Rheumatology Advance Access originally published online on March 27, 2008
Rheumatology 2008 47(5):738-739; doi:10.1093/rheumatology/ken113
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Rituximab in rheumatoid arthritis following anti-TNF-associated tuberculosis
1Department of Rheumatology and 2Department of Infectious Diseases, Addenbrooke's Hospital, Cambridge, UK.
Correspondence to: M. L. Burr, Rheumatology Research Unit, Addenbrooke's Hospital, Box 194 E6, Hills Road, Cambridge CB2 2QQ, UK. E-mail: marianlburr{at}doctors.org.uk
SIR, The link between anti-TNF therapy and reactivation of latent tuberculosis (TB) is well recognized [1–3]. These patients are more likely to present with disseminated infection and this carries considerable mortality. Managing active RA in patients with anti-TNF-associated TB can therefore be challenging. We present the case of a patient with RA who was successfully treated with rituximab, a chimaeric anti-CD20 monoclonal antibody, after developing disseminated isoniazid-resistant TB following treatment with infliximab.
A 54-yr-old white female with a 15-yr history of severe erosive RA commenced treatment with infliximab in October 2002 with concomitant methotrexate (12.5 mg weekly) and prednisolone (10 mg daily). She had previously failed multiple DMARDs including SSZ, MTX and CsA. Her RF was negative; however, she was anti-CCP antibody positive.
She responded well to infliximab and her 28-joint disease activity score (DAS28) score fell from 6.93 to 3.83. She was maintained on treatment for 42 months; however, in April 2006, she reported 4 weeks of fever, night sweats and lethargy. CT of the chest, abdomen and pelvis revealed multiple small pulmonary nodules, left lower lobe lung opacities, a low attenuation liver lesion and heterogeneous attenuation in the spleen suggestive of granulomatous disease. Subsequent bronchoscopy confirmed abundant acid-fast bacilli on both bronchoalveolar lavage and transbronchial biopsy. Infliximab was stopped and treatment with ethambutol, rifampicin, pyrazinamide and isoniazid was commenced. Isoniazid was later switched to moxifloxacin after culture revealed an isoniazid-resistant strain of Mycobacterium tuberculosis. She was treated with an extended course of anti-tuberculous therapy that she completed in April 2007.
Her TB responded to treatment but she had a severe flare of arthritis 14 weeks after her last dose of infliximab. She was commenced on etanercept after 3 months of anti-tuberculous therapy; however, she failed to respond to this. She continued to deteriorate and by February 2007 her DAS28 score was 7.2. In view of the failure of anti-TNF therapy, she was treated with two doses of 1000 mg rituximab, plus 100 mg methylprednisolone as pre-medication, a fortnight apart and continued on MTX 12.5 mg weekly and prednisolone 10 mg daily. Twelve weeks later, she showed remarkable improvement with her DAS28 dropping to 4.9 and her global health score visual analogue scale (VAS) improving from 90 to 25. Her tender joint count decreased from 23 to 12 and her swollen joint count from 18 to 8; her CRP fell from 24 to 13 mg/l. She reported reduced fatigue and greatly increased mobility and was considering returning to work. Her response was maintained for 9 months at which point her arthritis flared. She was re-treated with a second course of rituximab in November 2007 to which her response was even more impressive. Two months later her DAS28 was 2.71 approximating disease remission by DAS28 criteria.
There have been several hundred reported cases of TB associated with anti-TNF therapy [1–3]. In the majority, TB was diagnosed within the first few months of treatment and was attributed to reactivation of latent infection. Our patient was unusual in having been on infliximab for over 3 yrs before symptoms developed, highlighting the need to remain vigilant even in patients well established on therapy. She had no known history of TB and her screening chest X-ray prior to commencing infliximab was normal. However, she subsequently recalled having had a positive tuberculin skin test 30 yrs previously, suggesting that her TB represented reactivation rather than primary infection.
When her RA flared following withdrawal of infliximab, therapeutic options were limited as there was considerable reluctance to use further anti-TNF therapy in a patient with drug-resistant disseminated TB. Etanercept was trialled as it has been associated with a lower incidence of TB, but this was ineffective [2]. In the presence of aggressive disease, severely impairing her quality of life, further therapy was clearly required and rituximab was the favoured option.
Rituximab has been shown to be effective in RA and is approved for patients with an inadequate response to TNF inhibitors [4–6]. It has greater efficacy in RF-positive patients, but interestingly our seronegative patient responded well (she was, however, anti-CCP antibody positive). The mechanism of action of rituximab does not raise the same theoretical concerns as TNF inhibition with respect to TB reactivation. To date there have been no reports of TB in RA patients treated with rituximab. Furthermore, data from extensive use in non-Hodgkins lymphoma suggest no increase in the risk of TB or other opportunistic infections [7]. Rituximab, therefore, has potential advantages over TNF-blockers in RA patients with recent TB; however, we are unaware of any previous accounts of its use in this setting. There is a single previous description of rituximab used safely in a patient with TB to treat SLE-associated immune thrombocytopenic purpura [8].
In summary, we report the first use of B cell depleting therapy in an RA patient who had developed TB whilst under treatment with anti-TNF. This case demonstrates the safety and efficacy of rituximab in this setting.
Disclosure statement: A.J.K.Ö. has acted as a consultant and has received travel bursaries and honoraria from Abbott, Schering-Plough, Wyeth, Roche and Bristol-Myers Squibb Pharmaceuticals. All other authors have declared no conflicts of interest.
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