Hypertrophic Osteoarthropathy

What is Hypertrophic osteoarthropathy?

Hypertrophic osteoarthropathy can be defined as a medical condition in which the bones and the joints are affected. Basically, the finger and toes suffer from a process that is known as clubbing. This means that the extremities become enlarged, leading to the appearance of pain and inflammation (specifically at the level of the joints).Interestingly enough, this condition was described for the first time approximately 2500 years ago, by Hippocrates (hence the Hippocratic fingers used to described the clubbing). The condition took the name of the Pierre Marie-Bamberger disease in the 1890s – both Pierre Marie and Bamberger connected with the changes with chronic diseases affecting either the heart or the lungs.The condition can either be primary, appearing on its own or secondary, having an underlying condition to have caused it. The primary hypertrophic osteoarthropathy is a condition that is inherited and rare (3% of all the cases). The changes appear gradually, with the passing of time and, in most cases, there are no symptoms present. The patient might visit the doctor for the first time, upon feeling a minor pain at the level of the shoulder or, more specifically, in the hand.This form is also known as primary pachydermoperiostosis or the Touraine-Solente-Gole syndrome, after those who have described the features for the first time. It is possible that the patients who are diagnosed with the primary form to develop medical conditions that are otherwise considered to be the underlying causes of the secondary form. Among these conditions, there are: patent ductus arteriosus, Crohn disease and myelofibrosis. These can appear as late as 6-20 years after the initial debut of the primary hypertrophic osteoarthropathy.There are three forms of primary hypertrophic osteoarthropathy, meaning:

• Complete
• Pachydermia
• Digital clubbing
• Periostosis
• Incomplete
• No pachydermia
• Fruste
• Prominent pachydermia
• Few skeletal manifestations

In the situation of patients who suffer from secondary hypertrophic osteoarthropathy, pain and inflammation are the most common complaints. The fingers are clubbed, with the symptoms appearing all of a sudden and the progression being quite rapid. It is important to mention that 90% of the patients diagnosed with this form of hypertrophic osteoarthropathy also present a form of cancer; those who do not suffer from cancer present however a chronic disease, more commonly at the level of the heart, lungs, liver or intestines.

Pathophysiology

As the fingers and toes start to suffer from the clubbing transformation, the skin that surrounds the nails becomes red and tender to the touch. The skin might also thicken, with similar changes occurring at the level of the tubular bones. Periostosis – abnormal deposits of bone tissue around the outer surface of the respective bone – might occur as one of the features. While these changes might not cause symptoms, in some patients they can lead to the appearance of an intense burning sensation or pain (more commonly felt at the extremities and described as “deep-seated”). The main changes that occur in patients suffering from hypertrophic osteoarthropathy are: digital clubbing, periostosis and arthritis.The digital clubbing is characterized by the elevation of the nail, followed by the widening of the distal phalanx. These changes are actually caused by the inflammation that occurs at the level of the subungual capillary. The inflammation is because of the excessive collagen deposition, along with the interstitial inflammation and the associated edema. The proliferation of the local capillaries also contributes to the inflammatory process. Basically, the digital clubbing appears because of the increased vascular supply to the nail bed, along with the increased growth of the connective tissue in the area.The periostosis process refers to the formation of new bone along the tubular bones, with such changes occurring in a gradual manner. The distal end of the long bones is more commonly affected, with the following bones being more often involved: clavicle, humerus, femur, ulna, radius, fibula, tibia, metatarsus and metacarpus. The involvement of the bone epiphysis can be used in order to make the difference between the primary and secondary form (the latter does not lead to the affectation of the bone epiphysis).At the start of the disease, the periosteum is elevated by the connection tissue that is present in excess, along with the associated, subperiosteal edema. Then, with the passing of time, the excess bone growth brings its own contribution to the problem.The osteoblast proliferation at the level of the distal tubular bones is responsible for the formation of new bone in the subperiosteal area. The distal phalanges can suffer from two main types of bone changes, meaning hypertrophy and osteolysis. The hypertrophy is often encountered in patients who are suffering from lung cancer, while the osteolysis is more often found in those who have been diagnosed with congenital heart disease (cyanotic form).The age of the patient also determines the progression of the changes. If the digital clubbing appears during childhood, it is highly likely that the osteolysis is going to be more prominent. On the other hand, if the digital clubbing appears as a feature after puberty, the hypertrophy changes are going to appear as well. The subperiosteal changes, regardless of the age at which they appear, will lead to the involvement of the synovium as well.As you have already read, the skin is going to become thicker. It is characteristic for some forms to be accompanied by pachydermia, with the thickening of the skin face leading to a characteristic aspect (leonine face). Other skin-related changes include: cutis verticis gyrata and bilateral ptosis (the latter can ultimately lead to blepharoptosis). These changes can lead to a characteristic aspect of the face as well – this is known as the “bull-dog” appearance. Among the other features that can be present in patients suffering from hypertrophic osteoarthropathy, there are: acne, seborrhea, eczema. Palmoplantar hyperhidrosis can also be present in some patients. It is possible that the skin on the palms on the hands and feet is thickened as well.

Causes

As it was already mentioned, the primary hypertrophic osteoarthropathy is an inherited condition. On the other hand, the secondary type is often found in patients who already suffer from a form of cancer or a chronic disease involving vital organs. One of the most common associations is with peripheral non-small cell lung cancer. It is quite clear that the cancer appears first; however, in some patients, the symptoms of the hypertrophic osteoarthropathy might appear before the ones of the malignancy (more than one year difference).The mechanism lying behind the appearance of this condition has yet to be clarified. Among the potential factors presented as triggers, there are: hormonal imbalance (estrogen, growth hormone), neurogenic and circulating factors.

Diagnosis

These are the most common methods that can be used for the diagnosis of hypertrophic osteoarthropathy:

Laboratory testing

• Erythrocyte sedimentation rate (elevated)
• Serum alkaline phosphatase (elevated)
• Plasma factors (increased levels)

Imaging studies

• Plain X-ray
• Bone formation with hypertrophy or
• Bone dissolution with osteolysis
• Periosteal thickening
• Radionuclide bone scan
• Can be used to assess the progression or regression of the condition
• Tc-diphosphonate complexes
• Most sensitive tool for the diagnosis of hypertrophic osteoarthropathy
• Angiography
• Useful for the identification of the excessive vascularization at the level of the finger pads

Other investigations

• Skin biopsy
• Bone marrow biopsy

Treatment

For the patients who suffer from the secondary form of hypertrophic osteoarthropathy, the main purpose of the treatment is to address the underlying cancer or chronic disease. Upon removing the malignant growth, the symptoms involving the bones and the joints are improved within two weeks or one month. However, if the respective tissue has suffered from chronic damage, it is highly unlikely that the clubbing will be reversed. One of the most often encountered tissue changes is caused by the excess deposits of collagen. The symptomatic treatment includes NSAIDs, these bringing the necessary relief to patients who are suffering from both pain and inflammation.General treatment measures for hypertrophic osteoarthropathy include:

• Administration of botulinum toxin – temporary effect, cosmetic improvement
• Medication
• NSAIDs – relief from pain and inflammation
• Corticosteroids – useful to bring relief from the rheumatologic symptoms
• Retinoids – improvement of symptoms such as pachydermia, seborrhea or folliculitis
• Colchicine – recommended for the patients who experience pain due to the new bone formation that occurs at the subperiosteal level
• Other medication – tamoxifen citrate, risedronate
• For secondary hypertrophic osteoarthropathy:
• Treatment of primary cause
• Tumor resection
• Surgical intervention for heart disease
• Chemotherapy and radiation therapy
• Treatment for different types of infection
• Symptomatic treatment
• Bisphosphonate
• Octreotide
• NSAIDs
• Vagotomy
• Surgical intervention
• Tumor resection – improvement of hypertrophic osteoarthropathy symptoms
• Tumor cytoreduction (radiofrequency ablation)
• Lung transplantation – recommended for patients who have been diagnosed with cystic fibrosis
• Liver grafting or full liver transplantation – indicated for patients suffering from chronic diseases of the liver (liver failure)
• Surgery for cyanotic heart malformations
• Plastic surgery – indicated for the removal of excess facial skin (in patients diagnosed with primary hypertrophic osteoarthropathy).