Rheumatology Unit, Hôtel-Dieu, CHU Nantes, 44093, Nantes Cedex, France
SIR, A 50-yr-old male patient who had had seropositive [rheumatoid factor (RF) and antiperinuclear factor] and erosive rheumatoid arthritis (RA) for 12 yr was seen in September 1999. He fulfilled all seven of the 1987 American College of Rheumatology (ACR) criteria for this disease, including rheumatoid nodules, but no other extra-articular features (no sign suggestive of rheumatoid vasculitis). RA had remained active since its onset, despite treatment with a combination of low-dose steroids (815 mg/day of prednisone) and most disease-modifying anti-rheumatic drugs: injectable gold salts, d-penicillamine, tiopronin, sulphasalazine, methotrexate, hydroxychloroquine, azathioprine, cyclosporin and even a short (3 months) trial of chlorambucil. In September 1999, RA was still very active, with a disease activity score (DAS-28) of up to 6.8 (15 out of 28 joints painful, 12 out of 28 swollen, erythrocyte sedimentation rate 74 mm in 1st h). The haemoglobin level was 111 g/l, white blood count 10.4x109/l (including 8.1x109 polymorphonuclear leucocytes/l) and platelet count 452x109/l. The patient had not been tested for antineutrophil cytoplasmic antibodies (ANCA). The latest RF titres available were 160 IU/ml in the latex test (normal range 025) and 128 IU/ml in the WaalerRose test (normal range 012). On 1 September 1999, the patient gave informed consent to treatment with subcutaneous injections of etanercept (Enbrel; 25 mg twice weekly) [1]. At that time, and during the 4 months of treatment with etanercept, he was free of fever or other extra-articular signs (including features suggestive of rheumatoid vasculitis). There were no reactions to these injections, whether local or systemic. Unfortunately, improvement of RA was only modest (DAS-28 values after 1, 2, 3 and 4 months of treatment were 5.6, 5.4, 6.05 and 5.8 respectively). In December 1999, the patient considered that improvement was very slight and his condition more painful despite the replacement of fentanyl with hydromorphone. Both patient and physician decided to stop etanercept, but to continue steroids at the same dose. As before, the patient was still free of fever or other extra-articular symptoms, except chronic fatigue and a discrete sore throat. His muscles were not tender or weak, and neurological examination was normal. A short course of minocycline (Minolis-Gé; 100 mg/day) was administered on the basis of the favourable response of some RA patients to this treatment [24].
Ten days after the introduction of minocycline and 3 weeks after discontinuance of etanercept, the patient's general condition worsened dramatically, with fever (3839°C), progressive major asthenia, transient confusion, discrete bilateral pleural effusion and epigastric pain. Minocycline was stopped and the patient was admitted to hospital. Biological studies were normal (including renal and hepatic function), except for profound hypoalbuminaemia (17.2 g/l) and blood count abnormalities. The only apparent explanation for hyperleucocytosis (24x109/ml), thrombocytosis (800x109/ml) and frank anaemia (6.4 g haemoglobin/100 ml) was inflammation [C-reactive protein (CRP) concentration 179295 mg/l]. No schizocytosis or bleeding was observed. The Coombs test was positive with anti-C3 d antiglobulin but not with anti-immunoglobulin G (IgG) antiglobulin. As overt haemolysis was not observed (the haptoglobin level remained within the normal range), anaemia was treated by transfusion. The osteomedullary biopsy was normal. There was no evidence of disseminated intravascular coagulation. CRP and leucocytosis values remained within the same range throughout follow-up. Immunological testing was negative for anti-nuclear antibodies and anti-phospholipid antibodies, and only slightly positive for ANCA [1/20, with negative ELISA (enzyme-linked immunosorbent assay) tests for anti-myeloperoxidase and anti-proteinase 3 antibodies]. Conversely, testing for RF showed high concentrations both for human and animal IgG (more than 40 times the upper normal value). An extensive search for sepsis was unsuccessful (including swab, stool, urine and broncholavage cultures, haemocultures and myelocultures, which remained negative for mycobacteria or other organisms after 3 months). Echocardiogram and abdominal ultrasound were considered normal, as was an abdominal CT scan. Fever did not respond consistently to antibiotics (i.v. ceftriaxone and ofloxacin for 15 days followed by sulfamethoxazoletrimethoprime for 8 days) or antifungals [amphotericin B (Fungizone)], despite positive serology for candidosis and discrete development of Candida tropicalis in urine cultures and C. albicans in spur cultures. Screening for viral infection or reactivation also remained negative, including serology for herpes viruses that had tested frankly positive 4 yr previously. The patient's diffuse weakness could not be ascribed to a disorder of the nervous system (MRI, cerebrospinal fluid examination and cultures were normal). However, as electromyography suggested a combination of peripheral neuropathy and a myositis process, testing for muscle enzymes was performed several times. The patient complained of chest pain, although no changes were noted in the electrocardiogram. The chest pain was treated with Calciparin (heparin) after ventilationperfusion scintigraphy had suggested pulmonary embolism. The results of these tests were disturbing. Creatine phosphokinase was normal in each test (0.18 mkat; normal range 0.03.15), but values for myoglobin (4200 mg/l; normal range 0.070) (ELISA; Beckman-Coulter, Fullerton, CA, USA) and troponin (0.63 mg/l; normal range 0.00.05) (AxSym test; Abbott Laboratories, Abbott Park, IL, USA) were very high. Both of these tests use monoclonal mouse antibodies as reagents, whereas other kits that do not use rodent antibodies gave normal results for myoglobin [immunoturbidimetry: Hitachi (Roche Diagnostics, Mannheim, Germany), Intégra (Roche), Turbidimeter (Dade Behring, Newark, DE, USA); immuno-enzymo-fluorescence: AxSym, Abbott Laboratories] or troponin [Stratus CS and Opus systems (Dade Behring), ACS 180 system (Bayer Diagnostics, East Walpole, MA, USA), Elecsys system (Roche)]. A muscle biopsy showed no evidence of myositis, but some indications of segmental necrotizing arteritis were found in medium vessel joints (mainly) and some small vessels.
The steroid dose had been kept as low as 10 mg prednisone until this time, as the possibility of an opportunistic or crippling infection due to mycobacteria or other intracellular bacteria had not been ruled out completely. The prednisone dose was then raised to 30 mg/day, but the patient's condition worsened. Another embolic episode was strongly suspected, and the patient experienced fibrinolysis in the cardiology intensive care unit. Despite this treatment and transient improvement, the patient died in March 2000, 3 months after discontinuance of etanercept and 2 months after the 10-day minocycline treatment. An autopsy was performed, which showed no infection, especially in the lungs, pleurae and gallbladder. The gross anatomy (including the heart) was not suggestive of infarction; only signs of chronic and ongoing pericarditis and pleuritis were noted, and there was a thrombus at the vena cava entry into the right atrium. However, microscopy confirmed severe plurivisceral vasculitis, especially in the heart and gall bladder. The pattern was typical of granulomatous, necrotizing panarteritis, involving the medium vessels (mainly) and the adventitium of arterioles but not the veins. The arteritis lesions appeared to be old at some points (collagen fibrosis within the media) and recent at others. Myocarditis was also observed, but ischaemic lesions were mild and rare, despite the severity of vasculitis.
There is no certainty that this patient's death was due to a single cause. First, an undiagnosed rheumatoid vasculitis could have antedated by several months or years the dramatic worsening of his condition. This was suggested by the observations at autopsy showing both old and recent vasculitis lesions. In fact, rheumatoid vasculitis can occur without any suggestive clinical signs, i.e. in patients without general signs, distal necrosis, nerve palsy or muscle pain [5]. Although flares of rheumatoid vasculitis have not been reported so long after the withdrawal of etanercept therapy (rebound effect), they have been observed after the discontinuation of other drugs, such as methotrexate [6]. Secondly, as false-positive results for troponin have already been reported with the AxSym kit, which uses mouse antibodies, it is possible that our patient had RF against mouse IgG (human anti-chimeric antibodies), which could be responsible for the false-positive results in ELISA tests [78]. Such antibodies might also have worsened an underlying rheumatoid vasculitis. Thirdly, although leucocytoclastic vasculitis has been described recently with etanercept [9], the patient's condition worsened 10 days after the introduction of minocycline, which could also been a precipitating factor [10]. However, ANCA were only slightly positive, and the medium vessels were much more involved than small vessels.
Despite many uncertainties, this case is instructive. Indeed, our patient presented with spiking fever of rapid onset and chronic hyperleucocytosis. This condition led to a thorough search for deep sepsis and subsequent trials of antibiotics and antifungals for several days, which further delayed the introduction of immunosuppressive therapy. Physicians treating RA patients with new immunosuppressive drugs, such as anti-tumour necrosis factor (anti-TNF), should consider the possibility that severe vasculitis could be masked by these symptoms. Indeed, severe vasculitis requires treatment quite different from that used for occult sepsis, which is usually considered as the main safety issue for anti-TNF.
Notes
Correspondence to: J.-M. Berthelot, Service de Rhumatologie, Hôtel-Dieu, CHU Nantes, 44093, Nantes Cedex, France.
References
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