International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
Risk factors of adverse events during treatment in elderly patients with rheumatoid arthritis: an observational study Nozomi IWANAGA,1,2 Kazuhiko ARIMA,3 Kaoru TERADA,1 Yukitaka UEKI,1 Yoshiro HORAI,4 Takahisa SUZUKI,4 Yoshikazu NAKASHIMA,4 Shin-ya KAWASHIRI,3 Kunihiro ICHINOSE,4 Mami TAMAI,4 Hideki NAKAMURA,4 Kiyoshi AOYAGI,3 Atsushi KAWAKAMI,4 and Tomoki ORIGUCHI4,5 1
Department of Rheumatology, Sasebo Chuo Hospital, Sasebo-city 2Deparment of Rheumatology, Nagasaki Medical Center, Kubara Omura-city 3Departments of Public Health, 4Immunology and Rheumatology and 5Rehabilitation Sciences; Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki-city, Japan
Abstract Objectives: The risk factors of adverse events during a number of currently used treatments for rheumatoid arthritis (RA) in elderly patients were examined. Methods: A retrospective observational study was conducted for 300 elderly RA patients registered in December 2009 at Sasebo Chuo Hospital, Japan, and the adverse events during the treatments for RA were assessed. Results: The average age of the patients was 74.3 5.8 years. The Steinbrocker stage was IV in almost one-half of the patients. Methotrexate (MTX) was used in 54.0% of patients and biologics in 23.0% of patients. Adverse events occurred in 103 patients (34.3%). The most common adverse events were infections (46.6%), including pneumonia (21.4%). Multiple logistic analyses revealed that the factors significantly related to infection were advanced Steinbrocker stage and the existence of respiratory diseases, and that of pneumonia was the existence of diabetes mellitus (DM). Conclusions: The elderly RA patients with advanced stage, respiratory diseases or DM should be monitored for infections, including pneumonia, carefully during treatment. Key words: adverse event, drug treatment, rheumatoid arthritis.
INTRODUCTION The number of elderly patients with rheumatoid arthritis (RA) has been steadily increasing in Japan. Among 925 patients with RA being treated at Sasebo Chuo Hospital, Japan, the age distribution peaked at 50 years, but we have treated many RA patients in their 60s and 70s,
Correspondence: Tomoki Origuchi, MD, Department of Rehabilitation Sciences, Graduate School of Biomedical Sciences, Nagasaki University 1–7-1 Sakamoto, Nagasaki-city 852–8520, Japan. Email: [email protected]
and the ratio of the elderly patients 65 years or older has reached 32.4%. In elderly RA patients, the reduction in their activities of daily living (ADLs) due to RA influences their prognosis.1 Early control of RA disease activity helps people maintain their abilities to engage in ADLs, and it helps slow the progression of RA.2 New agents, including biologics, to treat RA are available in clinical practice. Several reports have suggested that applying screening before using biological treatment helps to reduce adverse events related to therapy, possibly leading to better disease outcome.3,4 However, the incidence of adverse events among patients being treated for RA is
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Iwanaga et al.
high, and it can be difficult to control RA disease. Aggressive RA treatment should not be withheld in the geriatric population and treatment should be individualized.5 The management of RA in the elderly requires special consideration in regard to comorbidities and increased frequency of adverse events.6 The present study was conducted to evaluate the risk factors of adverse events in treatment of elderly patients with RA.
PATIENTS AND METHODS Patients A retrospective observational study was performed using a series of RA patients over 65 years old. All had been diagnosed as having RA on the basis of the American College of Rheumatology criteria,7 and they had been followed-up for at least 12 months. The cases of a total of 325 patients were registered in the study at December 2009 and followed until November 2010. Among these 325 patients, 25 were excluded because of lack of data and no follow-up consultation. The adverse events of 300 patients were examined, using the baseline variables of age, gender, duration from disease onset to diagnosis, Steinbrocker’s stage, class, comorbidities, and treatment with prednisolone, methotrexate (MTX) and biologics (infliximab, etanercept, tocilizumab and adalimumab). Adverse events were evaluated, as were risk factors for adverse events. Approval from the ethics committee of our institute was obtained and it conformed to the provisions of the World Medical Association’s Declaration of Helsinki.
Statistical analysis Clinical data are expressed as the number of patients (%) with the indicated characteristic. Data for disease activities are expressed as percentages (%). The Mann– Whitney U-test was used to compare characteristics for continuous variables. The chi-square test was used for categorical variables. Associations with a P-value < 0.2 in these tests were set as explanatory variables, and multiple logistic regression analyses were performed to investigate which factors affected the occurrence of pneumonia or infection. The best-fitting model was selected based on Akaike’s information criteria (AIC), with lower AIC values indicating better model fit. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). A P-value < 0.05 denotes the presence of a significant difference. All statistical analyses were performed using SAS version 9.2 software (SAS Institute Inc., Cary, NC, USA).
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RESULTS Patient characteristics and treatments The average age of the 300 elderly RA patients was 74.3 5.8 years (Table 1); 242 patients (80.7%) were female. The average disease duration was 13.2 10.6 years. The Steinbrocker stage was IV in nearly one-half of the patients and the RA class was 2 in almost all of the patients (70.0%). The disease activity score 28 of 28 joints (DAS28) at study entry was high in 37 (12.4%), moderate in 147 (49.0%), and low in 49 (16.4%) among these patients. MTX, glucocorticoids and biologics were prescribed in 54.0%, 52.3% and 23.0% of patients, respectively. Among the biologics, etanercept was used most often, followed by tocilizumab.
Complications At time of registration in the study, the rates of complications were as follows: hypertension (141 patients, 47.0%); dyslipidemia (117 patients, 39.0%); respiratory diseases (96 patients, 32.0%) including interstitial pneumonia, bronchiectasis and chronic obstructive pulmonary disease (COPD); and history of tuberculosis and diabetes mellitus (DM) (61 patients, 20.3%). Nearly one-half of the patients with DM received glucocorticoids. The disease-modifying antirheumatic drug MTX was used in 162 patients (54.0%); the main doses of MTX were 6–8 mg per week. Biologics were used in 69 patients (23.0%) and biologic treatment for 17 patients (5.7%) was newly started during this research period. Among the biologics, etanercept was used the most often.
Adverse events Adverse events occurred in 103 patients (34.3%) during the 12 months’ follow-up (Table 2). These were infections (46.6%), including pneumonia (21.4%), cardiac disease (7.8%), bone fracture (6.8%), malignancies (6.8%), peptic ulcer (4.9%) and cerebrovascular disease (2.9%). Five patients died in this period. These patients had moderate or higher disease activity and were complicated with DM, cardiac disease or bronchiectasis. In one of these five patients, a biologic (adalimumab) was used for the treatment of RA, and 7 months after an artificial vessel replacement for an abdominal aorta aneurysm, she died due to the infectious rupture of the artificial vessel. The age-specific incidence of adverse events is summarized in Table 3 with the patients classified as < 70, 70–79 and ≥ 80 years old. The incidence of adverse
International Journal of Rheumatic Diseases 2014
Treatment adverse events in elderly RA patients
Table 1 Baseline characteristics of 300 elderly RA patients
No. of cases
300 (%)
Age (mean SD; 74.3 5.8 years) < 70 76 (25.3) 70–79 162 (54.0) > 80 62 (20.7) Sex Male 58 (19.3) Female 242 (80.7) Duration of rheumatoid arthritis (years) (13.2 10.6) 29 (9.7) 3–5 51 (17.0) 6–10 69 (23.0) > 10 151 (50.3) Stenbrocker’s stages I 38 (31.7) II 77 (25.7) III 54 (18.0) IV 131 (43.7) Steinbrocker’s functional classification 1 75 (25.0) 2 210 (70.0) 3 15 (5.0) 4 0 (0.0) Disease activities High disease activity 37 (12.4) Moderate disease 147 (49.0) activity Low disease activity 49 (16.4) Remission 56 (18.6)
Comorbidities Hypertension Dyslipidemia Respiratory disease Interstitial pneumonia Bronchiectasia COLD Old tuberculosis
141 (47.0) 117 (39.0) 96 (32.0) 54 (18.0) 24 (8.0) 12 (4.0) 9 (3.0)
Non-tuberculous mycobacteriosis Diabete mellitus Cardiac disorder Renal dysfunction Malignancies Cerebrovascular diseases Concomitant glucocorticosteroid Yes PSL ≤ 5 mg/day PSL ≥ 6 mg/day
157 (52.3) 118 (39.3) 39 (13.0)
Concomitant methotrexate Yes 2 mg/week 4 mg/week 6 mg/week 8 mg/week 10 mg/week
162 (54.0) 2 (0.7) 25 (8.3) 58 (19.3) 73 (24.3) 4 (1.3)
Biologics user New patients Infliximab Etanercept Adalimumab Tocilizumab
6 (2.0) 61 (20.3) 28 (9.3) 23 (7.7) 21 (7.0) 11 (3.7)
69 (23.0) 17 (5.7) 9 (3.0) 1 (13.7) 5 (1.7) 14 (4.7)
COLD, chronic obstructive lung disease; PSL, prednisolone.
events in the 80s (50.0%) group was significantly higher than those in the other two groups. Next, a comparison of the incidence of adverse events and the various treatments was conducted. Concerning glucocorticoids, the incidence of adverse events in the patients receiving more than 5 mg prednisolone (53.8%) was significantly higher than that in the patients receiving 5 mg or less prednisolone. Although the incidence of adverse events in the patients receiving biologics (43.4%) was also higher than that in the patients without biologics, the incidence in the patients receiving MTX was lower than that in the patients without MTX. The existence of respiratory disease influenced
International Journal of Rheumatic Diseases 2014
the incidence of adverse events: the incidence in the patients complicated with respiratory diseases was significantly higher than that in the patients without respiratory diseases. The existence of DM also influenced the incidence of adverse events. The incidence in patients complicated with DM was significantly higher than that in patients without DM. Among the adverse events, the most frequent infections were examined first. The univariate analysis (Table 4) showed that the factors significantly related to infection were higher age, glucocorticoid user, MTX non-user, advanced Steinbrocker stage, higher class in Steinbrocker’s functional classification,
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Table 2 Adverse events in elderly RA patients No. (%) No. of cases Infections Bacterial pneumonia Herpes zoster Enteritis Cellulitis Urinary tract infection Infectious arthritis Abscess Others Cardiac disease Bone fracture Malignancy Peptic ulcer Cerebrovascular disease Others
103 (34.3) 48 (46.6) 22 (21.4) 7 (6.8) 4 (3.9) 4 (3.9) 4 (3.9) 2 (1.9) 2 (1.9) 3 (2.9) 8 (7.8) 7 (6.8) 7 (6.8) 5 (4.9) 3 (2.9) 25 (24.3)
positive rheumatoid factors and the existence of respiratory diseases. Table 5 shows the results of the multiple logistic analysis. The factors significantly related to infection were advanced Steinbrocker stage
and the existence of respiratory diseases. The multiple logistic analysis also revealed that the only factor significantly related to pneumonia was the existence of DM (Table 6).
DISCUSSION The incidence of adverse events in the present study was 34.3%, and infectious disease was the most important and frequent adverse event, occurring in roughly onehalf of these patients. Epidemiological studies have identified the risk factors for infection in RA patients; these include advanced age, pulmonary comorbidities, corticosteroid use and impaired daily activity.8 The incidence of adverse events was higher in the present RA patients with the following factors: (i) age 80 years or older; (ii) use of glucocorticoids or biologics; or (iii) the existence of pre-existing lung disease or DM. The possibility of infections including pneumonia should be monitored carefully, as the multiple logistic analyses revealed that advanced Steinbrocker stage and the presence of respiratory disease or DM are risk factors for infection or pneumonia. To our knowledge, this is the
Table 3 Comparison of adverse events and infections according to clinical characteristics in elderly RA patients Adverse events No. of cases
(%)
Age < 70 70–79 ≥ 80
24 (31.6) 42 (25.9) 31 (50.0)
Glucocorticoid ( ) ≤ 5 mg/day > 5 mg/day
30 (20.9) 46 (39.0) 21 (53.8)
Methotrexate ( ) (+) Biologics ( ) (+) Respiratory diseases ( ) (+) Diabetes mellitus ( ) (+)
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Infections P-value
< 0.05 (vs. < 70 & 70–79)
< 0.01 (vs. ( )) < 0.001 (vs. ≤ 5 mg/day)
53 (38.4) 44 (27.2)
< 0.05
67 (29.0) 30 (43.4)
< 0.05
54 (26.5) 43 (44.8)
< 0.001
70 (29.2) 27 (44.3)
< 0.05
No. of cases
(%)
Age < 70 70–79 ≥ 80
11 (14.4) 22 (13.5) 18 (29.0)
Glucocorticoid ( ) ≤ 5 mg/day > 5 mg/day
13 (9.1) 26 (22.0) 12 (30.8)
Methotrexate ( ) (+) Biologics ( ) (+) Respiratory diseases ( ) (+) Diabetes mellitus ( ) (+)
P-value
< 0.05 (vs. < 70) < 0.001 (vs. 70–79)
< 0.001 (vs. ( )) < 0.01 (vs. ≤ 5 mg/day)
30 (21.7) 21 (13.0)
< 0.05
34 (14.7) 17 (24.6)
< 0.05
22 (10.7) 29 (30.2)
< 0.001
36 (15.1) 15 (24.6)
= 0.07
International Journal of Rheumatic Diseases 2014
Treatment adverse events in elderly RA patients
Table 4 Comparison of clinical characteristics according to the existence of infections in elderly RA patients Without infection n = 249
Variables Age (mean SD) Duration DAS28-ESR Glucocorticoid Sex Stage Functional classification Methotrexate DMARD Biologics Rheumatoid Factor CCP ANA Respiratory diseases Diabetes mellitus Hypertension Renal diseases
Year Year mg/day Male/Female I II III IV Steinbrocker Class 1/2/3/4 Steinbrocker ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+)
73.9 5.7 12.7 10.1 3.71 1.27 2.3 3.4 48/201 38/67/44/100 67/173/9/0 108/141 149/100 197/52 64/179 49/110 121/71 181/68 203/46 131/118 227/22
With infection n = 51 76.2 6.2 15.4 12.3 3.85 1.26 3.7 3.2 10/41 0/10/10/31 8/37/6/0 30/21 31/20 34/17 5/46 5/29 24/19 22/29 36/15 28/23 47/4
P-value 0.011 0.100 0.415 < 0.001 1.000 0.001 0.013 0.047 1.000 0.067 0.011 0.061 0.391 < 0.001 0.087 0.878 1.000
DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate; DMARD, disease-modifying antirheumatic drugs; CCP, anticyclic citrullinated peptide antibody; ANA, antinuclear antibody.
Table 5 Multiple adjusted odds ratios for infections in elderly RA patients Variables Age Glucocorticoid Stage Methotrexate Rheumatoid factor Respiratory diseases Diabetes mellitus
/1 year /1 mg/day Reference (–) Reference (–) Reference (–) Reference (–)
Odds ratio
95% CI
1.04 1.09 1.67 0.69 2.14 2.43 1.93
0.98–1.10 0.99–1.18 1.17–2.39 0.35–1.35 0.74–6.16 1.25–4.72 0.89–4.16
CI, Confidence interval.
Table 6 Multiple adjusted odds ratio for pneumonia in elderly RA patients Variables CCP Respiratory diseases Diabetes mellitus
Reference (–) Reference (–) Reference (–)
Odds ratio
95% CI
5.56 2.60 3.35
0.69–44.89 0.85–7.91 1.06–10.60
CCP, anticyclic citrullinated peptide antibody; CI, confidence interval.
first report to demonstrate the risk factors of adverse events during treatment of elderly patients with RA. Elderly patients frequently have one or more of the following characteristics: (i) renal dysfunction and delayed excretion of drugs; (ii) delayed metabolism of drugs; (iii) reduced content of water and muscles; (iv) reduced serum concentration of albumin; (v) being
International Journal of Rheumatic Diseases 2014
treated with multiple medications; and (vi) reduced immunocompetence. These states were linked to an increase in serum drug concentrations, interactions of drugs and an increased risk of infections. The total number of lymphocytes was decreased in an elderly population and aging was associated with a reduced percentage of mature T cells (CD3+ cells) and killer/suppresser T cells (CD8+ cells) and an increased percentage of activated T cells (CD3+ human leukocyte antigenDR+ cells).9,10 It was demonstrated in this study that advanced Steinbrocker stage was a risk factor for infections. Koike et al. showed the relationship between duration of RA and Steinbrocker functional class or radiographic stage in a post-marketing surveillance (PMS) study of etanercept, and reported that older age, higher Steinbrocker functional class and presence of comorbidities could be related to the higher incidence of serious adverse events among patients with longer duration of RA.11 Although Steinbrocker functional class was higher in our RA patients with infections than that in patients without infection, it was not selected as a risk factor for infections. In patients with RA, irrespective of the treatment, infections frequently involve the respiratory tract. Our multiple logistic analyses revealed that pre-existing chronic lung disease was one of the strong predictors of infections. Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA.12 ILD is found in
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up to 30% of patients with RA.13 Bronchiectasis was identified in 18% to 30% of RA patients in small studies by high-resolution computed tomography.14 The confirmation of pre-existing pulmonary diseases prior to treatment is strongly recommended to prevent elderly RA patients from infections. We have shown that the incidence of pneumonia is higher among RA patients with DM. The number of DM patients in Japan has been steadily increasing, and thus it has also increased among RA patients. We examined the levels of hemoglobin A1c (HbA1c) in 498 patients with RA.15 Serum HbA1c levels higher than 6.5% were found more often in RA patients (23.1%) compared to patients with other diseases (18.9%). The rate increased gradually with age. The treatment plan for a patient with RA should also include tests for DM. A large-scale PMS study was carried out to determine the safety profile of the monoclonal antibody infliximab in Japanese RA patients.16 The risk factors identified for bacterial pneumonia were male gender, age 60– 70 years or older, Steinbrocker stage III or IV, and comorbid respiratory disease.16 The Japan College of Rheumatology 2010 guidelines for the use of the biologic etanercept in RA indicated that the risk factors for bacterial pneumonia were advanced age, comorbid respiratory disease and use of corticosteroids.7 Although our article primarily attempts to demonstrate the risk factors for the treatments of elderly RA patients, we were unable to provide the difference in risk factors among the treatment regimens, including the biologics, and this could be regarded as a limitation. Since the numbers of elderly RA patients have been increasing, it is important to monitor the incidence of severe infections. Elderly patients with RA who have complications should be carefully selected before treatments are considered, and they should be followed-up closely for adverse events.
ACKNOWLEDGEMENTS All the authors contributed significantly to the submitted work, and they have read and approved the manuscript.
CONFLICT OF INTEREST AK has received lecture fees and/or research grants from Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Company, Pfizer Japan, Abbvie
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GK, Eisai Co., Chugai Pharmaceutical Co. and Astellas Pharma Inc. TO has received a research grant from Mitsubishi Tanabe Pharma Co.
REFERENCES 1 Komano Y, Tanaka M, Nanki T et al. (2011) Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a report from the registry of Japanese rheumatoid arthritis patients for long-term safety. J Rheumatol 38 (7), 1258–64. 2 Genevay S, Finckh A, Ciurea A et al. (2007) Tolerance and effectiveness of anti-tumor necrosis factor alpha therapies in elderly patients with rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 57 (4), 679–85. 3 Migliore A, Bizzi E, Lagana B et al. (2009) The safety of anti-TNF agents in the elderly. Int J Immunopathol Pharmacol 22 (2), 415–26. 4 Fleischmann R, Iqbal I (2007) Risk: benefit profile of etanercept in elderly patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis. Drugs Aging 24 (3), 239–54. 5 Majithia V, Peel C, Geraci SA (2009) Rheumatoid arthritis in elderly patients. Geriatrics 64 (9), 22–8. 6 Tutuncu Z, Kavanaugh A (2007) Rheumatic disease in the elderly: rheumatoid arthritis. Rheum Dis Clin North Am 33 (1), 57–70. 7 Arnett FC, Edworthy SM, Bloch DA et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31 (3), 315–24. 8 Koike R, Harigai M, Atsumi T et al. (2009) Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod Rheumatol 19 (4), 351–7. 9 Kawakami K, Kadota J, Iida K, Shirai R, Abe K, Kohno S (1999) Reduced immune function and malnutrition in the elderly. Tohoku J Exp Med 187 (2), 157–71. 10 Negoro S, Hara H, Miyata S et al. (1987) Age-related changes of the function of T cell subsets: predominant defect of the proliferative response in CD8 positive T cell subset in aged persons. Mech Ageing Dev 39 (3), 263–79. 11 Koike T, Harigai M, Inokuma S et al. (2012) Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis. Rheumatol Int 32 (6), 1511–9. 12 Kim EJ, Collard HR, King TE (2009) Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest 136 (5), 1397–405.
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13 Froidevaux-Janin S, Dudler J, Nicod LP, Lazor R (2011) Interstitial lung disease in rheumatoid arthritis. Rev Med Suisse 7 (318), 2272–7. 14 Geri G, Dadoun S, Bui T et al. (2011) Risk of infections in bronchiectasis during disease-modifying treatment and biologics for rheumatic diseases. BMC Infect Dis 11, 304. 15 Origuchi T, Yamaguchi S, Inoue A et al. (2011) Increased incidence of pre-diabetes mellitus at a department of rheu-
International Journal of Rheumatic Diseases 2014
matology: a retrospective study. Mod Rheumatol 21 (5), 455–9. 16 Takeuchi T, Tatsuki Y, Nogami Y et al. (2008) Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 67 (2), 189–94.
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ORIGINAL ARTICLE
Risk factors of adverse events during treatment in elderly patients with rheumatoid arthritis: an observational study Nozomi IWANAGA,1,2 Kazuhiko ARIMA,3 Kaoru TERADA,1 Yukitaka UEKI,1 Yoshiro HORAI,4 Takahisa SUZUKI,4 Yoshikazu NAKASHIMA,4 Shin-ya KAWASHIRI,3 Kunihiro ICHINOSE,4 Mami TAMAI,4 Hideki NAKAMURA,4 Kiyoshi AOYAGI,3 Atsushi KAWAKAMI,4 and Tomoki ORIGUCHI4,5 1
Department of Rheumatology, Sasebo Chuo Hospital, Sasebo-city 2Deparment of Rheumatology, Nagasaki Medical Center, Kubara Omura-city 3Departments of Public Health, 4Immunology and Rheumatology and 5Rehabilitation Sciences; Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki-city, Japan
Abstract Objectives: The risk factors of adverse events during a number of currently used treatments for rheumatoid arthritis (RA) in elderly patients were examined. Methods: A retrospective observational study was conducted for 300 elderly RA patients registered in December 2009 at Sasebo Chuo Hospital, Japan, and the adverse events during the treatments for RA were assessed. Results: The average age of the patients was 74.3 5.8 years. The Steinbrocker stage was IV in almost one-half of the patients. Methotrexate (MTX) was used in 54.0% of patients and biologics in 23.0% of patients. Adverse events occurred in 103 patients (34.3%). The most common adverse events were infections (46.6%), including pneumonia (21.4%). Multiple logistic analyses revealed that the factors significantly related to infection were advanced Steinbrocker stage and the existence of respiratory diseases, and that of pneumonia was the existence of diabetes mellitus (DM). Conclusions: The elderly RA patients with advanced stage, respiratory diseases or DM should be monitored for infections, including pneumonia, carefully during treatment. Key words: adverse event, drug treatment, rheumatoid arthritis.
INTRODUCTION The number of elderly patients with rheumatoid arthritis (RA) has been steadily increasing in Japan. Among 925 patients with RA being treated at Sasebo Chuo Hospital, Japan, the age distribution peaked at 50 years, but we have treated many RA patients in their 60s and 70s,
Correspondence: Tomoki Origuchi, MD, Department of Rehabilitation Sciences, Graduate School of Biomedical Sciences, Nagasaki University 1–7-1 Sakamoto, Nagasaki-city 852–8520, Japan. Email: [email protected]
and the ratio of the elderly patients 65 years or older has reached 32.4%. In elderly RA patients, the reduction in their activities of daily living (ADLs) due to RA influences their prognosis.1 Early control of RA disease activity helps people maintain their abilities to engage in ADLs, and it helps slow the progression of RA.2 New agents, including biologics, to treat RA are available in clinical practice. Several reports have suggested that applying screening before using biological treatment helps to reduce adverse events related to therapy, possibly leading to better disease outcome.3,4 However, the incidence of adverse events among patients being treated for RA is
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Iwanaga et al.
high, and it can be difficult to control RA disease. Aggressive RA treatment should not be withheld in the geriatric population and treatment should be individualized.5 The management of RA in the elderly requires special consideration in regard to comorbidities and increased frequency of adverse events.6 The present study was conducted to evaluate the risk factors of adverse events in treatment of elderly patients with RA.
PATIENTS AND METHODS Patients A retrospective observational study was performed using a series of RA patients over 65 years old. All had been diagnosed as having RA on the basis of the American College of Rheumatology criteria,7 and they had been followed-up for at least 12 months. The cases of a total of 325 patients were registered in the study at December 2009 and followed until November 2010. Among these 325 patients, 25 were excluded because of lack of data and no follow-up consultation. The adverse events of 300 patients were examined, using the baseline variables of age, gender, duration from disease onset to diagnosis, Steinbrocker’s stage, class, comorbidities, and treatment with prednisolone, methotrexate (MTX) and biologics (infliximab, etanercept, tocilizumab and adalimumab). Adverse events were evaluated, as were risk factors for adverse events. Approval from the ethics committee of our institute was obtained and it conformed to the provisions of the World Medical Association’s Declaration of Helsinki.
Statistical analysis Clinical data are expressed as the number of patients (%) with the indicated characteristic. Data for disease activities are expressed as percentages (%). The Mann– Whitney U-test was used to compare characteristics for continuous variables. The chi-square test was used for categorical variables. Associations with a P-value < 0.2 in these tests were set as explanatory variables, and multiple logistic regression analyses were performed to investigate which factors affected the occurrence of pneumonia or infection. The best-fitting model was selected based on Akaike’s information criteria (AIC), with lower AIC values indicating better model fit. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). A P-value < 0.05 denotes the presence of a significant difference. All statistical analyses were performed using SAS version 9.2 software (SAS Institute Inc., Cary, NC, USA).
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RESULTS Patient characteristics and treatments The average age of the 300 elderly RA patients was 74.3 5.8 years (Table 1); 242 patients (80.7%) were female. The average disease duration was 13.2 10.6 years. The Steinbrocker stage was IV in nearly one-half of the patients and the RA class was 2 in almost all of the patients (70.0%). The disease activity score 28 of 28 joints (DAS28) at study entry was high in 37 (12.4%), moderate in 147 (49.0%), and low in 49 (16.4%) among these patients. MTX, glucocorticoids and biologics were prescribed in 54.0%, 52.3% and 23.0% of patients, respectively. Among the biologics, etanercept was used most often, followed by tocilizumab.
Complications At time of registration in the study, the rates of complications were as follows: hypertension (141 patients, 47.0%); dyslipidemia (117 patients, 39.0%); respiratory diseases (96 patients, 32.0%) including interstitial pneumonia, bronchiectasis and chronic obstructive pulmonary disease (COPD); and history of tuberculosis and diabetes mellitus (DM) (61 patients, 20.3%). Nearly one-half of the patients with DM received glucocorticoids. The disease-modifying antirheumatic drug MTX was used in 162 patients (54.0%); the main doses of MTX were 6–8 mg per week. Biologics were used in 69 patients (23.0%) and biologic treatment for 17 patients (5.7%) was newly started during this research period. Among the biologics, etanercept was used the most often.
Adverse events Adverse events occurred in 103 patients (34.3%) during the 12 months’ follow-up (Table 2). These were infections (46.6%), including pneumonia (21.4%), cardiac disease (7.8%), bone fracture (6.8%), malignancies (6.8%), peptic ulcer (4.9%) and cerebrovascular disease (2.9%). Five patients died in this period. These patients had moderate or higher disease activity and were complicated with DM, cardiac disease or bronchiectasis. In one of these five patients, a biologic (adalimumab) was used for the treatment of RA, and 7 months after an artificial vessel replacement for an abdominal aorta aneurysm, she died due to the infectious rupture of the artificial vessel. The age-specific incidence of adverse events is summarized in Table 3 with the patients classified as < 70, 70–79 and ≥ 80 years old. The incidence of adverse
International Journal of Rheumatic Diseases 2014
Treatment adverse events in elderly RA patients
Table 1 Baseline characteristics of 300 elderly RA patients
No. of cases
300 (%)
Age (mean SD; 74.3 5.8 years) < 70 76 (25.3) 70–79 162 (54.0) > 80 62 (20.7) Sex Male 58 (19.3) Female 242 (80.7) Duration of rheumatoid arthritis (years) (13.2 10.6) 29 (9.7) 3–5 51 (17.0) 6–10 69 (23.0) > 10 151 (50.3) Stenbrocker’s stages I 38 (31.7) II 77 (25.7) III 54 (18.0) IV 131 (43.7) Steinbrocker’s functional classification 1 75 (25.0) 2 210 (70.0) 3 15 (5.0) 4 0 (0.0) Disease activities High disease activity 37 (12.4) Moderate disease 147 (49.0) activity Low disease activity 49 (16.4) Remission 56 (18.6)
Comorbidities Hypertension Dyslipidemia Respiratory disease Interstitial pneumonia Bronchiectasia COLD Old tuberculosis
141 (47.0) 117 (39.0) 96 (32.0) 54 (18.0) 24 (8.0) 12 (4.0) 9 (3.0)
Non-tuberculous mycobacteriosis Diabete mellitus Cardiac disorder Renal dysfunction Malignancies Cerebrovascular diseases Concomitant glucocorticosteroid Yes PSL ≤ 5 mg/day PSL ≥ 6 mg/day
157 (52.3) 118 (39.3) 39 (13.0)
Concomitant methotrexate Yes 2 mg/week 4 mg/week 6 mg/week 8 mg/week 10 mg/week
162 (54.0) 2 (0.7) 25 (8.3) 58 (19.3) 73 (24.3) 4 (1.3)
Biologics user New patients Infliximab Etanercept Adalimumab Tocilizumab
6 (2.0) 61 (20.3) 28 (9.3) 23 (7.7) 21 (7.0) 11 (3.7)
69 (23.0) 17 (5.7) 9 (3.0) 1 (13.7) 5 (1.7) 14 (4.7)
COLD, chronic obstructive lung disease; PSL, prednisolone.
events in the 80s (50.0%) group was significantly higher than those in the other two groups. Next, a comparison of the incidence of adverse events and the various treatments was conducted. Concerning glucocorticoids, the incidence of adverse events in the patients receiving more than 5 mg prednisolone (53.8%) was significantly higher than that in the patients receiving 5 mg or less prednisolone. Although the incidence of adverse events in the patients receiving biologics (43.4%) was also higher than that in the patients without biologics, the incidence in the patients receiving MTX was lower than that in the patients without MTX. The existence of respiratory disease influenced
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the incidence of adverse events: the incidence in the patients complicated with respiratory diseases was significantly higher than that in the patients without respiratory diseases. The existence of DM also influenced the incidence of adverse events. The incidence in patients complicated with DM was significantly higher than that in patients without DM. Among the adverse events, the most frequent infections were examined first. The univariate analysis (Table 4) showed that the factors significantly related to infection were higher age, glucocorticoid user, MTX non-user, advanced Steinbrocker stage, higher class in Steinbrocker’s functional classification,
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Table 2 Adverse events in elderly RA patients No. (%) No. of cases Infections Bacterial pneumonia Herpes zoster Enteritis Cellulitis Urinary tract infection Infectious arthritis Abscess Others Cardiac disease Bone fracture Malignancy Peptic ulcer Cerebrovascular disease Others
103 (34.3) 48 (46.6) 22 (21.4) 7 (6.8) 4 (3.9) 4 (3.9) 4 (3.9) 2 (1.9) 2 (1.9) 3 (2.9) 8 (7.8) 7 (6.8) 7 (6.8) 5 (4.9) 3 (2.9) 25 (24.3)
positive rheumatoid factors and the existence of respiratory diseases. Table 5 shows the results of the multiple logistic analysis. The factors significantly related to infection were advanced Steinbrocker stage
and the existence of respiratory diseases. The multiple logistic analysis also revealed that the only factor significantly related to pneumonia was the existence of DM (Table 6).
DISCUSSION The incidence of adverse events in the present study was 34.3%, and infectious disease was the most important and frequent adverse event, occurring in roughly onehalf of these patients. Epidemiological studies have identified the risk factors for infection in RA patients; these include advanced age, pulmonary comorbidities, corticosteroid use and impaired daily activity.8 The incidence of adverse events was higher in the present RA patients with the following factors: (i) age 80 years or older; (ii) use of glucocorticoids or biologics; or (iii) the existence of pre-existing lung disease or DM. The possibility of infections including pneumonia should be monitored carefully, as the multiple logistic analyses revealed that advanced Steinbrocker stage and the presence of respiratory disease or DM are risk factors for infection or pneumonia. To our knowledge, this is the
Table 3 Comparison of adverse events and infections according to clinical characteristics in elderly RA patients Adverse events No. of cases
(%)
Age < 70 70–79 ≥ 80
24 (31.6) 42 (25.9) 31 (50.0)
Glucocorticoid ( ) ≤ 5 mg/day > 5 mg/day
30 (20.9) 46 (39.0) 21 (53.8)
Methotrexate ( ) (+) Biologics ( ) (+) Respiratory diseases ( ) (+) Diabetes mellitus ( ) (+)
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Infections P-value
< 0.05 (vs. < 70 & 70–79)
< 0.01 (vs. ( )) < 0.001 (vs. ≤ 5 mg/day)
53 (38.4) 44 (27.2)
< 0.05
67 (29.0) 30 (43.4)
< 0.05
54 (26.5) 43 (44.8)
< 0.001
70 (29.2) 27 (44.3)
< 0.05
No. of cases
(%)
Age < 70 70–79 ≥ 80
11 (14.4) 22 (13.5) 18 (29.0)
Glucocorticoid ( ) ≤ 5 mg/day > 5 mg/day
13 (9.1) 26 (22.0) 12 (30.8)
Methotrexate ( ) (+) Biologics ( ) (+) Respiratory diseases ( ) (+) Diabetes mellitus ( ) (+)
P-value
< 0.05 (vs. < 70) < 0.001 (vs. 70–79)
< 0.001 (vs. ( )) < 0.01 (vs. ≤ 5 mg/day)
30 (21.7) 21 (13.0)
< 0.05
34 (14.7) 17 (24.6)
< 0.05
22 (10.7) 29 (30.2)
< 0.001
36 (15.1) 15 (24.6)
= 0.07
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Treatment adverse events in elderly RA patients
Table 4 Comparison of clinical characteristics according to the existence of infections in elderly RA patients Without infection n = 249
Variables Age (mean SD) Duration DAS28-ESR Glucocorticoid Sex Stage Functional classification Methotrexate DMARD Biologics Rheumatoid Factor CCP ANA Respiratory diseases Diabetes mellitus Hypertension Renal diseases
Year Year mg/day Male/Female I II III IV Steinbrocker Class 1/2/3/4 Steinbrocker ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+) ( )/(+)
73.9 5.7 12.7 10.1 3.71 1.27 2.3 3.4 48/201 38/67/44/100 67/173/9/0 108/141 149/100 197/52 64/179 49/110 121/71 181/68 203/46 131/118 227/22
With infection n = 51 76.2 6.2 15.4 12.3 3.85 1.26 3.7 3.2 10/41 0/10/10/31 8/37/6/0 30/21 31/20 34/17 5/46 5/29 24/19 22/29 36/15 28/23 47/4
P-value 0.011 0.100 0.415 < 0.001 1.000 0.001 0.013 0.047 1.000 0.067 0.011 0.061 0.391 < 0.001 0.087 0.878 1.000
DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate; DMARD, disease-modifying antirheumatic drugs; CCP, anticyclic citrullinated peptide antibody; ANA, antinuclear antibody.
Table 5 Multiple adjusted odds ratios for infections in elderly RA patients Variables Age Glucocorticoid Stage Methotrexate Rheumatoid factor Respiratory diseases Diabetes mellitus
/1 year /1 mg/day Reference (–) Reference (–) Reference (–) Reference (–)
Odds ratio
95% CI
1.04 1.09 1.67 0.69 2.14 2.43 1.93
0.98–1.10 0.99–1.18 1.17–2.39 0.35–1.35 0.74–6.16 1.25–4.72 0.89–4.16
CI, Confidence interval.
Table 6 Multiple adjusted odds ratio for pneumonia in elderly RA patients Variables CCP Respiratory diseases Diabetes mellitus
Reference (–) Reference (–) Reference (–)
Odds ratio
95% CI
5.56 2.60 3.35
0.69–44.89 0.85–7.91 1.06–10.60
CCP, anticyclic citrullinated peptide antibody; CI, confidence interval.
first report to demonstrate the risk factors of adverse events during treatment of elderly patients with RA. Elderly patients frequently have one or more of the following characteristics: (i) renal dysfunction and delayed excretion of drugs; (ii) delayed metabolism of drugs; (iii) reduced content of water and muscles; (iv) reduced serum concentration of albumin; (v) being
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treated with multiple medications; and (vi) reduced immunocompetence. These states were linked to an increase in serum drug concentrations, interactions of drugs and an increased risk of infections. The total number of lymphocytes was decreased in an elderly population and aging was associated with a reduced percentage of mature T cells (CD3+ cells) and killer/suppresser T cells (CD8+ cells) and an increased percentage of activated T cells (CD3+ human leukocyte antigenDR+ cells).9,10 It was demonstrated in this study that advanced Steinbrocker stage was a risk factor for infections. Koike et al. showed the relationship between duration of RA and Steinbrocker functional class or radiographic stage in a post-marketing surveillance (PMS) study of etanercept, and reported that older age, higher Steinbrocker functional class and presence of comorbidities could be related to the higher incidence of serious adverse events among patients with longer duration of RA.11 Although Steinbrocker functional class was higher in our RA patients with infections than that in patients without infection, it was not selected as a risk factor for infections. In patients with RA, irrespective of the treatment, infections frequently involve the respiratory tract. Our multiple logistic analyses revealed that pre-existing chronic lung disease was one of the strong predictors of infections. Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA.12 ILD is found in
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up to 30% of patients with RA.13 Bronchiectasis was identified in 18% to 30% of RA patients in small studies by high-resolution computed tomography.14 The confirmation of pre-existing pulmonary diseases prior to treatment is strongly recommended to prevent elderly RA patients from infections. We have shown that the incidence of pneumonia is higher among RA patients with DM. The number of DM patients in Japan has been steadily increasing, and thus it has also increased among RA patients. We examined the levels of hemoglobin A1c (HbA1c) in 498 patients with RA.15 Serum HbA1c levels higher than 6.5% were found more often in RA patients (23.1%) compared to patients with other diseases (18.9%). The rate increased gradually with age. The treatment plan for a patient with RA should also include tests for DM. A large-scale PMS study was carried out to determine the safety profile of the monoclonal antibody infliximab in Japanese RA patients.16 The risk factors identified for bacterial pneumonia were male gender, age 60– 70 years or older, Steinbrocker stage III or IV, and comorbid respiratory disease.16 The Japan College of Rheumatology 2010 guidelines for the use of the biologic etanercept in RA indicated that the risk factors for bacterial pneumonia were advanced age, comorbid respiratory disease and use of corticosteroids.7 Although our article primarily attempts to demonstrate the risk factors for the treatments of elderly RA patients, we were unable to provide the difference in risk factors among the treatment regimens, including the biologics, and this could be regarded as a limitation. Since the numbers of elderly RA patients have been increasing, it is important to monitor the incidence of severe infections. Elderly patients with RA who have complications should be carefully selected before treatments are considered, and they should be followed-up closely for adverse events.
ACKNOWLEDGEMENTS All the authors contributed significantly to the submitted work, and they have read and approved the manuscript.
CONFLICT OF INTEREST AK has received lecture fees and/or research grants from Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Company, Pfizer Japan, Abbvie
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GK, Eisai Co., Chugai Pharmaceutical Co. and Astellas Pharma Inc. TO has received a research grant from Mitsubishi Tanabe Pharma Co.
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