[57] Secondary HOA is rarely encountered in children and adolescents; it most commonly affects individuals aged 55-75 years.[8]

 

Presentation

History

The clinical presentation of hypertrophic osteoarthropathy (HOA; pachydermoperiostosis [PDP]) varies according to the rapidity of onset and the evolution of the underlying disease. Primary HOA and slowly progressive secondary HOA are insidious and essentially asymptomatic.

Primary PDP usually begins after puberty. Some changes may start early in childhood. Skin and bone changes become progressively more severe for 5–10 years and then usually remain unchanged throughout life. Sometimes, disease may continue to progress.

Such patients rarely voluntarily report symptoms, because the clubbing and skin manifestations have developed slowly, over many years, and have become part of the patient's body image; the patient usually considers them more or less normal. Instead, these patients initially seek medical help for minor pains in the shoulders or hands, or recurrent swelling of a mechanical nature (effusions) in the knees (hydroarthrosis) or ankles (osteoarthritis),[12] They may be surprised by the physician’s interest in their clubbed fingers.

 Because of autonomic dysfunction (sympathetic hyperactivity), patients may have hyperhidrosis of the palms and soles.[58]  With HOA secondary to neoplastic or inflammatory pulmonary conditions, patients report pain and swelling in joints and long bones. These rheumatic symptoms follow a mechanical diurnal pattern.

This picture can precede the appearance of constitutional signs and symptoms (eg, fatigue, fever, weight loss) or respiratory signs and symptoms (eg, cough, hemoptysis, chest pain, dyspnea) by several months.

In secondary HOA, which occurs predominantly in men aged 30–70 years, the bone changes are the most obvious feature, develop more rapidly, and are often more painful than in primary form. The skin changes are absent or relatively mild. 

Although secondary HOA usually appears after the underlying disease is established, it can precede manifestation of the underlying disorder by more than a year; hence, follow-up of patients is essential.

Physical

The diagnostic criteria for hypertrophic osteoarthropathy (HOA) include clubbing and periostosis of the tubular bones.[59]  Three incomplete forms of hypertrophic osteoarthropathy are described:

  • Clubbing alone
  • Periostosis without clubbing in the setting of an illness known to be associated with HOA
  • Pachydermia associated with minor manifestations (eg, synovial effusion, seborrhea, hyperhidrosis, hypertrophic gastropathy, acroosteolysis)

The presence of periostitis and limb pain/swelling, even without clubbing, can suffice for a diagnosis of an incomplete form of HOA. For the complete form of HOA, the major diagnostic criteria are the triad of digital clubbing, hypertrophic skin changes (pachydermia), and painful swelling of the limbs (from periostosis of long bones).[54, 7]  Hypertrophy of soft tissues can also be seen, resulting in coarse facial features, cylindrical calves (elephant feet), ptosis of the eyelids, and cutis verticis gyrata or prominent frontal cerebroid wrinkles.

Earliest manifestations of primary HOA include delayed closure of the cranial sutures and patent ductus arteriosus. The most common clinical features of primary HOA include the following:

  • Clubbing (89%)
  • Swelling of periarticular tissue (with subperiosteal new bone formation revealed by radiography)(97%)
  • Pachyderma, coarsening of skin, seborrhea (90%)
  • Acne, folliculitis, palmo-plantar hyperhidrosis (44-67%)
  • Partial ptosis and cutis verticis gyrata (24%)

Clubbing

Clubbing usually progresses through the following 4 phases[18] :

  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 angle (Lovibond angle[60] ) formed by the dorsal surface of the distal phalanx and the nail plate; in healthy fingers, the Lovibond angle is approximately 165°; however, with clubbing the angle becomes 180° or greater

  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 skin creases and appearance of longitudinal striation of the nail

Clubbing can be classified into 3 topographical groups[61, 62] :

  • Symmetrical: All the fingers and toes are involved, as depicted in the image below
    Clubbing associated with hypertrophic osteoarthrop 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.
  • 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 .

  • Normal skin color: This occurs with insidious onset of mildly symptomatic clubbing, evolving over years, that is usually associated with chronic low-grade inflammatory and infectious diseases or primary .

  • Red skin color: This occurs with recent onset, 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 occurs with chronic clubbing associated with cyanotic cardiopulmonary conditions.

Five clinical signs can be used to describe clubbing.

  • The profile sign: On lateral views, a loss of the normal 165° 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 (Schamroth) sign: When the dorsal surfaces of the left and right index fingers are placed in apposition, with the distal interphalangeal (DIP) joints and the nail beds touching, an oblong diamond-shaped aperture is normally visible between the two juxtaposed nail beds; with clubbing, this space is obliterated.[63, 64]

  • 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.[65, 33]

Clubbing can be quantified using instruments to determine the nail bed angles or the phalangeal depth ratio (PDR). However, this is not performed routinely. 

Bone and joint findings

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.[18] In some cases, dysesthesia of the fingers is present, with accompanying heat, sweating, clumsiness, and stiffness of the hands.[18] Adults with primary hypertrophic osteoarthropathy are asymptomatic.[57]

Joint symptoms range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles.[18] 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).[64] The effusions are more likely a sympathetic reaction to nearby periostosis; arthrocentesis in such cases reveals a very thick noninflammatory fluid, with a cell count of less than 500 cells/µL.[23]

Inflammation and reduction of the joint space may be present, and contractures may develop in later stages. Rarely, periarticular erosions can occur.[28, 66] In the axial skeleton, changes are spondylolisthesis, with narrowing of intervertebral disk spaces and foramina, ligamentous ossification and laxity.[28, 66]

Very often, a history of arthralgia of the ankles, knees, wrists, elbows, and occasionally the small joints is noted. Most likely this pain does not originate from the joints per se but rather is caused by active inflammation of the periosteum. Typically, these rheumatologic symptoms disappear when the periostitis is arrested.[67]   

Symmetrical cylindrical thickening of long bones has also been observed because of periosteal proliferation and subperiosteal new bone formation. It may appear as elephant foot in one fourth of cases. Articular and periarticular pain, particularly in ankles and knees is prevalent and mild articular limitation of motion may be due to periarticular bony over growth. Symmetrical involvement of small and large joints may appear as rheumatoid arthritis. 

Other common clinical presentations include progressive widening of distal part of long bones, bulbous deformities of fingers and toes, synovial effusions (41%), arthritis (20-40%), and paresthesias. The skeletal involvement occurs commonly in the form of symmetrical distal long bone enlargement. In advanced disease, proximal long bones and flat bones of the pelvic and shoulder girdles, musculotendinous insertions, and interosseous membranes get involved.  [68]

Cutaneous findings

These are more prominent in, but not exclusive to, primary HOA. In pachyderma, the skin of the face and forehead is thickened and furrowed, which results in leonine facies, a major cause of cosmetic and functional morbidity in these patients.[69]  The scalp skin is also thickened and folded and appears as "cutis verticis gyrata."

Ocular findings consist mainly of ptosis and chronic tarsitis; however, corneal leucoma, cataract, and presenile macular dystrophy have been reported. Thickened and ptotic upper eyelids are a common feature of pachydermoperiostosis (PDP). 

Other skin manifestations include seborrheic dermatitis, as eczematoid dermatitis of hands and feet, and also acne vulgaris.  Although promotional influences of prostaglandins and prostaglandin analogues on the hair follicle are obvious by virtue of clinical observations and experimental data, hair growth and hair structure are usually not affected in primary HOA.[70]

These cutaneous features cause the patient to look prematurely aged. Thickened ears and lips may appear. Hyperhidrosis and overactivity of sebaceous glands of the skin, particularly of scalp and face, is common. In a review of the PDP literature, hyperhidrosis was found to be present in 27% of 126 patients.[58]  The skin of palms and soles is also thickened and rough, and the thenar and hypothenar areas become prominent.

Causes

Primary or idiopathic hypertrophic osteoarthropathy (HOA; pachydermoperiostosis [PDP]) comprises about 3-5% of all cases of hypertrophic osteoarthropathy.[67] PDP is considered to be hereditary, although a family history of the disease can be traced in only about 25-38% of cases. Familial recurrence of PDP has been reported in 33–100% of pedigrees. Inheritance is autosomal dominant inheritance, although autosomal recessive and X-linked inheritance has been suggested.[12]  It occurs predominantly in males (male-to-female ratio of 9:1), and males usually show a more severe phenotype.[52] PDP is more common in African Americans.[69]

PDP has been mapped to band 4q33-q34 on chromosome 4. Homozygous and compound heterozygous germline mutations in HPGD encoding 15-hydroxyprostaglandin dehydrogenase, whose enzyme activity is NAD+ dependent. The key enzyme of prostaglandin degradation has been identified.[69] Homozygous HPGD mutations have so far been reported in 10 families; all but one displayed parental consanguinity. Only 2 of these families were of European origin. The c.175_176delCT frameshift mutation appears to be recurrent and to be the most common HPGD mutation in Caucasian families.[71]

So far, 7 HPGD alterations are known. Allelic spectrum of HPGD gene include a novel c.217+1G>A mutation. Seven coding HPGD exons encode the 266 amino acid 15-hydroxyprostaglandin dehydrogenase, which is ubiquitously expressed. All HPGD mutations constitute loss-of-function alleles due to protein truncation or missense changes that affect hydrogen bonds lining the 15-PGDH enzyme reaction cavity. Individuals with homozygous mutations have chronically elevated prostaglandin E2 (PGE2) levels. The various clinical manifestations of PDP fit well with the pleiotropic range of physiologic actions of PGE2 in different tissues. Excess PGE2 may account for the periostosis, acro-osteolysis, clubbing, and patent ductus arteriosus. The exact effects of PGE2 on the skin are not completely understood. Various mechanism suggested are effect of PGE2 on vasculature and Wnt signaling.

The Wnt signaling consists of canonical and noncanonical pathways. These signaling pathways are mediated by Wnt protein, which binds to a frizzled Wnt receptor. Wnt signaling is modulated by several different families of secreted down-regulators. Among them, Dickkopf (DKK) is a family of cysteine-rich proteins comprising at least four different forms (DKK1, DKK2, DKK3, and DKK4), which are coordinately expressed in mesodermal lineages.

The best studied of these is DKK1, which blocks the canonical Wnt signaling by inducing endocytosis of lipoprotein receptor-related protein 5/6 (LRP5/6) complex12 without affecting the frizzled Wnt receptor. High mRNA levels of DKK1 in human dermal fibroblasts of the palms and soles inhibit the function and proliferation of melanocytes via the suppression of catenin and microphthalmia- associated transcription factor. These findings suggest that DKK1 is deeply involved in the formation and differentiation of the skin. Decreased expression of DKK1 in fibroblasts and enhanced expression of catenin in the skin of patients with PDP, suggest that Wnt signaling is enhanced in PDP. These results suggest that enhanced Wnt signaling contributes to the development of pachydermia.[26]

Various rare associations like hypertrophic gastropathy, peptic ulcers, gynecomastia, acro-osteolysis of fingers and toes, Crohn disease, atherothrombotic brain infarction,[58] renal amyloid A (AA) amyloidosis, and bone marrow failure due to myelofibrosis have been described. Only 6 cases of myelofibrosis in primary HOA have been described so far. The development of myelofibrosis makes primary HOA a disease with unfavorable outcome.[68]  Several factors including increased collagen fibers, infiltration and overgrowth of fibroblasts in bone marrow, and overactivity of platelet-derived growth factor may play a role in this complication.[72] An increase in human leukocyte antigen (HLA) B12 has been shown in one study of this syndrome.[47] Tanaka et al reported pulsed steroid therapy with parenteral iron having been able to improve the anemia and pancytopenia but insufficient to relieve the bone marrow fibrosis, splenomegaly, or cause any resolution in his skin or bone findings. Other associated abnormalities include cranial suture defects, gynecomastia, female hair distribution, striae, compressive neuropathy, corneal leukemia, and patent ductus arteriosus.[70]

Secondary hypertrophic osteoarthropathy is also called Pierre Marie-Bamberger syndrome. In adulthood, 90% of generalized hypertrophic osteoarthropathy is associated with an intrathoracic infectious or neoplastic condition.

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.[18, 73] In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition. The association with malignancy is relatively common in adults.[74, 75]

Digital clubbing and hypertrophic osteoarthropathy are linked, and many authors postulate a single pathological entity, regardless of the etiology, which evolves in a centripetal fashion, with finger or toe clubbing appearing first and thickening of the tubular bones of the extremities occurring at later stages of the process. Hypertrophic osteoarthropathy with no clubbed nails appears to be rare and few cases have been reported. Periosteal new bone formation is a hallmark of hypertrophic osteoarthropathy and it mostly affects the appendicular skeleton, usually bilaterally and symmetrically along the metadiaphyseal regions of the bones.[76]  

Conditions underlying secondary hypertrophic osteoarthropathy can be easily separated into malignant and nonmalignant diseases. Paraneoplastic HOA is more common in subjects aged 50–70 years.[77] Among malignancy-related hypertrophic osteoarthropathy, pulmonary malignancies compose 80% of reported cases, most of which are non-small cell lung cancer such as squamous cell or adenocarcinoma. As many as 5% of adults with lung cancer demonstrate signs of HOA.[46]  Lung cancer accounts for almost 20% of isolated digital clubbing and over 60% of hypertrophic osteoarthropathy in adults.[8] These data suggest that hypertrophic osteoarthropathy or simple digital clubbing in adults must be considered as a warning and should prompt lung cancer screening, even in the absence of detectable respiratory symptoms, so that patients could benefit from early treatment ensuring better outcome.

Over 90% of secondary HOA cases develop as a paraneoplastic syndrome or the anomaly associated with chronic suppurative infections and can precede the diagnosis of an underlying disease.[77]

However, patients with HOA rarely show the complete triad of signs. Less than 1% of the lung cancer patients developed hypertrophic osteoarthropathy as a paraneoplastic manifestation. Males, heavy smokers, and advanced disease predominated in lung cancer patients with hypertrophic osteoarthropathy.[78] Other malignancies reported in the literature to be associated with HOA include the following:

  • Nasopharyngeal cancer
  • Mesothelioma, renal cell carcinoma, esophageal cancer, gastric tumor, pancreatic cancer, breast phyllodes tumor, melanoma, thymic cancer and Hodgkin’s lymphoma. [8]  

Nonmalignant causes of hypertrophic osteoarthropathy include a number of GI and other diseases, including neoplastic, pulmonary, cardiac, infectious, endocrine, psychiatric, and multisystem diseases.

Chronic respiratory diseases include cystic fibrosis, pulmonary fibrosis, sarcoidosis, lung transplant,[21] chronic obstructive lung disease, and chronic infections like pulmonary tuberculosis, pulmonary primary intestinal lymphangiectasia (Waldmann disease), pulmonary epithelioid hemangioendothelioma, bronchiectasis, diffuse inflammatory lung disease, pulmonary arteriovenous malformations, and chronic hypoxemia. Yao and coworkers described the first case of hypertrophic osteoarthropathy associated with chronic lung transplant rejection.[79] An association of sarcoidosis with hypertrophic osteoarthropathy has been reported and nodular periostitis by roentgenography has been reported in 1 case.[80]

Inflammatory bowel disease (Crohn disease and ulcerative colitis), celiac sprue,[57] gastric hypertrophy, laxative abuse, polyposis, intestinal acute cellular rejection ACR, primary intestinal lymphoma, juvenile polyps of the stomach, and gastric adenocarcinoma are associated with hypertrophic osteoarthropathy.Liver disease and cirrhosis resulting from cholestasis, chronic active hepatitis, biliary atresia, primary sclerosing cholangitis, Wilson disease, primary biliary cirrhosis, and alcoholic cirrhosis are also causes.[8] These also include hepatocellular carcinoma and primary liver rhabdomyosarcoma.To our knowledge, hypertrophic osteoarthropathy has not been reported to occur with liver steatosis in the English literature. Hypertrophic osteoarthropathy has been associated with organ transplant in one isolated liver transplant recipient with chronic liver rejection.[81]   No association with transplant medications has been noted.[82]

Congenital cyanotic congenital heart diseases, rheumatic diseases, and left ventricular tumors have been implicated as well.[83]

Neurologic causes include primitive neuroectodermal tumors (PNETs).[84]

Other causes include chronic infections associated with cystic fibrosis, HIV,[82] tuberculosis, aspergillus, infective endocarditis, subacute bacterial endocarditis, vascular prosthesis infections, syphilis, and immune deficiency syndrome and amyloidosis.

Mediastinal causes include esophageal carcinoma, thymoma, and achalasia.

Miscellaneous causes include the following:

  • Graves disease
  • Thalassemia
  • Diverse malignancies
  • Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) 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
  • Deep infections such as vascular graft infection and perianal abscess

Primary HOA and POEMS syndrome overlap; both conditions are associated with digital clubbing, pachyderma, hyperhidrosis, gynecomastia, and bone proliferation.

 

ther 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.[62] In patients with patent ductus arteriosus, pulmonary hypertension causes right-to-left shunting of blood, which may cause HOA of the toes and fingers on the left side.[62, 33] Development of hypertrophic osteoarthropathy localized to areas distal to a vascular prosthesis may allow early diagnosis of graft infection. Around 30 cases of bilateral or monomelic hypertrophic osteoarthropathy of the lower limbs (or isolated clubbing of the toes) revealing an aortic prosthesis infection have been reported in the last 40 years.[85] Therefore, unilateral clubbing always suggests a condition affecting the vessels or nerves of the arm, leg, or thoracic outlet.[62]

Thomas first described thyroid acropachy in 1933.[86] 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.[87] It usually coexists with exophthalmos and pretibial myxoedema, and patients can be hypothyroid, euthyroid, or hyperthyroid.[64]

Various medications including prostaglandin, vitamin A, and fluoride can produce periostitis and bony changes resembling hypertrophic osteoarthropathy.[88] The association between finger clubbing and senna misuse and the reversibility of finger clubbing, were reported in 1975.

Voriconazole has been reported to probably induce periostitis, but no apparent inflammatory arthritis was present in the case series report.[46] The presentation more closely resembles nodular periostitis or periostitis deformans than hypertrophic osteoarthropathy. Unlike patients with hypertrophic osteoarthropathy, patients with voriconazole-associated periostitis lack the cardinal features of digital clubbing and noninflammatory joint effusions.[88] The periosteal reaction was dense and irregular, as opposed to the smooth and single layer periostitis described in lung-cancer-associated hypertrophic osteoarthropathy. In addition to the involvement of tubular bones characteristic of classic hypertrophic osteoarthropathy, the patients also had variable involvement of the clavicles, ribs, scapulae, and pelvis. Chen and Mulligan suggested that fluoride toxicity may be the cause of voriconazole-associated periostitis.[89]

Hypertrophic osteoarthropathy was also noted in one case after a long-term use of bevacizumab metastatic colorectal cancer.[90]

 

Hypertrophic osteoarthropathy is an uncommon disease in the pediatric age group characterized by noninflammatory joint effusions, terminal digit clubbing, and radiographic evidence of periosteal new bone formation affecting the hands, feet, and distal limbs. The hepatopulmonary syndrome is also uncommon in childhood and presents as hepatic dysfunction, impaired arterial oxygenation, and intrapulmonary shunting. Consider hypertrophic osteoarthropathy as an imitator of juvenile rheumatoid arthritis, recognize its known association with chronic liver disease, and know that hepatopulmonary syndrome can occur in the setting of hypertrophic osteoarthropathy.[91]

In children, most cases of generalized hypertrophic osteoarthropathy are due to non-neoplastic causes such as pulmonary infections, cystic fibrosis, and congenital cyanotic heart disease.[46] Case reports have described an association with biliary atresia. 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. Malignancy-associated hypertrophic osteoarthropathy in children and young adults is not well documented but numerous case reports describe the association with carcinoma of the nasopharynx, osteosarcoma with lung metastasis, rhabdomyosarcoma, Hodgkin lymphoma, thymic carcinoma and pleural mesothelioma.[46] A case report has described hypertrophic osteoarthropathy presenting as the first symptom of recurrent infantile fibrosarcoma.[92]

The authors did not identify any reported cases of hypertrophic osteoarthropathy associated with lung carcinoma in children or young adults in the literature.[46] Intrathoracic disease should be considered when hypertrophic osteoarthropathy is detected in a child with a known or suspected malignant disease, and the occurrence of hypertrophic osteoarthropathy during follow-up should alert the physicians for possible recurrence of the neoplastic disease or intrathoracic involvement. To the authors' knowledge, only 34 pediatric patients with hypertrophic osteoarthropathy have been reported to have neoplastic diseases to date. Among these, 12 had carcinoma of the nasopharynx, 8 had osteosarcoma, 8 had Hodgkin lymphoma, 3 had thymic carcinoma, 1 had periosteal sarcoma, 1 had pleural mesothelioma, and 1 had recurrent infantile fibrosarcoma.[93, 92]

An atypical form of hypertrophic osteoarthropathy has presentation limited to lower extremities.[94]

 

 

DDx

Diagnostic Considerations

The importance of recognizing hypertrophic osteoarthropathy (HOA) 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 lungs and heart.

Other disorders to consider in the differential diagnosis include acromegaly, thyroid acropachy, and scleromyxedema, syphilitic periostitis, osteopetrosis, and Paget disease. The disfigurements in facial and skeletal appearances have been confused with leprosy and syphilis, which are especially important considerations in some developing countries. 

Inflammatory arthropathy may be incorrectly diagnosed in cases of malignant lung tumors, in which painful arthropathy can be the presenting feature of HOA. HOA is more likely when the following factors are present:

  • Pain that extends beyond the joint into the adjacent bone
  • Absence of rheumatoid factor
  • Noninflammatory synovial fluid

Acromegaly may be suggested in cases of exuberant skin hypertrophy and enlarged hands and feet.[95]  However,  in acromegaly, bones in general are larger in the face, jaw (prognathism), skull, and limbs; this is very evident in a radiographic study in the absence of signs of periostosis.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 HOA include the following:

Other diseases associated with periostitis should be included in the differential diagnosis. In HOA, the periostitis involves the distal diaphysis of long bones and metacarpal joints, while in other diseases, the involvement is as follows:

  • 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
  • Facial infections - Mandible, orbital
  • 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 interleukin-11 - Clavicle, long bones
  • Osteomyelitis - Variable
  • Chronic leg ulcers - Tibia
  • Synovitis-acne-pustulosis-hyperostosis (SAPHO) syndrome - Variable

Various causes of unidigital clubbing include the following:

  • Aortic/subclavian aneurysm
  • Brachial plexus injury
  • Shoulder subluxation
  • Superior sulcus (Pancoast) tumor
  • Median nerve injury
  • Trauma
  • Maffucci syndrome
  • Gout, sarcoidosis
  • Severe herpetic whitlow
  • Hemodialysis

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.[61, 62]  

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

 

 

 

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).[18] .

Serum alkaline phosphatase levels may be elevated secondary to periosteal new bone formation.[18] These bone markers can be used to monitor disease activity. Isolated reports have shown an increase in some bone formation markers and resorption such as TAP, BAP, BGP, carboxyterminal propeptide of type I procollagen, or NTX (see N-Terminal Telopeptide) in patients with either primary or secondary HOA, suggesting that measurement could be useful for monitoring disease activity. 

Biallelic HPGD mutations are found in most patients with typical primary HOA. Sequencing of the HPGD gene is a highly specific first-line investigation for patients presenting in this way, particularly during childhood.[96]  This gene codes for 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation; consequently, homozygous individuals with this mutation show elevated levels of prostaglandin E2 and its metabolite, PGE-M, which suggests that its measurement can be useful in early investigations of patients with HOA.

If a joint effusion is present, the synovial fluid is noninflammatory (cell count < 500/µL), with a predominantly lymphocytic and monocytic infiltrate. Synovial histology shows hypercellularity and vascular thickening without inflammatory cell infiltration. 

An evaluation for the underlying condition is warranted in patients with possible secondary HOA. Presence of the characteristic features should prompt an intensive search for an underlying malignant disease, usually of thoracic organs.[7]

Imaging Studies

Radiologic findings are periostitis and symmetrical thickening of distal tubular bones, particularly the tibia, fibula, radius, and ulna. Bilateral and symmetrical periostosis are frequently observed as a marked irregular periosteal ossification of the tibias and fibulas.[26]  Distinguishing between clubbed and nonclubbed fingers using plain radiography is possible.[97]  Plain radiographs show 2 types of changes: bone formation with hypertrophy and bone dissolution with acro-osteolysis.[16]  Acro-osteolysis may be seen in the distal tufts in patients with long-standing HOA.

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.[18]  However, there are documented cases of HOA without radiographically detectable periostitis.[76]

Radionuclide bone scan using technetium (Tc) 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. This technique is the most sensitive tool for the detection and evaluation of the extent ofnmHOA; it can delineate the subtleties in progression and regression of the disease when findings from plain radiographs are doubtful.[76] The clubbed digits may also show increased uptake in early passage flow studies, as depicted in the images below.[18, 64]

Clubbing associated with hypertrophic osteoarthrop 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.
Joint symptoms of hypertrophic osteoarthropathy ra 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).

Angiography findings may demonstrate hypervascularization of the finger pads.[98, 22]

For more information, see Imaging in Hypertrophic Osteoarthropathy

Histologic Findings

Biopsy of the skin and bone marrow may show an exacerbated proliferation of fibroblasts, which are associated with diffuse epidermal hyperplasia and lymphohistiocytic infiltration with collagen redistribution. 

Histopathologic findings of the eyelid include sebaceous gland hyperplasia, enlargement of sweat glands, thickening of the dermis with an increase in collagen content, deposition of mucin, and perivascular lymphocytic infiltration.[99]

 

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]

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.

 

Medication

Medication Summary

No drug effectively treats hypertrophic osteoarthropathy (HOA). Nonsteroidal anti-inflammatory drugs (NSAIDs) and other medications may be used for symptomatic relief. Beta-blockers may be used for the treatment of hyperhidrosis of primary HOA.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Class Summary

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 (Motrin, Advil, Ibu, Caldolor)

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.

Piroxicam (Feldene)

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

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.

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.

Diclofenac (Voltaren XR, Cataflam, Cambia)

This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.

Adrenergic beta-blockers

Class Summary

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

Propranolol (Inderal LA, InnoPran XL)

Opposes multisystemic effects of excessive adrenergic tone.

 

Follow-up

Further Outpatient Care

With specific curative treatment for the underlying conditions, secondary hypertrophic osteoarthropathy may remit, with only analgesic and anti-inflammatory supportive treatment required in the meantime. 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. In cancer-related cases, a re-emergence of symptoms often heralds disease relapse and may precede symptoms from the primary tumor.

Inpatient & Outpatient Medications

Any of the classic NSAIDs or a COX-2 inhibitor 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.

Prognosis

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

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.