□
CASE REPORT
□
Mycobacterium abscessus Pulmonary Infection under Treatment with Tocilizumab Daisuke Kobayashi 1,2, Satoshi Ito 1, Akira Hirata 3,4, Asami Abe 1, Akira Murasawa 1, Ichiei Narita 2,4 and Kiyoshi Nakazono 1
Abstract Although biological agents are of considerable benefit to patients with rheumatoid arthritis (RA), the potential for opportunistic infections is a critical issue. It is therefore important to achieve a balance between treatment efficacy and controlling opportunistic infection. We herein report the successfully managed case of a 53-year-old patient with RA who developed pulmonary Mycobacterium abscessus infection during treatment with tocilizumab and methotrexate. Key words: Mycobacterium abscessus, non-tuberculous mycobacterium, opportunistic infection, rheumatoid arthritis (Intern Med 54: 1309-1313, 2015) (DOI: 10.2169/internalmedicine.54.3956)
Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by inflammation of the synovium and the breakdown of bone and cartilage in the joints, leading to functional disability. Biological disease-modifying antirheumatic drugs (DMARDs) are of considerable benefit in preventing joint destruction in RA patients, although the administration of these agents increases the possibility of opportunistic infection involving non-tuberculous mycobacterium (NTM) (1, 2). In North America, the crude incidence of NTM per 100,000 patient-years in the general population, RA patients treated without tumor necrosis factor (TNF) antagonists and RA patients treated with TNF antagonists is reported to be 4.1, 19.2 and 105, respectively (3). NTM infection is of particular concern in patients with RA, particularly those who use biological DMARDs, and is regarded as a contraindication to the use of these medications in principle, although discontinuing these drugs inevitably results in flare-ups of the RA activity. One previous study reported a death rate of 9% in patients using TNF antagonists who developed NTM infec-
tion (4). Among these patients, 12% had Mycobacterium abscessus infection. M. abscessus is the third most frequently recovered NTM respiratory pathogen in the United States, whereas it is rarely responsible for NTM respiratory infection in Japan (5). This microbe is a rapidly growing mycobacteria (RGM) and causes severe pulmonary infection resistant to conventional antibiotics and anti-tuberculosis agents. Although this bacterium is susceptible to clarithromycin (CAM), amikacin (AMK), cefoxitin (CXT) and imipenem/cilastatin (IPM/CS), no effective drug regimens have been firmly established (6). The prognosis of M. abscessus pulmonary infection is poor, with a reported mortality rate of 16-20% (7, 8). Relapse after remission is also frequent, and providing successful treatment for M. abscessus pulmonary infection is considered to be difficult. We herein report a case of M. abscessus pulmonary infection associated with the use of tocilizumab (TCZ) and methotrexate (MTX). The infection was successfully controlled and the RA disease activity was managed with iguratimod (IGU) and salazosulfapyridine (SASP), despite the need to discontinue treatment with TCZ and MTX.
１
Niigata Rheumatic Center, Japan, ２Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan, ３Niigata Prefectural Shibata Hospital, Japan and ４Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Japan Received for publication August 22, 2014; Accepted for publication September 25, 2014 Correspondence to Dr. Daisuke Kobayashi, [email protected]
1309
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Case Report A 53-year-old Japanese woman complained of a mild productive cough occasionally associated with hemosputum at a regular hospital visit in August 2013. Her symptoms had developed over the course of one week. She had a history of gastroesophageal reflux disease and had been treated for RA for 17 years. She had also undergone surgery several times for bone destruction due to poor disease control. She had previously received many DMARDs, including auranofin, bucillamine, D-penicillamine, mizoribine, MTX and adalimumab (ADA). Because her disease activity remained high despite the use of ADA, she was administered TCZ. In 2009, prior to the introduction of TCZ, bronchoscopy was performed to treat bilateral bronchiectasis and a nodular lung shadow suggestive of NTM infection. However, an examination of the bronchoalveolar fluid failed to demonstrate NTM. The patient was then treated with MTX at a dose of 8 mg/week and TCZ at a dose of 8 mg/kg/4 weeks without corticosteroids and finally achieved a low disease activity according to the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR) (9). The patient’s height was 164 cm and her body weight was 48 kg. Her body temperature was 36.5 degrees C, her blood pressure was 126/66 mmHg, her heart rate was 76 beats per minute and her respiratory rate was 12 breaths per min. Coarse crackles were heard over the left lung. Deformities of the joints was evident in the bilateral wrists, knees and left elbow. Blood tests revealed a white blood cell count of 6,900/mm3, C-reactive protein concentration of 0.01 mg/dL and rheumatoid factor level of 154 IU/mL. Antiglycopeptidolipid (GPL) core antibodies were positive, suggesting NTM infection. A chest radiograph disclosed a small nodular lesion in the left lung that had not been evident in the scan obtained in April 2013. A computed tomography scan of the chest confirmed focal infiltration with bronchiectasis (Figure a, d, g), again suggesting NTM infection. The patient rarely experienced respiratory symptoms, and we did not detect any signs of active infection on routine radiographic and laboratory examinations conducted previously. We subsequently withdrew the dose of TCZ immediately; however, the productive cough persisted and we thus switched the MTX to SASP one month later. A sputum culture and cytology did not demonstrate NTM infection. Nevertheless, bronchoscopy with bronchoalveolar lavage was performed, and M. abscessus was identified on DNA-DNA hybridization (DDH Mycobacteria; Kyokuto, Tokyo, Japan). Because the patient’s symptoms did not improve, and lung infiltration progressed in October 2013 (Figure b, e, h), a regimen consisting of CAM (800 mg, per os), AMK (15 mg/kg div) and IPM/CS (1.5 g/day div) was started and continued for one month then switched to CAM (800 mg, per os) and levofloxacin (500 mg, per os). Although her symptoms and radiographic findings gradually improved (Figure c, f, i), the discontinuation of TCZ, and later MTX,
caused worsening of the RA disease activity. In particular, the Clinical Disease Activity Index (CDAI) (10) increased from 8.5 to 14, the DAS28-ESR increased from 1.89 to 4.26 and the serum matrix metalloprotease-3 level increased from 48.2 to 207.6 ng/mL. Iguratimod (IGU) was administered orally at a dose of 25 mg/day for the first four weeks followed by 50 mg/day, and the disease activity was successfully suppressed in combination with SASP therapy. In June 2014, the patient’s CDAI was 8.6, and her cough and hemosputum had disappeared.
Discussion Although M. abscessus pulmonary infection can be a lifethreatening complication in patients with RA, only four such cases have been reported [(11-14) (Table)]. These RA patients included two individuals who had been treated with TNF antagonists (11, 12) and two who had not been treated with biological DMARDs (13, 14). Two of these four cases were fatal (11, 13). Because the mortality rate of M. abscessus infection is reported to be 16-20% (7, 8), clinicians must aware of its potential development in RA patients. It has been reported that the onset of pulmonary NTM disease in RA patients appears to spread from pre-existing lung lesions, such as those involving bronchiectasis or nodules (12). However, it is currently unclear whether these preexisting abnormalities reflect the subclinical presence of pulmonary NTM colonization or constitute an extra-articular manifestation of RA. The present patient developed NTM infection four years after being started on TCZ therapy. She had both nodular lesions and bronchiectasis, and bronchoscopy performed prior to the initiation of TCZ treatment showed no signs of any pathogens. Therefore, the patient appears to have developed an exogenous NTM infection, rather than endogenous reactivation. In cases of exogenous NTM infection, obtaining a timely diagnosis of pulmonary NTM disease is critical. We were able to control our patient’s infection successfully. First, we effectively identified the pathogen in an expeditious manner and promptly started adequate treatment. M. abscessus pulmonary infection is critical and sometimes fatal due to its rapid exacerbation and resistance to ethambutol (EB) and rifampicin (RFP), which are usually employed for other NTM infections (6, 7). Because CAM monotherapy rapidly leads to acquired resistance and treatment failure, the use of a multi-drug regimen including CAM with AMK plus CXT or IPM/CS is recommended (5, 6). Mori et al. also highlighted the importance of early isolation and identification of the causative NTM species in cases of M. abscessus infection (14). Recently, testing for anti-GPL-core antibodies has become commercially available. This useful serologic test can be used to differentiate RA with M. avium complex (MAC) from RA without MAC, with a sensitivity of 100% and specificity of 90% (15). However, caution is required when interpreting the results. As RGM including M. abscessus has GPL-core antigens, positivity on this test
1310
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Figure. High-resolution computed tomography (HRCT) imaging. HRCT performed in August 2013 (a, d, g) revealed mild bronchiectasis in the left lung (a) with small centrilobular nodules in both lungs (a, g). An HRCT scan performed in October 2013 showed new infiltrates in the left upper and lower lobes (b, e, h). An HRCT scan performed after four weeks of treatment with intravenous imipenem/ cilastatin and amikacin and oral clarithromycin showed that the abnormal findings had improved (c, f, i).
may also indicate the presence of RGM infection. In the present case, polymerase chain reaction (PCR) for M. avium and M. intracellulare yielded a negative result, while DDH demonstrated M. abscessus infection. Second, the patient’s underlying lung structure was relatively normal, apart from mild bronchiectasis. Cases of treatment-resistant NTM are sometimes associated with cavity formation, gastroesophageal disorders and/or cystic fibrosis (6, 7, 11, 13, 16, 17). Third, our patient had no history of CAM usage. Macrolide resistance in the setting of NTM is thought to result from previous exposure to antibiotics (18). Therefore, clinical isolates are believed to be sensitive to CAM, the anchor drug for the treatment of M. abscessus infection. Sensitivity tests for the isolated pathogen were not performed in the present case because this technique requires a special culture me-
dium and the drug sensitivity of M. abscessus in the lungs did not reflect the need for this test in vitro. Finally, the speedy withdrawal of TCZ may have contributed to the patient’s favorable outcome via the resolution of immune insufficiency. Recently, a species closely related to M. abscessus, M. massiliense, has been described (19, 20). M. massiliense displays a lower frequency of acquired resistance to macrolides, and patients with pulmonary M. massiliense infection exhibit a milder clinical course than those with M. abscessus pulmonary infection (21, 22). Because M. massiliense cannot be distinguished from M. abscessus using traditional methods (23), there is a possibility that the infection in our patient may have been caused by M. massiliense. The development of a convenient phenotyping method and treatment regimens tailored to each species is desirable in the fu-
1311
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Table. Clinical Characteristics of Pulmonary M. abscessus Infection. Patients’ characteristics M, 56y, USA 11 y-history of RA
Immunosuppressive agents Pre-existing lung disease Treatment and possible risk factors PSL 2mg/d RA lung AMK+CAM+CXT LEF 20mg/d Bilateral nodular ETN 2x25 mg/w and reticular shadow
Outcome
References
Death 2 m after diagnosis
[11]
F, 72y, Japan 14 y-history of RA
PSL ETN
BE
No treatment
Survive with no radiological change
[12]
M, 70y, Japan 10 y-history of RA
PSL
Old tuberculosis COPD Lung fibrosis BMI 13.0 Peptic ulcer
AMK+CAM+IPM/CS Death 4 m after diagnosis
[13]
F, 70y, Japan 6 m-history of RA
MTX 12mg/w PSL 15mg/d
BE
CAM+LVFX
[14]
F, 53y, Japan 17 y-history of RA
MTX 8 mg/w TCZ 400mg/m
Survive
BE AMK+CAM+ IPM/CS Survive This case BMI 17.8 ĺCAM+LVFX GERD M:male, F:female, y: year, m: month; w: week, d:day, PSL: prednisolone, LEF: leflunomide, MTX: methotrexate, ETN: etanercept, TCZ: tocilizumab, RA: rheumatoid arthritis, BE: bronchiectasis, COPD: chronic obstructive pulmonary disease, BMI: body mass index, GERD: gastroesophageal reflex disorder, AMK: amikacin, CAM: clarithromycin, CXT: cefoxitin, IPM/CS: Imipenem/cilastatin, LVFX: levofloxacin
ture. In this case, the discontinuation of TCZ and MTX resulted in an RA flare-up. MTX and biological DMARDs are effective in treating RA, although they have an immunosuppressive effect. There is no evidence that the use of MTX increases the incidence of NTM infection. Hence, the careful continuation of MTX is an alternative choice. Nevertheless, Mori et al. reported a case in which M. abscessus lung disease rapidly progressed during treatment with 12 mg/week of MTX and 15 mg/day of prednisolone (PSL) (14). In the current case, we discontinued the dose of MTX because the patient’s productive cough and hemosputum continued despite the withdrawal of TCZ. IGU is a newly developed DMARD that was approved in Japan in September 2012. A double-blind, placebo-controlled study of IGU in Japanese patients with RA showed a 20% improvement rate based on the American College of Rheumatology criteria, being almost equivalent to the effect of SASP (24). In a phase III clinical trial, the incidence of infectious disease was 1.5% (2/131) in the IGU group, 2.0% (3/147) in the SASP group and 4.4% (3/68) in the placebo group, and no statistically significant differences were noted in the incidence of adverse reactions between the subjects treated with IGU and SASP (24, 25). In the present case, we changed TCZ and MTX to IGU and SASP, immunomodulators and not immunosuppressants, which resulted in the successful control of the RA activity. Various reports have documented the reintroduction of biological DMARDs after treatment for MAC pulmonary infection or successful MAC treatment with the continuous use of biological DMARDs (26, 27). In addition, the Japan College of Rheumatology guidelines for the use of biological DMARDs were recently modified (28). However, the continuation or resumption of biological DMARDs is contraindicated in patients who develop pulmonary NTM dis-
ease caused by RGM, including M. abscessus. Although M. abscessus pulmonary infection is rare in Japan, clinicians must keep the potential for this disease in mind when treating patients with RA. The authors state that they have no Conflict of Interest (COI). Acknowledgement We thank our colleagues at the Niigata Rheumatic Center for their detailed comments on this case.
References
1312
1. Takeuchi T, Kameda H. The Japanese experience with biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 6: 644-652, 2010. 2. Winthrop KL, Iseman M. Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy. Nat Rev Rheumatol 9: 524-531, 2013. 3. Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis 72: 37-42, 2013. 4. Winthrop KL, Chang E, Yamashita S, Iademarco MF, LoBue PA. Nontuberculous mycobacteria infections and anti-tumor necrosis factor-alpha therapy. Emerg Infect Dis 15: 1556-1561, 2009. 5. Kurashima A. Treatment of relatively rare species nontuberculous pulmonary mycobacteriosis. Kekkaku (Tuberculosis) 86: 923-932, 2011 (in Japanese, Abstract in English). 6. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/ IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 175: 367-416, 2007. 7. Griffith DE, Girard WM, Wallace RJ Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients. Am Rev Respir Dis 147: 1271-1278, 1993. 8. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis 52: 565-571, 2011.
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
9. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38: 44-48, 1995. 10. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 7: R796R806, 2005. 11. Thomas JE, Taoka CR, Gibbs BT, Fraser SL. Fatal pulmonary Mycobacterium abscessus infection in a patient using etanercept. Hawaii Med J 65: 12-15, 2006. 12. Mori S, Tokuda H, Sakai F, et al. Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. Mod Rheumatol 22: 727737, 2012. 13. Fujita K, Tanaka E, Hatta K, Kori Y, Taguchi Y. An autopsy case of Mycobacterium abscessus pulmonary infection complicated with rheumatoid arthritis. Intern Med 47: 1273-1276, 2008. 14. Mori S, Imamura F, Koga Y, Uramoto H, Ezaki T, Sugimoto M. Pulmonary Mycobacterium abscessus disease in a patient receiving low-dose methotrexate for treatment of early rheumatoid arthritis. J Infect Chemother 19: 1146-1151, 2013. 15. Komazaki Y, Miyazaki Y, Fujie T, et al. Serodiagnosis of Mycobacterium avium complex pulmonary disease in rheumatoid arthritis. Respiration 87: 129-135, 2014. 16. Hayashi M, Takayanagi N, Kanauchi T, Miyahara Y, Yanagisawa T, Sugita Y. Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 185: 575-583, 2012. 17. Yamakawa H, Takayanagi N, Miyahara Y, et al. Prognostic factors and radiographic outcomes of nontuberculous mycobacterial lung disease in rheumatoid arthritis. J Rheumatol 40: 1307-1315, 2013. 18. Wallace RJ Jr, Meier A, Brown BA, et al. Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus. Antimicrob Agents Chemother 40: 1676-1681, 1996.
19. Adékambi T, Reynaud-Gaubert M, Greub G, et al. Amoebal coculture of “Mycobacterium massiliense” sp. nov. from the sputum of a patient with hemoptoic pneumonia. J Clin Microbiol 42: 5493-5501, 2004. 20. Zelazny AM, Root JM, Shea YR, et al. Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii. J Clin Microbiol 47: 1985-1995, 2009. 21. Koh WJ, Jeon K, Lee NY, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 183: 405-410, 2011. 22. Harada T, Akiyama Y, Kurashima A, et al. Clinical and microbiological differences between Mycobacterium abscessus and Mycobacterium massiliense lung diseases. J Clin Microbiol 50: 35563561, 2012. 23. Gray TJ, Kong F, Jelfs P, Sintchenko V, Chen SC. Improved identification of rapidly growing mycobacteria by a 16S-23S internal transcribed spacer region PCR and capillary gel electrophoresis. PLoS One 9: e102290, 2014. 24. Hara M, Abe T, Sugawara S, et al. Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study. Mod Rheumatol 17: 1-9, 2007. 25. Eisai Co., Ltd.. Product information for Iguratimod. [Internet]. [cited 2014 Sep. 15]. Available from: http://www.eisai.jp/medical/p roducts/careram/guide_01.pdf (in Japanese). 26. Mori S, Sugimoto M. Is continuation of anti-tumor necrosis factor-alpha therapy a safe option for patients who have developed pulmonary mycobacterial infection?: Case presentation and literature review. Clin Rheumatol 31: 203-210, 2012. 27. Yamakawa H, Takayanagi N, Ishiguro T, Kanauchi T, Hoshi T, Sugita Y. Clinical investigation of nontuberculous mycobacterial lung disease in Japanese patients with rheumatoid arthritis receiving biologic therapy. J Rheumatol 40: 1994-2000, 2013. 28. Japan College of Rheumatology. Guidelines for the use of tocilizumab in rheumatoid arthritis. [Internet]. [cited 2014 Sep. 15]. Available from: http://www.ryumachi-jp.com/info/guideline_tcz.ht ml (in Japanese).
Ⓒ 2015 The Japanese Society of Internal Medicine http://www.naika.or.jp/imonline/index.html
1313
CASE REPORT
□
Mycobacterium abscessus Pulmonary Infection under Treatment with Tocilizumab Daisuke Kobayashi 1,2, Satoshi Ito 1, Akira Hirata 3,4, Asami Abe 1, Akira Murasawa 1, Ichiei Narita 2,4 and Kiyoshi Nakazono 1
Abstract Although biological agents are of considerable benefit to patients with rheumatoid arthritis (RA), the potential for opportunistic infections is a critical issue. It is therefore important to achieve a balance between treatment efficacy and controlling opportunistic infection. We herein report the successfully managed case of a 53-year-old patient with RA who developed pulmonary Mycobacterium abscessus infection during treatment with tocilizumab and methotrexate. Key words: Mycobacterium abscessus, non-tuberculous mycobacterium, opportunistic infection, rheumatoid arthritis (Intern Med 54: 1309-1313, 2015) (DOI: 10.2169/internalmedicine.54.3956)
Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by inflammation of the synovium and the breakdown of bone and cartilage in the joints, leading to functional disability. Biological disease-modifying antirheumatic drugs (DMARDs) are of considerable benefit in preventing joint destruction in RA patients, although the administration of these agents increases the possibility of opportunistic infection involving non-tuberculous mycobacterium (NTM) (1, 2). In North America, the crude incidence of NTM per 100,000 patient-years in the general population, RA patients treated without tumor necrosis factor (TNF) antagonists and RA patients treated with TNF antagonists is reported to be 4.1, 19.2 and 105, respectively (3). NTM infection is of particular concern in patients with RA, particularly those who use biological DMARDs, and is regarded as a contraindication to the use of these medications in principle, although discontinuing these drugs inevitably results in flare-ups of the RA activity. One previous study reported a death rate of 9% in patients using TNF antagonists who developed NTM infec-
tion (4). Among these patients, 12% had Mycobacterium abscessus infection. M. abscessus is the third most frequently recovered NTM respiratory pathogen in the United States, whereas it is rarely responsible for NTM respiratory infection in Japan (5). This microbe is a rapidly growing mycobacteria (RGM) and causes severe pulmonary infection resistant to conventional antibiotics and anti-tuberculosis agents. Although this bacterium is susceptible to clarithromycin (CAM), amikacin (AMK), cefoxitin (CXT) and imipenem/cilastatin (IPM/CS), no effective drug regimens have been firmly established (6). The prognosis of M. abscessus pulmonary infection is poor, with a reported mortality rate of 16-20% (7, 8). Relapse after remission is also frequent, and providing successful treatment for M. abscessus pulmonary infection is considered to be difficult. We herein report a case of M. abscessus pulmonary infection associated with the use of tocilizumab (TCZ) and methotrexate (MTX). The infection was successfully controlled and the RA disease activity was managed with iguratimod (IGU) and salazosulfapyridine (SASP), despite the need to discontinue treatment with TCZ and MTX.
１
Niigata Rheumatic Center, Japan, ２Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan, ３Niigata Prefectural Shibata Hospital, Japan and ４Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Japan Received for publication August 22, 2014; Accepted for publication September 25, 2014 Correspondence to Dr. Daisuke Kobayashi, [email protected]
1309
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Case Report A 53-year-old Japanese woman complained of a mild productive cough occasionally associated with hemosputum at a regular hospital visit in August 2013. Her symptoms had developed over the course of one week. She had a history of gastroesophageal reflux disease and had been treated for RA for 17 years. She had also undergone surgery several times for bone destruction due to poor disease control. She had previously received many DMARDs, including auranofin, bucillamine, D-penicillamine, mizoribine, MTX and adalimumab (ADA). Because her disease activity remained high despite the use of ADA, she was administered TCZ. In 2009, prior to the introduction of TCZ, bronchoscopy was performed to treat bilateral bronchiectasis and a nodular lung shadow suggestive of NTM infection. However, an examination of the bronchoalveolar fluid failed to demonstrate NTM. The patient was then treated with MTX at a dose of 8 mg/week and TCZ at a dose of 8 mg/kg/4 weeks without corticosteroids and finally achieved a low disease activity according to the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR) (9). The patient’s height was 164 cm and her body weight was 48 kg. Her body temperature was 36.5 degrees C, her blood pressure was 126/66 mmHg, her heart rate was 76 beats per minute and her respiratory rate was 12 breaths per min. Coarse crackles were heard over the left lung. Deformities of the joints was evident in the bilateral wrists, knees and left elbow. Blood tests revealed a white blood cell count of 6,900/mm3, C-reactive protein concentration of 0.01 mg/dL and rheumatoid factor level of 154 IU/mL. Antiglycopeptidolipid (GPL) core antibodies were positive, suggesting NTM infection. A chest radiograph disclosed a small nodular lesion in the left lung that had not been evident in the scan obtained in April 2013. A computed tomography scan of the chest confirmed focal infiltration with bronchiectasis (Figure a, d, g), again suggesting NTM infection. The patient rarely experienced respiratory symptoms, and we did not detect any signs of active infection on routine radiographic and laboratory examinations conducted previously. We subsequently withdrew the dose of TCZ immediately; however, the productive cough persisted and we thus switched the MTX to SASP one month later. A sputum culture and cytology did not demonstrate NTM infection. Nevertheless, bronchoscopy with bronchoalveolar lavage was performed, and M. abscessus was identified on DNA-DNA hybridization (DDH Mycobacteria; Kyokuto, Tokyo, Japan). Because the patient’s symptoms did not improve, and lung infiltration progressed in October 2013 (Figure b, e, h), a regimen consisting of CAM (800 mg, per os), AMK (15 mg/kg div) and IPM/CS (1.5 g/day div) was started and continued for one month then switched to CAM (800 mg, per os) and levofloxacin (500 mg, per os). Although her symptoms and radiographic findings gradually improved (Figure c, f, i), the discontinuation of TCZ, and later MTX,
caused worsening of the RA disease activity. In particular, the Clinical Disease Activity Index (CDAI) (10) increased from 8.5 to 14, the DAS28-ESR increased from 1.89 to 4.26 and the serum matrix metalloprotease-3 level increased from 48.2 to 207.6 ng/mL. Iguratimod (IGU) was administered orally at a dose of 25 mg/day for the first four weeks followed by 50 mg/day, and the disease activity was successfully suppressed in combination with SASP therapy. In June 2014, the patient’s CDAI was 8.6, and her cough and hemosputum had disappeared.
Discussion Although M. abscessus pulmonary infection can be a lifethreatening complication in patients with RA, only four such cases have been reported [(11-14) (Table)]. These RA patients included two individuals who had been treated with TNF antagonists (11, 12) and two who had not been treated with biological DMARDs (13, 14). Two of these four cases were fatal (11, 13). Because the mortality rate of M. abscessus infection is reported to be 16-20% (7, 8), clinicians must aware of its potential development in RA patients. It has been reported that the onset of pulmonary NTM disease in RA patients appears to spread from pre-existing lung lesions, such as those involving bronchiectasis or nodules (12). However, it is currently unclear whether these preexisting abnormalities reflect the subclinical presence of pulmonary NTM colonization or constitute an extra-articular manifestation of RA. The present patient developed NTM infection four years after being started on TCZ therapy. She had both nodular lesions and bronchiectasis, and bronchoscopy performed prior to the initiation of TCZ treatment showed no signs of any pathogens. Therefore, the patient appears to have developed an exogenous NTM infection, rather than endogenous reactivation. In cases of exogenous NTM infection, obtaining a timely diagnosis of pulmonary NTM disease is critical. We were able to control our patient’s infection successfully. First, we effectively identified the pathogen in an expeditious manner and promptly started adequate treatment. M. abscessus pulmonary infection is critical and sometimes fatal due to its rapid exacerbation and resistance to ethambutol (EB) and rifampicin (RFP), which are usually employed for other NTM infections (6, 7). Because CAM monotherapy rapidly leads to acquired resistance and treatment failure, the use of a multi-drug regimen including CAM with AMK plus CXT or IPM/CS is recommended (5, 6). Mori et al. also highlighted the importance of early isolation and identification of the causative NTM species in cases of M. abscessus infection (14). Recently, testing for anti-GPL-core antibodies has become commercially available. This useful serologic test can be used to differentiate RA with M. avium complex (MAC) from RA without MAC, with a sensitivity of 100% and specificity of 90% (15). However, caution is required when interpreting the results. As RGM including M. abscessus has GPL-core antigens, positivity on this test
1310
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Figure. High-resolution computed tomography (HRCT) imaging. HRCT performed in August 2013 (a, d, g) revealed mild bronchiectasis in the left lung (a) with small centrilobular nodules in both lungs (a, g). An HRCT scan performed in October 2013 showed new infiltrates in the left upper and lower lobes (b, e, h). An HRCT scan performed after four weeks of treatment with intravenous imipenem/ cilastatin and amikacin and oral clarithromycin showed that the abnormal findings had improved (c, f, i).
may also indicate the presence of RGM infection. In the present case, polymerase chain reaction (PCR) for M. avium and M. intracellulare yielded a negative result, while DDH demonstrated M. abscessus infection. Second, the patient’s underlying lung structure was relatively normal, apart from mild bronchiectasis. Cases of treatment-resistant NTM are sometimes associated with cavity formation, gastroesophageal disorders and/or cystic fibrosis (6, 7, 11, 13, 16, 17). Third, our patient had no history of CAM usage. Macrolide resistance in the setting of NTM is thought to result from previous exposure to antibiotics (18). Therefore, clinical isolates are believed to be sensitive to CAM, the anchor drug for the treatment of M. abscessus infection. Sensitivity tests for the isolated pathogen were not performed in the present case because this technique requires a special culture me-
dium and the drug sensitivity of M. abscessus in the lungs did not reflect the need for this test in vitro. Finally, the speedy withdrawal of TCZ may have contributed to the patient’s favorable outcome via the resolution of immune insufficiency. Recently, a species closely related to M. abscessus, M. massiliense, has been described (19, 20). M. massiliense displays a lower frequency of acquired resistance to macrolides, and patients with pulmonary M. massiliense infection exhibit a milder clinical course than those with M. abscessus pulmonary infection (21, 22). Because M. massiliense cannot be distinguished from M. abscessus using traditional methods (23), there is a possibility that the infection in our patient may have been caused by M. massiliense. The development of a convenient phenotyping method and treatment regimens tailored to each species is desirable in the fu-
1311
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
Table. Clinical Characteristics of Pulmonary M. abscessus Infection. Patients’ characteristics M, 56y, USA 11 y-history of RA
Immunosuppressive agents Pre-existing lung disease Treatment and possible risk factors PSL 2mg/d RA lung AMK+CAM+CXT LEF 20mg/d Bilateral nodular ETN 2x25 mg/w and reticular shadow
Outcome
References
Death 2 m after diagnosis
[11]
F, 72y, Japan 14 y-history of RA
PSL ETN
BE
No treatment
Survive with no radiological change
[12]
M, 70y, Japan 10 y-history of RA
PSL
Old tuberculosis COPD Lung fibrosis BMI 13.0 Peptic ulcer
AMK+CAM+IPM/CS Death 4 m after diagnosis
[13]
F, 70y, Japan 6 m-history of RA
MTX 12mg/w PSL 15mg/d
BE
CAM+LVFX
[14]
F, 53y, Japan 17 y-history of RA
MTX 8 mg/w TCZ 400mg/m
Survive
BE AMK+CAM+ IPM/CS Survive This case BMI 17.8 ĺCAM+LVFX GERD M:male, F:female, y: year, m: month; w: week, d:day, PSL: prednisolone, LEF: leflunomide, MTX: methotrexate, ETN: etanercept, TCZ: tocilizumab, RA: rheumatoid arthritis, BE: bronchiectasis, COPD: chronic obstructive pulmonary disease, BMI: body mass index, GERD: gastroesophageal reflex disorder, AMK: amikacin, CAM: clarithromycin, CXT: cefoxitin, IPM/CS: Imipenem/cilastatin, LVFX: levofloxacin
ture. In this case, the discontinuation of TCZ and MTX resulted in an RA flare-up. MTX and biological DMARDs are effective in treating RA, although they have an immunosuppressive effect. There is no evidence that the use of MTX increases the incidence of NTM infection. Hence, the careful continuation of MTX is an alternative choice. Nevertheless, Mori et al. reported a case in which M. abscessus lung disease rapidly progressed during treatment with 12 mg/week of MTX and 15 mg/day of prednisolone (PSL) (14). In the current case, we discontinued the dose of MTX because the patient’s productive cough and hemosputum continued despite the withdrawal of TCZ. IGU is a newly developed DMARD that was approved in Japan in September 2012. A double-blind, placebo-controlled study of IGU in Japanese patients with RA showed a 20% improvement rate based on the American College of Rheumatology criteria, being almost equivalent to the effect of SASP (24). In a phase III clinical trial, the incidence of infectious disease was 1.5% (2/131) in the IGU group, 2.0% (3/147) in the SASP group and 4.4% (3/68) in the placebo group, and no statistically significant differences were noted in the incidence of adverse reactions between the subjects treated with IGU and SASP (24, 25). In the present case, we changed TCZ and MTX to IGU and SASP, immunomodulators and not immunosuppressants, which resulted in the successful control of the RA activity. Various reports have documented the reintroduction of biological DMARDs after treatment for MAC pulmonary infection or successful MAC treatment with the continuous use of biological DMARDs (26, 27). In addition, the Japan College of Rheumatology guidelines for the use of biological DMARDs were recently modified (28). However, the continuation or resumption of biological DMARDs is contraindicated in patients who develop pulmonary NTM dis-
ease caused by RGM, including M. abscessus. Although M. abscessus pulmonary infection is rare in Japan, clinicians must keep the potential for this disease in mind when treating patients with RA. The authors state that they have no Conflict of Interest (COI). Acknowledgement We thank our colleagues at the Niigata Rheumatic Center for their detailed comments on this case.
References
1312
1. Takeuchi T, Kameda H. The Japanese experience with biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 6: 644-652, 2010. 2. Winthrop KL, Iseman M. Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy. Nat Rev Rheumatol 9: 524-531, 2013. 3. Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis 72: 37-42, 2013. 4. Winthrop KL, Chang E, Yamashita S, Iademarco MF, LoBue PA. Nontuberculous mycobacteria infections and anti-tumor necrosis factor-alpha therapy. Emerg Infect Dis 15: 1556-1561, 2009. 5. Kurashima A. Treatment of relatively rare species nontuberculous pulmonary mycobacteriosis. Kekkaku (Tuberculosis) 86: 923-932, 2011 (in Japanese, Abstract in English). 6. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/ IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 175: 367-416, 2007. 7. Griffith DE, Girard WM, Wallace RJ Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients. Am Rev Respir Dis 147: 1271-1278, 1993. 8. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis 52: 565-571, 2011.
Intern Med 54: 1309-1313, 2015
DOI: 10.2169/internalmedicine.54.3956
9. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38: 44-48, 1995. 10. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 7: R796R806, 2005. 11. Thomas JE, Taoka CR, Gibbs BT, Fraser SL. Fatal pulmonary Mycobacterium abscessus infection in a patient using etanercept. Hawaii Med J 65: 12-15, 2006. 12. Mori S, Tokuda H, Sakai F, et al. Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. Mod Rheumatol 22: 727737, 2012. 13. Fujita K, Tanaka E, Hatta K, Kori Y, Taguchi Y. An autopsy case of Mycobacterium abscessus pulmonary infection complicated with rheumatoid arthritis. Intern Med 47: 1273-1276, 2008. 14. Mori S, Imamura F, Koga Y, Uramoto H, Ezaki T, Sugimoto M. Pulmonary Mycobacterium abscessus disease in a patient receiving low-dose methotrexate for treatment of early rheumatoid arthritis. J Infect Chemother 19: 1146-1151, 2013. 15. Komazaki Y, Miyazaki Y, Fujie T, et al. Serodiagnosis of Mycobacterium avium complex pulmonary disease in rheumatoid arthritis. Respiration 87: 129-135, 2014. 16. Hayashi M, Takayanagi N, Kanauchi T, Miyahara Y, Yanagisawa T, Sugita Y. Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 185: 575-583, 2012. 17. Yamakawa H, Takayanagi N, Miyahara Y, et al. Prognostic factors and radiographic outcomes of nontuberculous mycobacterial lung disease in rheumatoid arthritis. J Rheumatol 40: 1307-1315, 2013. 18. Wallace RJ Jr, Meier A, Brown BA, et al. Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus. Antimicrob Agents Chemother 40: 1676-1681, 1996.
19. Adékambi T, Reynaud-Gaubert M, Greub G, et al. Amoebal coculture of “Mycobacterium massiliense” sp. nov. from the sputum of a patient with hemoptoic pneumonia. J Clin Microbiol 42: 5493-5501, 2004. 20. Zelazny AM, Root JM, Shea YR, et al. Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii. J Clin Microbiol 47: 1985-1995, 2009. 21. Koh WJ, Jeon K, Lee NY, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 183: 405-410, 2011. 22. Harada T, Akiyama Y, Kurashima A, et al. Clinical and microbiological differences between Mycobacterium abscessus and Mycobacterium massiliense lung diseases. J Clin Microbiol 50: 35563561, 2012. 23. Gray TJ, Kong F, Jelfs P, Sintchenko V, Chen SC. Improved identification of rapidly growing mycobacteria by a 16S-23S internal transcribed spacer region PCR and capillary gel electrophoresis. PLoS One 9: e102290, 2014. 24. Hara M, Abe T, Sugawara S, et al. Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study. Mod Rheumatol 17: 1-9, 2007. 25. Eisai Co., Ltd.. Product information for Iguratimod. [Internet]. [cited 2014 Sep. 15]. Available from: http://www.eisai.jp/medical/p roducts/careram/guide_01.pdf (in Japanese). 26. Mori S, Sugimoto M. Is continuation of anti-tumor necrosis factor-alpha therapy a safe option for patients who have developed pulmonary mycobacterial infection?: Case presentation and literature review. Clin Rheumatol 31: 203-210, 2012. 27. Yamakawa H, Takayanagi N, Ishiguro T, Kanauchi T, Hoshi T, Sugita Y. Clinical investigation of nontuberculous mycobacterial lung disease in Japanese patients with rheumatoid arthritis receiving biologic therapy. J Rheumatol 40: 1994-2000, 2013. 28. Japan College of Rheumatology. Guidelines for the use of tocilizumab in rheumatoid arthritis. [Internet]. [cited 2014 Sep. 15]. Available from: http://www.ryumachi-jp.com/info/guideline_tcz.ht ml (in Japanese).
Ⓒ 2015 The Japanese Society of Internal Medicine http://www.naika.or.jp/imonline/index.html
1313
