Voriconazole-associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature.

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and osseous tissue frequently associated with underlying pulmonary disorders. Cardinal features include digital clubbing, periostitis and significant joint and bone pain. A number of recent reports have emerged of HOA and periostitis occurring in association with the antifungal agent voriconazole. METHODS: We present two additional cases of voriconazole-induced HOA and periostitis in lung transplant recipients with a review the medical literature. RESULTS: In both cases, symptoms were painful and severe enough to require opioid medication. Rapid improvement occurred within days of voriconazole cessation. A review of existing literature revealed an additional 17 cases of voriconazole-induced HOA and periostitis in lung transplant patients. CONCLUSION: We highlight the importance of recognizing the association of voriconazole with painful HOA and periostitis in lung transplant patients receiving antifungal therapy. Management of this painful condition involves cessation of voriconazole therapy, which may necessitate alternative anti-fungal drug therapies as well as adjustment of immunosuppressive drug dosage since voriconazole is a strong drug-inducer.

An unusual side effect of interferon alfa 2A: digital clubbing.

Interferon Alfa has been widely used to treat chronic hepatitis C virus infection. In this report, we present a case series of two patients referred to Sarwar Zuberi Liver Centre, Civil Hospital Karachi, who suffered from chronic hepatitis C. After getting detailed clinical examination and baseline work up prior to starting treatment, these patients were offered therapy with usual recommended dose of 3 million units of alpha-interferon subcutaneously thrice weekly. Both these patients developed clubbing of fingers during the course of treatment, one developing it during the 2nd month while the other during the 4th month. It was of grade II in one patient and of grade III in another and was bilateral in both the cases. Clubbing was not presented prior to start of treatment and no other secondary cause of clubbing was found in any of the case. These patients were not on any other drug that is known to interfere with interferon or can be associated with clubbing. No national or international data regarding such unusual side effect is available. Whether this effect is idiosyncratic or dose related and whether it is reversible or not after completion of treatment is yet to be established.

Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy.

BACKGROUND: Leflunomide (LEF) is indicated in adults for the treatment of active rheumatoid arthritis (RA). LEF inhibits dehydroorotate dehydrogenase, a key enzyme of the pyrimidine synthesis in activated lymphocytes. Among rare adverse effects, fatal interstitial lung disease has been recently reported during treatment of RA with LEF in Japan. Clinical trials outside Japan do not suggest that LEF causes an excess of pulmonary adverse effects. Development and increase of peripheral rheumatoid nodules in typical sites of RA patients following LEF therapy has been recently reported. OBJECTIVES: Two cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study. METHODS: LEF treatment was administered to two male patients (77 and 66 years old) with long-standing active seropositive nodular RA with failure of multiple second line drugs and without lung involvement. Clinical and laboratory assessment using the American College of Rheumatology response criteria, chest computed tomography (CT), quantification of serum rheumatoid factor (RF), and monocyte count of peripheral blood along with routine laboratory follow up were performed on both patients before and during therapy. In case 1, a bone scan was performed due to sustained limbs pain. Open lung biopsy was performed in case 1 and core lung biopsy in case 2. RESULTS: Both patients achieved full clinical remission during 2 months of LEF therapy. In case 1, the first complaints were limbs pain after 10 months of treatment associated with intensive bone uptake on a bone scan consistent with hypertrophic pulmonary osteopathy. Productive cough developed after 3 months of the therapy in case 2. Initially, these complaints were not attributed to therapy. New lung disease was present on CT with cherry-like progressive cavitary nodules, predominantly involving the basal segments of the right lung. The first lung lesions were found by CT 13 months (case 1) and 7 months (case 2) after the beginning of therapy and were erroneously related to bronchiectasia in case 2. In both cases, the lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid lung node. The time that elapsed between the beginning of the first symptoms to LEF discontinuation was very long: 13 months in case 1 and 24 months in case 2. Discontinuation of LEF therapy was followed by an arrest in growth of lung nodules, resolution of limb pain, and gradual improvement of bone scan. A significant decrease of monocyte count and RF level in peripheral blood was observed during LEF therapy in both cases. CONCLUSION: For the first time, we described rheumatoid lung nodulosis as complication of successful LEF therapy for RA. Hypertrophic pulmonary osteopathy with severe limbs pain and dry cough were the first manifestations of the lung nodulosis. Monocytopenia during LEF therapy is proposed to be involved in pathogenesis of this rare complication of LEF therapy.

Hypertrophic osteopathy in rats following chronic administration of SDZ MNS 949, an isoquinoline.

SDZ MNS 949, 6,7-dimethoxy-3-methyl-1-(3',5'-bis (methoxyethoxy) phenyl)-isoquinoline, a bronchodilating anti-inflammatory drug that inhibits phosphodiesterase, had been proposed for the treatment of bronchial asthma. Groups of 14 male and 14 female Wistar rats were administered doses of 12, 50, and 130 mg/kg/day in feed for 26 weeks. Periodic radiographic examinations were performed in addition to clinical observations, clinical chemistry measurements and urinalysis. At study termination full necropsy and histopathological examinations were performed on all animals. The principal clinical signs observed were unilateral edematous, red and painful swelling of the distal hindlimbs in 8 of 28 high dose animals, and abdominal swelling in 19 of 28 high dose animals. At radiographic examination periosteal new bone formation was predominantly along the tibia. Lesions at necropsy included dilated small and large intestines. Microscopically, enteritis was observed, and the periosteal new bone formation was confirmed. Hematological findings consisted of thrombocytosis and lymphocytosis, especially in high dose animals. The clinical, radiographical and histological findings in treated rats were consistent with the diagnosis of "hypertrophic osteopathy" or "Marie's Disease".

Hypertrophic osteoarthropathy caused by PGE1 in a patient with congestive heart failure during cardiac rehabilitation.

Continuous chronic drug infusion with PGE1 via a portable pump and neuromuscular electrical stimulation (NMES) help to improve the quality of life in patients with severe chronic heart failure waiting for a donor heart, as both treatments can be performed at home. We report a 56-year-old woman suffering from severe chronic heart failure, who was referred for a cardiac rehabilitation program because of progressive muscle weakness and weight loss. Due to her underlying heart disease she was unable to perform voluntary exercise. NMES of both knee extensor muscles was started. Under simultaneous chronic drug infusion with PGE1 via a portable pump the patient developed clinical signs of hypertrophic osteoarthropathy, which prevented her from continuing the rehabilitation program. X-ray examinations and bone scans concurred with the diagnosis of secondary hypertrophic osteoarthropathy. After the PGE1 dose had been reduced, the clinical signs of the osteoarthropathy resolved and the patient was able to continue the rehabilitation program with no difficulty. This case report underlines the importance of being aware of the potential side effects of modern cardiac drugs in the complex treatment of patients waiting for a donor heart.

Finger clubbing in match factory workers in Fiji.

This communication reports of two cases of digital clubbing in a factory manufacturing matches in Vitilevu, Fiji Islands. Both these cases were occupationally exposed to chemicals used in the manufacture of matches. They had physical contact with these chemicals including rhodamine B dye. Subjects who worked in the same factory area, including one worker who had FEV1.0 and FVC values below the predicted normal, but who did not handle chemicals showed no evidence of finger clubbing.

Clubbing and hypertrophic osteoarthropathy in two patients taking long-term bevacizumab for metastatic colorectal cancer.

INTRODUCTION: The authors report two cases of young patients who developed clubbing and hypertrophic osteoarthropathy in one case or lung diffusion disorder in the second, after a long-term use of bevacizumab plus chemotherapy in a palliative setting of metastatic colorectal cancer. DISCUSSION: We propose that patients on long-term bevacizumab be examined for clubbing and undergo respiratory function tests and that this would be studied prospectively before beginning trials in evaluating this monoclonal antibody given for 2 years in an adjuvant setting.

Finger clubbing associated with laxative abuse.

We have added two cases of finger clubbing in laxative-abusing patients to the four other cases recorded in the literature. Laxative abuse should be added to the already long list of diseases in which clubbing may appear. The pathophysiologic basis of clubbing is still obscure.

Purgative abuse associated with reversible cachexia, hypogammaglobulinaemia, and finger clubbing.

Laxative abuse may cause systemic and metabolic changes, but cachexia has not been reported as a predominant feature. A patient with finger clubbing and extreme wasting recovered when senna intake was stopped and nutritional care provided. A diagnosis had been made of acquired common variable hypogammaglobulinaemia with absence of circulating B lymphocytes. The immunological abnormalities were corrected after senna intake was stopped and lean body mass restored.

Finger clubbing and aspartylglucosamine excretion in a laxative-abusing patient.

A young woman with a previous history of anorexia nervosa presented with severe finger clubbing. Urine samples intermittently contained significant amounts of aspartylglucosamine. Liver biopsy showed abnormal cytoplasmic inclusions in phagocytic cells. The patient was found to be abusing senna laxative.

Malignant sacrococcygeal germ cell tumour in an adult.

In adults, malignant sacrococcygeal germ cell tumour is a rare cause for a presacral tumour, with only 17 cases having been reported in the literature since 1907. We report the case of a 34 year old male who presented with a 6 month history of symptoms relating to a malignant presacral tumour which required en bloc excision including the lower sacrum and rectum. He died with lung and mediastinal metastasis 7 months following surgical excision and adjuvant chemotherapy using Cisplatin, Bleomycin and Etoposide. Prior to his death, he had a severe polyarthritis of his peripheral joints and evidence of hypertrophic osteo-arthropathy. The literature indicates that adults with these tumours have a poor prognosis, with only one reported long-term survivor. Surgical excision offers the only chance of cure, with the role of adjuvant therapy not having been defined because of the small numbers.