Voriconazole-induced arthritis,enthesitis and periostitis

Abstract

Voriconazole is a fluoride-containing anti-fungal. Prolonged exposure can result in fluoride deposition within the bone extracellular matrix, resulting in periostitis and arthritis. We report a patient who developed widespread bony pain and polyarthralgia while on voriconazole therapy for COVID-19-associated pulmonary aspergillosis. No associated autoimmune rheumatic disease or alternative cause was noted. Blood investigations showed elevated total serum alkaline phosphatase, bone-specific ALP and fluoride levels, with normal serum voriconazole levels. A whole body nuclear bone scan showed multifocal periostitis. A diagnosis of voriconazole-induced periostitis and arthritis was made. Complete resolution of clinical symptoms with normalisation of the serum ALP occurred within four weeks of voriconazole cessation. While voriconazole-induced periostitis/arthritis is a recognised phenomenon in solid organ and haematopoietic stem cell transplant patients on long-term voriconazole, this case highlights the importance of having a high index of suspicion in other settings including CAPA. Clinical presentation can be mistaken for bony metastatic disease or other inflammatory arthritis.

Introduction

Voriconazole is used for invasive aspergillosis, both as treatment and prophylaxis against this organism in solid organ and haematopoietic stem cell transplant (HSCT) patients. ¹ Voriconazole contains fluoride which can be deposited within the bony matrix causing musculoskeletal symptoms. We report a case of voriconazole-induced polyarthritis, enthesitis and periostitis in a patient with COVID-19-associated pulmonary aspergillosis (CAPA) requiring prolonged voriconazole therapy, with complete symptom resolution upon voriconazole discontinuation.

Case report

A gentleman in his early 60s, unvaccinated against COVID-19 with underlying diabetes mellitus and hypertension had a five-month hospitalisation for COVID-19 infection. He presented with severe COVID-19 pneumonitis requiring intubation, renal replacement therapy and inotropic support. He received remdesivir, intravenous dexamethasone and baricitinib and subsequently had tracheostomy after four weeks of intubation. At seven weeks following admission, he developed CAPA. His computed tomography (CT) chest demonstrated multiple cavitating lesions bilaterally up to 32 mm in diameter with Aspergillus fumigatus complex isolated from bronchoalveolar lavage. He was commenced on anidulafungin and oral voriconazole 300 mg twice daily. Anidulafungin was ceased once therapeutic voriconazole levels were reached, with serial voriconazole trough levels maintained within the therapeutic range. Additionally, his admission was further complicated by deep vein thrombosis, staphylococcal sepsis, critical illness polyneuropathy, pneumomediastinum and ventilator associated pneumonia. Voriconazole therapy led to clinical improvement and radiological resolution of the cavitary lesions, and he was transferred to general ward for rehabilitation.

He was first noted to have bilateral shoulder pain and a restricted range of motion eight weeks after starting voriconazole. His symptoms progressed over the next two weeks by which time, he complained of significant generalised polyarthralgia. Examination showed no joint swelling, however, there was marked tenderness over bilateral shoulders, elbows, wrists and multiple entheseal points with near global restriction of movement due to severe pain.

Blood investigations at the time of musculoskeletal symptom onset showed raised inflammatory markers, with a C-reactive protein (CRP) of 31 mg/L (normal, <5 mg/L) and a negative immunology panel including antinuclear antibody, rheumatoid factor, anti-cyclic citrullinated peptide and human leukocyte antigen (HLA-B27). The serum alkaline phosphatase (ALP) was elevated at 184 U/L (normal, 40–120 IU/L), with a high bone-specific ALP of 31.9 μg/L (normal, 5.5–24.6 μg/L).

Musculoskeletal ultrasound showed evidence of tendinopathy affecting bilateral supraspinatus and right subscapularis tendons without any glenohumeral effusion. There was sonographic evidence of synovitis involving bilateral elbows and wrists with associated extensor tendons tenosynovitis. Whole body Technetium^99m bone scan revealed osteoblastic activity affecting bilateral shoulders, wrists, small hand joints and ankles suggestive of inflammatory polyarthritis, multiple areas of enthesopathies, osteitis involving the right iliac wing, bilateral greater trochanters, multiple ribs, right humerus and presence of periosteal reaction (Figure 1). The serum fluoride level was elevated at 10 μmol/L (normal, 0.3–2.2 μmol/L) with a normal voriconazole serum trough level of 3.4 mg/dL (normal, 1–5.5 mg/L).

Figure 1.

Whole body Technetium^99m bone scan demonstrating osteoblastic activity affecting bilateral shoulders, wrists, small hand joints and ankles suggestive of inflammatory polyarthritis. Multiple areas of enthesopathy/osteitis involving the right iliac wing, bilateral greater trochanters, multiple ribs and uptake in the right humerus with periosteal reaction.

A diagnosis of voriconazole-induced arthritis, enthesitis and periostitis was made. Voriconazole was discontinued after total three months of therapy. Despite discontinuation of voriconazole for two weeks, the patient still reported significant pain even with standard analgesia. Hence, prednisolone in tapering doses (starting at 15 mg daily) was administered over six weeks with a good response. His inflammatory markers and serum ALP also normalised without recurrence of the symptoms.

Discussion

Voriconazole is a trifluorinated compound (usual maintenance dose of 400 mg per day) that contains 65 mg of fluoride.^1,2 Major side effects include hepatotoxicity, cutaneous lesions (rashes, Stevens-Johnson syndrome, photosensitivity, carcinogenesis), cardiac arrhythmias (prolonged QT interval), transient visual impairment, peripheral neuropathy and electrolyte derangements (hyponatremia, hyperkalaemia). ¹

An uncommon adverse effect of voriconazole is periostitis as a consequence of fluoride accumulation in the bone matrix, especially in patients who have taken the drug for a long time or at a high dose. ¹

Fluoride is found throughout the body, with the majority being stored in calcium-rich bone and teeth. Hydroxyapatite is the major constituent of the inorganic elements of the bone extracellular matrix. Excess fluoride can form fluorapatite in the extracellular matrix making it more resistant to resorption and enhancing bone density.^3–6 This in turn causes osteosclerosis which is characterised by bone brittleness, decreased mechanical competence and increased fracture susceptibility.^3–6

Fluorapatite also induces disordered osteoblastic activity which causes periostitis, exostoses, osteosclerosis, and osteophytes at tendon, fascial and muscle insertions resulting in musculoskeletal manifestations. A fluoride-independent mechanism that upregulates cytokine expression especially vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which in turn increases osteoblast activity has also been proposed. ⁷ The osteoblastic activity is reflected by an increase in serum ALP and can be demonstrated with a nuclear bone scan.^3–6

Wermers et al. ² evaluated plasma fluoride levels in 10 post-transplant patients who took voriconazole for at least six months at a dose of 400 mg daily. All of them had elevated serum fluoride levels. Painful periostitis was observed in five (50%) of them, while two (20%) had numerous exostoses. Cessation of voriconazole led to pain relief and decreased serum ALP and fluoride levels. ²

Musculoskeletal symptoms can manifest on average six months to three years after treatment begins. However, some patients may become symptomatic as early as six weeks and as late as eight years. ² In this patient, symptoms were first noted after eight weeks.

There is a predilection for the involvement of the appendicular skeleton (shoulder girdle bones, pelvis bones, upper limbs and lower limbs). ⁸ The ribs are commonly affected, ⁶ while bony changes can be unilateral, bilateral, or more commonly in multiple sites ⁸ mimicking bony metastases which can be challenging. The multifocal periosteal reaction has also been reported in other conditions including hypertrophic osteoarthropathy, venous stasis, thyroid acropachy and hypervitaminosis A. ⁴

Clinical symptoms include diffuse bony pain, with or without clinical tenderness, myalgia, polyarthralgia, enthesitis, capsulitis and arthritis. Some patients may have palpable bone overgrowths and nodules.^2,9 The musculoskeletal pain can be intense, with a lack of response to analgesics and corticosteroids due to the non-inflammatory aetiology. ¹⁰

Blood investigations show elevated total serum ALP with high fractionated bone-specific ALP, while voriconazole troughs are often within the normal range. In documented cases, serum ALP levels vary from 111 to 1000 IU/L, ¹¹ and serum fluoride levels vary from 7.5 to 27 μmol/L.^11,12

Plasma fluoride levels above 8 μmol/L are 95% sensitive and 100% specific for voriconazole-induced periostitis. ⁸ However, elevated serum fluoride should not be regarded as necessary for the diagnosis as some patients may have a normal or even a low serum fluoride level.

Plain x-rays may demonstrate periosteal reaction with elevation and thickening over the affected bones and can cause dense, heterogeneous, regular or asymmetrical changes. ² Enthesopathy abnormalities can also be seen.

The Technetium^99m nuclear bone scan is the imaging modality of choice especially in patients with normal radiographic findings. It demonstrates multifocal high radiotracer uptake in areas of increased osteoblastic activity which can be a linear, non-contiguous or focal pattern and is sensitive to periosteal response. ⁴ Other advanced imaging modalities including single photon emission computed tomography/computed tomography (SPECT/CT) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) have also been reported. ⁴

Voriconazole-induced periostitis has a good outcome and resolves after drug withdrawal, though reduction of voriconazole dose may lead to symptom resolution. Moon et al. found that dose reduction or withdrawal improved symptoms in 89% of 19 patients with voriconazole-induced periostitis. ⁸ Clinical improvement was seen as early as 2–5 days and at an average of two weeks to four months later. ⁸ Similarly, serum ALP levels and radiologic findings generally normalise within three to four months. ⁴ Wang et al. demonstrated significant radiological improvement in two patients with follow-up whole body nuclear bone scans; one at two months and the other at six months following voriconazole withdrawal. ¹³

In patients requiring ongoing anti-fungal therapy, alternative agents like itraconazole, posaconazole or isavuconazole can be used, as they do not affect serum fluoride levels or cause periostitis. ¹⁰

Lastly, an important differential diagnosis in this patient would be post COVID-19 reactive arthritis which generally occurs one to seven weeks post infection and commonly presents as predominant lower limb large joint oligoarthritis. However, the involvement of upper limb joints, sacroilitis, enthesitis, dactylitis and tenosynovitis have also been reported. ¹⁴ Patients may also test positive for HLA-B27, and the overall prognosis is good with expected complete recovery with supportive therapy, non-steroidal anti-inflammatory drugs (NSAIDs), systemic or intraarticular glucocorticoids within several weeks. ¹⁴

The constellation of widespread pain, polyarthritis with upper limb predominance occurring eight weeks while on voriconazole and nearly 16 weeks after initial COVID-19 infection, presence of periostitis and raised serum ALP and fluoride support the diagnosis of voriconazole-induced musculoskeletal event instead of post COVID-19 reactive arthritis.

Conclusion

Prolonged exposure to voriconazole can cause arthritis, enthesitis and periostitis due to the deposition of fluoride within the bony matrix. This is clinically characterised by elevated serum ALP levels, with or without elevated plasma fluoride levels and radiological periostitis. Overall, it carries a good prognosis with clinical improvement upon voriconazole cessation and normalisation of serum ALP levels and even radiological resolution. Clinicians outside the setting of haematological and solid organ transplants should remain vigilant regarding the possibility of this condition, including patients with CAPA requiring long-term voriconazole.