http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(6): 1001–1004 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.874745

CASE REPORT

A case of bilateral rheumatoid pleuritis successfully treated with tocilizumab Keiko Ohtsuka, Kimihiko Takeuchi, Masatoshi Matsushita, and Tetsuo Aramaki Departments of Orthopedics and Rheumatology, Isesaki Fukushima Hospital, Otemachi, Isesakishi, Gumma, Japan, Kiryu-shi, Gumma, Japan Abstract

Keywords

The patient was a 77-year-old woman diagnosed as having rheumatoid arthritis (RA) in 1973. She was initiated on infliximab therapy in addition to methotrexate administration in 2009. The therapeutic response decreased after the fifth dose of infliximab, and the patient developed rheumatoid pleuritis due to increased RA disease activity. The therapy was switched from infliximab to tocilizumab, which resulted in amelioration of the arthralgias well as pleuritis. Our results suggest that tocilizumab is an effective treatment alternative for the treatment of rheumatoid pleuritis.

Bilateral pleural effusion, Extra-articular manifestations, Rheumatoid pleuritis, Rheumatoid arthritis, Tocilizumab History Received 21 June 2012 Accepted 24 January 2013 Published online 13 March 2013

Case presentation

Laboratory findings (Table 1)

The patient was a 77-year-old woman with stage IV and class III RA (American College of Rheumatology classification). She had been diagnosed as having RA in 1973. Treatment with methotrexate at 4 mg/week had been commenced in 2004, with the dose of the drug increased to 6 mg/week since January 2007; she was currently maintained on this dose. Since the RA disease activity increased [disease activity score– C-reactive protein (DAS-CRP), 4.47; CRP, 4.62 mg/dl; matrix metalloproteinase-3 (MMP-3), 366 mg/ml] during her in-hospital treatment for symptoms of lumbar spinal canal stenosis in January 2009, the treatment with infliximab (3 mg/kg) was initiated in February 2009. However, the therapeutic response decreased after the fifth dose of infliximab; therefore, infliximab was continued at a shorter dose interval of 4 weeks from the sixth dose onwards. However, since a stable therapeutic response was still not achieved (DAS-CRP, 4.41; CRP, 4.25 mg/dl; MMP-3, 123 mg/ml), we decided to perform surgery. A bilateral metatarsophalangeal arthroplasty was performed in February 2010. The patient became febrile and complained of dyspnea on exertion on March 15, i.e., 2 weeks after she received the 12th dose of infliximab on March 2. Chest radiography and computed tomography (CT) revealed a rightsided pleural effusion (Figure 1). Thoracentesis yielded 290 ml of fluid on March 17, and the pleural effusion reduced subsequently in size in response to diuretic treatment. Thereafter, infliximab was administered twice; however, no significant response was obtained (DAS-CRP, 3.66; CRP, 6.16 mg/dl; MMP-3, 120 mg/ml). Since the dyspnea on exertion worsened gradually from early June 2010, and chest radiography and CT showed bilateral pleural effusions on June 10 (Figure 2), the patient was admitted to our hospital for further workup and treatment.

The serum levels of the inflammatory indicators were elevated; however, no other abnormalities were observed.

Correspondence to: K. Ohtsuka, Departments of Orthopedics and Rheumatology, Isesaki Fukushima Hospital, Otemachi, Isesakishi, Gumma, Japan 2-90-6 Kawauchi-cho, Kiryu-shi, Gumma 376-0041, Tel: 81-2-77657682. Fax: +81-2-77657682 Japan, E-mail: keikonbukeiko@ yahoo.co.jp

Examination of the pleural aspirate (Table 2) The amount of the pleural aspirate was 110 ml. The fluid was yellow in color and clear (pH 7.5), and further analysis of the fluid revealed the following: lactate dehydrogenase (LDH), 378 IU/l; adenosine deaminase (ADA), 56.8; rheumatoid factor, 147; glucose, 102; complement, 12.0. These findings are characteristic of rheumatoid pleural effusion. Culture of the fluid was negative for bacteria, and the polymerase chain reaction (PCR) tests for Mycobacterium tuberculosis and non-tuberculous acid-fast bacteria were also negative. The patient was diagnosed as having pleural effusion associated with pleuritis as an extra-articular manifestation of RA, because the RA disease activity had worsened due to secondary failure of infliximab therapy. Therefore, the biological drug treatment was changed from infliximab to tocilizumab in an attempt to control the RA disease activity. Consequently, the DAS-CRP, CRP, and MMP-3 levels improved (Figure 3), and chest radiographic and CT evidence of pleural effusion also disappeared (Figure 4). The patient has been relapse-free since.

Discussion Pleural involvement is the most common manifestation of extraarticular pulmonary involvement in patients with RA [4]. Estimates of its clinical prevalence vary from 5 % for pleural effusions [1] to 20 % for pleuritic chest pain [2]. Post-mortem studies indicate a much higher prevalence of pleural disease, with 75 % of patients with long-standing rheumatoid disease showing pleural abnormalities in one study [3]. Another report described 16–24 % of RA patients as exhibiting pleuritic changes such as pleural thickening, observed with chest radiography, even when subjective symptoms of pulmonary involvement

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Mod Rheumatol, 2014; 24(6): 1001–1004

Table 1. Laboratory findings. Hematologic test results WBC Hb Ht Plt Biochemical test results TP GOT GPT BUN Cr Immunological test results CRP MMP-3 RF KL-6 β-D-glucan IgG Quanti FERON test Tuberculin skin test Endocrine test results BNP DAS-CRP(3) = 5.14

4,900/μl (Seg 77.4 %, Ly 14.0 %) 8.5 g/dl 27.20 % 30,000/μl 7.2 g/dl 31 IU/l 16 IU/l 20 mg/dl 0.92 mg/dl 9.0 mg/dl 150 ng/ml 147 IU/ml 135 U/ml 13.2 pg/ml 2814 mg/dl (−) (−) 0 × 0/2 × 5 mm 102 pg/ml >5.1 = high disease activity

The values of inflammatory indicators were elevated, but no other abnormalities were observed

were sparse [5]. Chest CT is useful for visualizing even small pleural effusions and slight pleural thickening, and pleural lesions are detected on chest CTs in approximately 10 % of RA patients [6]. The pleural effusion associated with rheumatoid pleuritis, which is usually unilateral, is exudative, occurring as a result of increased vascular permeability associated with inflammation. The pleural effusion associated with RA is similar in characteristics to that associated with tuberculous pleuritis and parapneumonic pleural effusion; therefore, differential diagnosis from these conditions is important. Furthermore, various adverse effects have been reported during TNFα antagonist treatment of RA, of which the most common and serious is infection [7, 8]. One report [9] showed a relative risk of 3.0 (95 % CI 1.8–5.1). In particular, utmost caution is required to prevent tuberculous pleuritis. In the present case, bacterial infections, non-tuberculous acidfast bacterial infections, and malignant tumors were ruled out as causes of the pleural effusion, because the results of bacterial culture and cytological examination of the pleural fluid were negative for bacterial growth, non-tuberculous acid-fast bacterial PCR-test, and atypical cells. Tuberculous pleuritis was ruled out because (1) acid-fast bacteria were not detected in smears, bacterial culture, or PCR-tests of the pleural fluid; (2) the results of a tuberculin

test and peripheral blood QuantiFERON assay were negative; (3) the pleural effusion showed features more characteristic of rheumatoid pleural effusion, such as a positive test for RF [10], low complement titers, and elevated levels of LDH and ADA [11, 12]; in addition, microscopic examination of the fluid revealed a predominance of lymphocytes. It is also necessary in a case of rheumatoid pleural effusion to exclude drug-induced lupus (DIL) pleuritis. The characteristics of DIL are similar to those of idiopathic lupus [13]. We considered the lack of clinical symptoms, high pleural levels of glucose, low titers, and absence of lupus erythematosus cells in the pleural fluid as suggesting a remote possibility of DIL. In any case, any drug should be considered as a potential cause of an undiagnosed exudative effusion. In such a case, pleural fluid eosinophilia (defined as >10 % of nucleated cells) may provide a clinical clue to the presence of drug-induced pleural disease; however, its presence or absence is a non-specific finding. Therefore, in this case, we took into account the possibility of the pleural effusion being an adverse effect of treatment with the IFN inhibitors [14]. Taking all of the above into consideration, we considered that the pleural effusions observed in the present case were most likely to be a consequence of rheumatoid pleuritis. There are sporadic reports of pleural effusion occurring during treatment with biologic agents [15], and in most such cases, the effusion was diagnosed as tuberculous pleuritis [16–18]. Oral corticosteroids are usually used for the treatment of rheumatoid pleuritis [19–21]. However, the efficacy of systemic steroid therapy remains unclear, and there are divergent views with regard to intrathoracic administration of corticosteroids [22]. Rheumatoid pleuritis is generally unrelated to the disease progression of arthritis, although the arthritis may worsen in patients presenting with pleural effusions [23]. Therefore, rheumatoid pleural effusion is highly likely to respond well to intensified treatment when the RA disease activity is high. In the present case, we changed the biologic therapy from infliximab to tocilizumab, without concomitant oral corticosteroid medication, because the extra-articular manifestation, i.e., pleuritis, worsened as a result of the secondary failure of infliximab therapy. Consequently, the extra-articular manifestations also responded well to the treatment. Ozaki et al. [24] also reported the possibility of efficacy of interleukin-6 (IL-6) on rheumatoid pericarditis. They suggested that anti TNF therapy and IL-6 therapy exert different effects on the extra-articular manifestations of RA. However, the comparison was related to the treatment of rheumatoid pericarditis. To the best of our knowledge, this is the first report documenting successful treatment of rheumatoid pleural effusion by targeting an alternate cytokine. Furthermore, inhibition of IL-6 may be effective for the

Table 2. Pleural aspirate was characteristics of rheumatoid pleural effusions. Volume Bacterial culture Mycobacterial tuberculosis PCR MAC PCR Cytological exam pH LDH

Right side 290 ml, left side 110 ml (−) (−) (−) Negative for atypical cells, lymphocytes dominate other cells 7.5 378 (exudative effusion >200 U/l) (Tb-like >500 U/l)

ADA RF

56.8 (Tb-like >50 IU/l) 147 (RA-like >10 U/ml)

Glucose Complement titer

102 (SLE-like >60 mg/dl, RA-like

A case of bilateral rheumatoid pleuritis successfully treated with tocilizumab.

The patient was a 77-year-old woman diagnosed as having rheumatoid arthritis (RA) in 1973. She was initiated on infliximab therapy in addition to meth...
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