Acute monoarthritis complicating therapy with indinavir

HIV disease is complicated by rheumatological disorders related to the viral infection, opportunistic infections, the immune phenomenon and drug therapy [1]. Complex HIV drug treatments may create further rheumatological problems. Previous reports have described gout associated with ritonavir/didanosine treatment [2] and arthralgias with rifabutin therapy [3]. Although indinavir is associated with enthesopathies, arthralgias [4], and adhesive capsulitis [5], it has not been reported as a cause of arthritis. We report the case of a man with AIDS, without a previous history of rheumatological disease, who developed acute monoarthritis 6 weeks after starting an antiretroviral regimen that included indinavir. A 37-year-old man with advanced HIV disease (CD4 cell count 46 cells/mm3, viral load > 800 000 copies/ml) presented with a 4 day history of pain, tenderness and swelling of the left knee 6 weeks after starting indinavir 800 mg every 8 h, stavudine 40 mg twice a day, and lamivudine 150 mg twice a day. There were no symptoms suggesting an antecedent or concurrent viral illnesses. He had no complaints of skin rash, psoriasis, urethritis, diarrhoea, conjunctivitis, dactylitis, enthesitis or inflammatory type low back pain. He was hepatitis B immune and hepatitis C seronegative. There was no personal or family history of rheumatic disorders. On examination his temperature was 38.3°C. The knee was warm, swollen, and tender without erythema. The joint had a large effusion and a limited range of movement. There were no ocular findings, genital lesions, new skin lesions or other involved joints. The blood leukocyte count was 6.5 × 109/l. Serum urate was 440 μmol/l (normal 210–450). Plain X-rays of the knee showed only evidence of an effusion. The synovial fluid was yellow and cloudy with a leukocyte count of 5.0 × 109 cells/l (94% neutrophils). Gram stain and culture for bacteria and fungus were negative. Special stain and culture for mycobacteria were negative. No urate or pyrophosphate crystals were identified by repeated polarized light microscopy. An indinavir concentration of 1.36 μg/ml (2215 nM) was measured in the knee by high performance liquid chromatography. Electron microscopy did not demonstrate crystals. Repeated knee aspirations, rehydration and treatment with indomethacin resulted in complete resolution of the symptoms in 4 days. A magnetic resonance imaging and bone scan performed 3 weeks after the event were normal. It is possible that the acute monoarthritis was secondary to indinavir deposition within the knee joint. Indinavir crystallizes within the kidney [6] and may accumulate elsewhere under similar conditions. Synovial fluid is an ultrafiltrate of serum that is similar to glomerular filtrate [7]. The entry of small molecules into synovial fluid (< 10 000 Mr) is limited by diffusion through the interstitial spaces between synovial cells, whereas the entry of larger molecules, such as proteins, is limited by the fenestrations in the capillary endothelium [8]. Other small molecules have been shown to be far less soluble in the protein-deficient synovial fluid than in plasma [9]. Furthermore, certain non-steroidal anti-inflammatory drugs have been shown to persist in synovial fluid at higher levels and for a prolonged period of time when compared with plasma [7]. Factors favouring drug deposition within the synovial fluid, such as reduced solubility and sustained levels, may have precipitated indinavir deposition. The level of indinavir measured in the synovial fluid from this patient's knee was 1.36 μg/ml, a level within the serum range for total drug (0.154–7.74 μg/ml). Indinavir base solubility is poor in water, varies inversely with pH, and is reported as being 30 μg/ml at pH 6 [10]. The pH of synovial fluid is rarely less than 7.0 [7]. Therefore, at the pH within the knee joint, indinavir solubility would be less than 30 μg/ml. In the setting of gout, intra-articular crystal formation occurs with urate concentrations that are an order of magnitude lower than those required for crystal formation in vitro[11]. It is thus plausible, analogous to urate crystal formation, that the conditions of higher pH and lower protein found within the synovial fluid would favour indinavir deposition. In our patient, laboratory investigations failed to demonstrate a bacterial, fungal or crystal-induced cause of the arthritis. Complete resolution of the symptoms without specific therapy argues against mycobacterial infection. There were no symptoms or signs of Reiter's syndrome. The acute monoarticular, inflammatory nature of the illness and the rapid response to non-steroidal anti-inflammatory drugs would argue against AIDS-associated reactive arthritis [12]. Heating during sample preparation may account for the failure to demonstrate indinavir crystals by electron microscopy. This is the first time that intra-articular indinavir levels have been reported. We describe features of synovial physiology that may decrease indinavir solubility. The temporal relationship to indinavir therapy, improvement with hydration, and the absence of another demonstrable aetiology, suggests that indinavir deposition within the joint resulted in monoarthritis. Acknowledgements The authors are grateful to Dr J. Karsh for his insightful review of the manuscript. James I. Brooks Keith Gallicano Gary Garber Jonathan B. Angel

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