Rheumatology Advance Access originally published online on April 16, 2008
Rheumatology 2008 47(6):932-933; doi:10.1093/rheumatology/ken143
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Efficacy and safety of rituximab in a patient with active rheumatoid arthritis and chronic disseminated pulmonary aspergillosis and history of tuberculosis
Department of Internal Medicine I, Division of Immunology and Rheumatology, University of Cologne, Cologne, Germany.
Correspondence to: N. Jung, Department of Internal Medicine I, Division of Immunology and Rheumatology, University of Cologne, Kerpener Str. 62, 50935 Cologne, Germany. E-mail: norma.jung{at}uni-koeln.de
SIR, In RA, the rate of infections and infection-related mortality is up to 4 to 6 times higher as compared with the general population [1] and an increased risk has been associated in particular with the use of steroids [2] and TNF inhibitors [3]. Therefore, treatment of RA in patients with underlying chronic infections represents a challenge given that therapeutic options are limited.
We here report on a patient with active RA, who developed tuberculosis during treatment with steroids and MTX, followed by chronic disseminated pulmonary aspergillosis as a secondary complication. Rituximab, a chimeric monoclonal antibody directed against CD20, was applied as monotherapy and led to a long-lasting improvement of signs and symptoms of RA. During a follow-up period of 15 months there was no evidence for progression of pulmonary disease.
A 63-yr-old Caucasian woman presented to our clinic with active seropositive RA from which she had been suffering for >10 yrs. Initial therapies including gold, chloroquine, SSZ and AZA proved ineffective. In 1995, treatment with oral MTX (15 mg once weekly) was initiated but was stopped when active pulmonary tuberculosis was diagnosed. Quadruple tuberculostatic therapy was administered, upon which the patient improved. Upon aggravation of RA symptoms, low-dose steroids were restarted. Ten months later, the patient presented with cough, spiking fever and increasing dyspnoea. An X-ray and computer scan (CT) were carried out and revealed a single, contrast-enhancing peripheral lesion within the right upper lobe, consistent with the diagnosis of an aspergilloma inhabiting a pulmonary cavity (Fig. 1). Moreover, a fine, interstitial bilateral shadowing was noted suggesting accompanying disseminated aspergillosis. The patient was started on amphotericin, and then switched to liposomal amphotericin, but this medication had to be discontinued when kidney function deteriorated. The patient then received a 4-week course of intravenous voriconazole, which was well tolerated and followed by surgical lobectomy of the right upper lung. Diagnosis of aspergillosis was confirmed histologically. The patient recovered well and oral voriconazole was continued. During the follow-up period, RA symptoms were mainly controlled using NSAIDs and analgesics.
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In August 2006, the patient experienced a severe exacerbation of arthritis with a 28-joint disease activity score (DAS28) of 7.4. A CT scan at that time did not reveal any active pulmonary lesions. Given that the patient's RA symptoms continued to worsen, therapy with rituximab was initiated. The patient received two infusions of rituximab 1000 mg 2 weeks apart without concomitant methylprednisolone, which were well tolerated. Upon that regimen, the patient's condition improved dramatically during the following weeks. Three months later, a DAS28 of 4.1 was recorded and at 6 and 12 months after rituximab, a DAS28 of 3.2 indicated low disease activity. The patient is still receiving prophylactic oral voriconazole and has had no relapse of pulmonary symptoms to date.
In summary, we report on a patient with active RA and a past medical history of pulmonary tuberculosis and aspergillosis, in whom rituximab monotherapy resulted in significant reduction of disease activity without adversely affecting the pulmonary condition.
Although rituximab has been approved for the treatment of RA in patients with an inadequate response to TNF inhibitors in combination with MTX, rituximab may also be applied to patients with contraindications to TNF blockers according to the recommendations established by an international expert committee [4]. However, in selected patients, combination of rituximab with MTX may not be warranted.
Pulmonary aspergillosis is a severe and potentially life-threatening infection complicating the clinical course of patients with immunodeficiency. It is infrequently encountered in patients with systemic autoimmune disorders treated with steroids and immunsuppressive drugs, but a recent survey demonstrated that mortality in these patients is even higher than in neutropenic patients [5]. In the randomized controlled clinical trials with rituximab in RA patients, only few cases of severe infections have been observed and noteworthy, no cases of tuberculosis or aspergillosis were recorded [6]. Thus, in individual patients with underlying chronic infections that are controlled by appropriate anti-microbial treatment, rituximab may represent a therapeutic option. However, two case reports have been published that describe the occurrence of aspergillosis in a patient with autoimmune thrombocytopenic purpura and in two patients with post-transplant lymphoproliferative disorders that were treated with rituximab [7–9]. As all these patients received extensive additional immunosuppressive treatment, the exact role of rituximab is difficult to define. However, experiments in B-cell deficient mice are in line with a slightly deteriorated anti-fungal immunity [10].
Our case report suggests that rituximab may present a therapeutic option in patients with severe RA and underlying chronic infections given that appropriate anti-microbial treatment is continued. However, in the individual patient, a careful consideration of the potential benefits of controlling RA and the risk of aggravating the underlying chronic infection has to be undertaken.
Disclosure statement: The authors have declared no conflicts of interest.
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*N. Jung and K. Owczarczyk equally contributed to this work.
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