Hypertrophic Pulmonary Osteoarthropathy: An ...

Hypertrophic Pulmonary Osteoarthropathy: An Unusual Presentation Adnan N. Kiani1, Pooja Kumari1, Paul Yeung1, Abuzaid Medani1 Marshfield Clinic Saint Joseph Hospital Marshfield WI 54449 Correspondence to:

Adnan N Kiani M.D. M.P.H. Marshfield Clinic Saint Joseph Hospital 522 West Ives Street Marshfield, WI 54449

Telephone: 443-722-9807 Fax no: 443-722-9807 E-mail: [email protected] Other authors Adnan N. Kiani M.D. M.P.H. Marshfield Clinic 522 West Ives Street Marshfield, WI 54449 Pooja Kumari M.D. Marshfield Clinic 522 West Ives Street Marshfield, WI 54449 Paul Yeung M.D. Marshfield Clinic 522 West Ives Street Marshfield, WI 54449 Abuzaid Medani M.D. Marshfield Clinic 522 West Ives Street Marshfield, WI 54449

There are no relevant financial disclosures. There are no potential conflicts of interest for any authors listed. Keywords: Hypertrophic pulmonary osteoarthropathy, clubbing, malignancy. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Downloaded from https://academic.oup.com/rheumap/advance-article-abstract/doi/10.1093/rap/rky009/5040548 by guest on 20 June 2018

Hypertrophic Pulmonary Osteoarthropathy: An Unusual Presentation Abstract Objectives: Hypertrophic pulmonary osteoarthropathy (HPOA) is a syndrome characterized by triad of periostitis, digital clubbing and painful arthropathy of large joints especially involving the lower limbs. Hypertrophic pulmonary osteoarthropathy without clubbing of digits is considered an incomplete form of HPOA and is been reported rarely. We are presenting here a case of HPOA without clubbing in a patient with lung cancer. Methods: A 52-year-old female active smoker presented with complaint of multiple joint pains with associated morning stiffness, swelling and weight loss for 3 months. On examination, patient had tenderness to palpation over anterior shin, no obvious clubbing was noted. Plain film of lower extremities revealed periosteal thickening compatible with hypertrophic pulmonary osteoarthropathy. Results: Bone scan showed increased uptake along periosteum and cortex of long bones. In view of her smoking history and weight loss, chest x-ray was done which revealed upper lung mass, a diagnosis of lung carcinoma was made on biopsy. Conclusion: Our case demonstrates the unusual finding of hypertrophic pulmonary osteoarthropathy in the absence of clubbing is a rare entity and can often be missed. Once diagnosed a prompt search of other associated conditions should be conducted.

Keywords: Hypertrophic pulmonary osteoarthropathy, clubbing, malignancy. Key message: Once diagnosis of hypertrophic pulmonary osteoarthropathy is made search for other conditions including pulmonary malignancy should be taken into account.

Downloaded from https://academic.oup.com/rheumap/advance-article-abstract/doi/10.1093/rap/rky009/5040548 by guest on 20 June 2018

Introduction Hypertrophic pulmonary osteoarthropathy (HPOA) is a syndrome characterized by triad of periostitis, digital clubbing and painful arthropathy of large joints especially involving the lower limbs. Hypertrophic pulmonary osteoarthropathy without clubbing of digits is considered an incomplete form of HPOA and is been reported rarely [1]. Clubbing is characterized by bulbous enlargement of terminal segments of the fingers and toes due to proliferation of subungual connective tissue [2]. Clubbing was first described by Hippocrates in the 5th century BC[3], the association of clubbing, arthralgia, and periostitis as a distinct clinical syndrome known as hypertrophic pulmonary osteoarthropathy was not recognized until 1889 and 1890 by Bamberger[4] and Marie[5], respectively, so it is also known as Bamberger–Marie syndrome. Hypertrophic pulmonary osteoarthropathy without clubbing of digits is a rare entity and can easily be missed. Bone scintigraphy is the most sensitive method to detect the HPOA. Case Report A 52-year-old female with past medical history (PMH) of asthma, seasonal allergies, and active smoker with 30 packs/year smoking history presented with 3 month history of progressively worsening joint pains affecting hands, wrists, elbows, knees, ankles and toes, associated swelling and morning stiffness. Patient also reported weight loss of 35 pounds within the last 3 months. Patient reported recent travel to Vermont. She denied any symptoms of sore throat, abdominal discomfort, nausea, vomiting or dysuria. She denied any fevers at home, however, she was febrile upon presentation. She denied any history of skin psoriasis or inflammatory bowel disease, inflammatory low back pain, dactylitis, enthesitis or uveitis. She also denied any history of photosensitive skin rash or malar rash, oral or nasal ulcers. There was no recent use of any antibiotics, any hospitalizations or intravenous drug abuse. On physical examination, the patient had a temperature of 99.1 Fahrenheit, pulse 104, blood pressure 104/57, respiratory rate 18, and oxygen saturating 96 to 97% on room air. Musculoskeletal exam was positive for findings of tenderness over her anterior leg over the shin, tenderness on palpation across multiple joints. No obvious clubbing in her fingers was noted. She had swelling with mild synovitis across her wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, knees, ankle and metatarsophalangeal (MTP) and interphalangeal (IP) joints. The patient’s bloodwork showed elevated acute phase reactions, namely ESR at 39 and CRP at 11.2. She had a normal CBC with a white count of 9.5, hemoglobin 12.6 and platelets 323. Her albumin was 3.3, which is suppressed. Her kidney function was normal. She had mild elevation in procalcitonin at 0.68. Rheumatology was consulted with concern of inflammatory polyarthritis and patient was started on fentanyl for pain relief and Solumedrol. Subsequently joint aspiration of left knee was performed and joint fluid analysis revealed total neutrophil count (TNC) of 197, RBC 20353, neutrophils 30, lymphocyte 6, negative gram stain and culture, and no crystals. Negative


rheumatic factor 90%) are associated with pulmonary malignancies [6] or chronic suppurative pulmonary diseases. Pulmonary malignancies including primary [7], metastatic lung cancer, and intrathoracic lymphoma account for 80% cases of secondary HPOA. Adenocarcinoma of the lung is the most frequent and small cell carcinoma is the least frequently histopathological type of lung cancer associated with HPOA [7]. Other associated extra-thoracic malignancies include nasopharyngeal carcinoma, renal cell carcinoma, esophageal cancer, gastric tumor [8], pancreatic cancer, breast phylloids tumor [9], melanoma, thyroid cancer, osteosarcoma, and intestinal lymphoma. Various rheumatologic conditions including rheumatoid arthritis[10], ankylosing spondylitis[11],


polyartrtis nodosa, systemic lupus erythematous[12], takayasu disease[13], sarcoidosis, antiphospholipid syndrome, and Mediterranean fever are known to be associated with this condition as well. Other pulmonary conditions such as cystic fibrosis, tuberculosis, idiopathic pulmonary fibrosis [14] and lung transplantation have also been associated with HPOA. Other associated conditions include hepatic cholestatic disease, hepatopulmonary syndrome, cryptogenic cirrhosis, celiac disease, inflammatory bowel disease, cyanotic congenital disease, subacute bacterial endocarditis, and interstitial lung disease with right to left shunt. Regardless of the etiology clubbing is the commonest manifestation of this syndrome and periostitis is the hallmark of HPOA. Our case demonstrates the unusual presentation of HPOA without clubbing reported only in few case reports in the literature. Signs and symptoms of HPOA include asymptomatic disease or burning sensation of fingers and excruciating deep joint pain. Physical examination is particularly important to look for findings of clubbing and skin hypertrophy in primary HPOA, with coarse facial features and cylindrical soft tissue swelling of soft tissues of legs (elephant legs). Periostitis is a radiographic finding, which clinically manifest as tenderness on palpation of the involved anatomic area. Effusions of large joints are frequently observed and range of motions is slightly decreased [15]. Differentials for causes of periostitis are tumors, drug-related periostitis and periostitis related to chronic venous insufficiency and infection-related periostitis. There were no signs of underlying malignancy on imaging. The patient was not on any drugs that could cause periostitis such as variconazole, vitamin A, prostaglandins or fluoride. MRI and physical exam did show signs of edema but based on X-ray, but periostitis caused by chronic venous stasis would typically show a solid undulating reaction that is separated from the cortex. Periostitis can been seen in osteomyelitis but this patient’s MRI did not show signs of osteomyelitis. Bone Scintigraphy is the most sensitive test showing periosteal involvement. Characteristic findings on bone scan are bilateral symmetrical linear uptake of the tracer along the cortical margins of long bones which is also known as “Tram line” or “double stripe sign” [6,16] The pathophysiology of this condition demonstrates increased vascular permeability and stimulation of smooth muscle cells and fibroblasts. Exact mechanism of clubbing in HPOA is not known but several theories have been proposed. Dickinson and Martin proposed a Megakaryocyte-platelets clumping hypothesis stating that normally megakaryocyte and platelet usually gets destroyed in lung, any process that destroys the pulmonary vasculature, in turn leads to transfer of whole megakaryocyte and platelets clumps to gain access to the periphery where it releases the platelet-derived growth factor (PDGF), which is a general growth promoter leading to fibroblast proliferation [17].


Vascular endothelial growth factor (VEGF) is a cytokine induces vascular hyperplasia, new bone formation, and edema, has also been proposed to be involved in the pathogenesis [18]. Silveria studied 24 patients with HPOA and found an increased level of vascular endothelial growth factor in patients with primary and secondary HPOA due to lung cancer [19]. Olan and coworkers described a case of HPOA in a patient with lung cancer with high level of VEGF and a dramatic disappearance of skeletal abnormalities and a decrease level of VEGF after tumor removal [20]. Prostaglandin E also induces the periostitis, Lette and co-workers observed 5 infants developed limb pain and swelling associated with periostitis after chronic infusion of PGE for congenital ductal dependent heart disease [23]. The management of HPOA includes treatment of underlying condition. Pharmacologic therapy for HPOA includes traditional nonsteroidal anti-inflammatory drugs (NSAIDS), opiates, bisphosphonates, octreotide and palliative radiation.

Conclusion Hypertrophic pulmonary osteoarthropathy without clubbing is a rare entity. The importance of recognizing this condition cannot be overemphasized due to its association with various other conditions. Once diagnosed a prompt search of those conditions especially pulmonary malignancy should be conducted.


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