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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To elucidate the safety of adalimumab for rheumatoid arthritis (RA) patients with renal insufficiency, including those with end-stage renal disease undergoing hemodialysis.

Methods

Sixty-five RA patients, including 2 patients undergoing hemodialysis, treated with adalimumab in our hospital from December 1, 2008 to June 30, 2011 were retrospectively analyzed. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) calculated from the Cockcroft-Gault formula at the start and end of followup after adalimumab treatment. The proportion of the patients who discontinued or switched adalimumab treatment and the change of the eGFR were compared between patients with (n = 39) and without (n = 26) renal insufficiency, defined as an eGFR <60 ml/minute/1.73 m2.

Results

There was no significant difference between the 2 groups in the proportion of the patients who discontinued or switched adalimumab treatment (51.3% versus 50.0%; P = 0.53). The mean ± SD changes of eGFR were from 41.6 ± 13.3 to 43.4 ± 17.9 ml/minute/1.73 m2 in patients with renal insufficiency and from 83.6 ± 17.5 to 83.0 ± 16.8 ml/minute/1.73 m2 in patients without renal insufficiency, and the differences in each group were not statistically significant (P = 0.92 and P = 0.78, respectively). No severe infections or other severe adverse events were observed in either group during adalimumab treatment.

Conclusion

Our data indicate that adalimumab does not worsen renal function and has no serious adverse events even for RA patients with renal insufficiency, including those undergoing hemodialysis, and suggest that it could be a potential therapeutic option for them.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by inflammatory changes in joints, and sometimes involves extraarticular features. Renal insufficiency is a common comorbidity in patients with RA, caused by drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs), including gold compounds, D-penicillamine, cyclosporine, and methotrexate (MTX), secondary renal amyloidosis, and various types of glomerulonephritis (1). Some RA-related drugs, such as NSAIDs and DMARDs, may also have serious toxic effects when used in patients with even mild renal insufficiency. As for the use of MTX, which has been established as the anchor drug for the treatment of RA, severe or fatal consequences can occur even at very low doses (2.5 mg once a week) and after a single administration in patients with a glomerular filtration rate (GFR) <15 ml/minute/1.73 m2 (2). Therefore, decreased renal function is a major limiting factor for the use of RA-related drugs, such as NSAIDs and DMARDs.

Recently, the efficacy and safety of anti–tumor necrosis factor α (TNFα) agents have been established in patients with RA, even for patients who have become refractory to DMARDs. Some reports have demonstrated the efficacy and safety of anti-TNFα agents even in RA patients with renal insufficiency (3, 4). However, these have only been case reports or small case series, and there are no available data supporting the safety of a specific anti-TNFα agent in a larger population of RA patients with renal insufficiency.

To elucidate the safety of a specific anti-TNFα agent, adalimumab, for RA patients with renal insufficiency, including those with end-stage renal disease (ESRD) undergoing hemodialysis, we retrospectively analyzed 65 RA patients treated with adalimumab in our hospital.

Significance & Innovations

  • Few studies have reported the use of adalimumab in the treatment of rheumatoid arthritis (RA) patients with renal insufficiency, and no data are available regarding the treatment of those patients undergoing hemodialysis.

  • Adalimumab does not worsen renal function and has no serious adverse events even in RA patients with renal insufficiency, including those receiving hemodialysis, and could be a potential therapeutic option for them as well as for those patients without renal insufficiency.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Patients and study design.

Sixty-five consecutive patients with RA, including 2 patients undergoing hemodialysis, who started treatment with adalimumab (40 mg subcutaneously every other week) in our hospital from December 1, 2008 to June 30, 2011 were retrospectively analyzed in this study. The 2 patients underwent hemodialysis 3 times per week for 4 hours each visit, and were administered adalimumab on a nonhemodialysis day. A manual chart review of all patients was performed at our hospital. Inclusion criteria required that all patients fulfill the American College of Rheumatology 1987 criteria for RA (5) and show an unsatisfactory response to treatment with DMARDs and/or prednisone, NSAIDs, or other biologic agents for at least 3 months. Patients with persistent or severe infections or a history of active tuberculosis were excluded. The following data were obtained at the time of the first administration of adalimumab: age; sex; body mass index (BMI); serum creatinine; rheumatoid factor (RF); anti–citrullinated protein antibody (ACPA); matrix metalloproteinase 3 (MMP-3); C-reactive protein (CRP) level; duration of RA and adalimumab treatment; Steinbrocker stage and class; history of hypertension and diabetes mellitus; use of prednisone, MTX, and other nonbiologic DMARDs; and pretreatment with other biologic agents.

Renal function was evaluated by the estimated GFR (eGFR) calculated from the Cockcroft-Gault formula modified for Japanese patients: [0.789 × (140 − age) × weight (kg)/(72 × serum creatinine) × (0.85 for women) × (body surface area/1.73 m2)] (6, 7). Renal insufficiency was defined as an eGFR <60 ml/minute/1.73 m2.

The 65 patients were divided into 2 groups with (n = 39) and without (n = 26) renal insufficiency, and were followed until discontinuation or switching of adalimumab treatment or July 31, 2011, whichever came first. The proportion of the patients who discontinued or switched adalimumab treatment because of a lack of efficacy (physician statement) or adverse events and the change of eGFR at the start and end of followup after adalimumab treatment were assessed and compared between the 2 groups. Two patients undergoing hemodialysis were excluded from the evaluation of eGFR because of ESRD. This study was approved by the ethical committee of Toranomon Hospital. All of the patients provided written informed consent prior to enrollment in the study.

Statistical analysis.

The results are expressed as the mean ± SD or median with interquartile range (IQR), as appropriate. The significance of differences between continuous variables was tested using either the t-test or Mann-Whitney U test, as appropriate. The difference in the distribution of categorical variables was tested using the chi-square test. P values less than 0.05 were considered statistically significant. Statistical analyses were performed using SPSS software package for Windows, version 11.01J.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Baseline characteristics of the patients.

Table 1 shows the characteristics of the analyzed RA patients at the start of adalimumab treatment. The mean ± SD age was 64.8 ± 12.7 years and 20.0% were men. The mean ± SD serum creatinine level and eGFR were 0.71 ± 0.32 mg/dl and 58.9 ± 25.7 ml/minute/1.73 m2, respectively. There were no significant differences between the 2 groups in sex, BMI, RF, ACPA, MMP-3, CRP level, duration of RA and adalimumab treatment, Steinbrocker stage and class, history of diabetes mellitus, use of prednisone and other nonbiologic DMARDs, and pretreatment with other biologic agents. There was also no significant difference in the median duration of adalimumab treatment between the 2 groups (31.0 weeks [IQR 28.6 weeks] versus 23.4 weeks [IQR 25.2 weeks]; P = 0.27).

Table 1. Clinical and laboratory findings of patients with RA treated with adalimumab*
 With renal insufficiency (n = 39)Without renal insufficiency (n = 26)Total (n = 65)P
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; eGFR = estimated glomerular filtration rate; RF = rheumatoid factor; ACPA = anti–citrullinated protein antibody; MMP-3 = matrix metalloproteinase 3; IQR = interquartile range; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug.

  • By chi-square test, unpaired t-test, and Mann-Whitney U test.

  • Two patients requiring hemodialysis were excluded.

Age, mean ± SD years70.1 ± 8.156.8 ± 14.364.8 ± 12.7< 0.001
Male sex7 (17.9)6 (23.1)13 (20.0)0.61
Body mass index, mean ± SD kg/m220.3 ± 3.321.7 ± 4.120.9 ± 3.70.24
Serum creatinine, mean ± SD mg/dl0.83 ± 0.350.54 ± 0.160.71 ± 0.32< 0.001
eGFR, mean ± SD ml/minute/1.73 m241.6 ± 13.383.6 ± 17.558.9 ± 25.7< 0.001
RF positive25 (64.1)20 (76.9)45 (69.2)0.27
ACPA positive27 (69.2)17 (65.4)44 (67.7)0.15
MMP-3, median (IQR) ng/ml131.5 (156.9)113.7 (129.7)131.0 (144.7)0.72
CRP level, median (IQR) mg/dl0.7 (2.5)1.7 (1.8)1.0 (2.4)0.057
Duration of RA, median (IQR) years9.5 (9.2)5.5 (12.0)14.3 (10.0)0.60
Duration of adalimumab treatment, median (IQR) weeks31.0 (28.6)23.4 (25.2)23.4 (28.2)0.27
Steinbrocker stage, mean ± SD3.1 ± 0.92.7 ± 1.02.9 ± 0.90.19
Steinbrocker class, mean ± SD2.7 ± 0.82.4 ± 0.92.6 ± 0.80.30
Hypertension20 (51.3)4 (15.4)24 (36.9)0.003
Diabetes mellitus5 (12.8)3 (11.5)8 (12.3)0.60
Prednisone use22 (56.4)17 (65.4)39 (60.0)0.27
Methotrexate use21 (53.8)20 (76.9)41 (63.1)0.059
Other DMARD use17 (43.6)11 (42.3)28 (43.1)0.78
Pretreatment with biologic agents19 (48.7)16 (61.5)35 (53.8)0.31

Compared with patients without renal insufficiency, age and history of hypertension were significantly greater in patients with renal insufficiency (mean ± SD 70.1 ± 8.1 years versus 56.8 ± 14.3 years; P < 0.001 and 20 [51.3%] of 39 patients versus 4 [15.4%] of 26 patients; P = 0.003, respectively). Although the difference between the 2 groups was not significant, the use of MTX tended to be lower in patients with renal insufficiency compared with patients without renal insufficiency.

Discontinuation or switching of adalimumab and renal function during treatment.

There was no significant difference in the proportion of the patients who discontinued or switched adalimumab treatment because of either lack of efficacy or adverse events between the 2 groups (20 [51.3%] of 39 patients versus 13 [50.0%] of 26 patients; P = 0.53).

Among 20 of the 39 patients who discontinued or switched adalimumab in patients with renal insufficiency, the reasons for discontinuation or switching of adalimumab did not include exacerbation of renal function, but rather were due to lack of efficacy (n = 17 [43.6%]) and adverse events (skin rash: n = 3 [7.7%]). Similarly, among 13 of the 26 patients who discontinued or switched adalimumab in patients without renal insufficiency, the reasons for discontinuation or switching of adalimumab were not exacerbation of renal function, but rather lack of efficacy (n = 10 [38.5%]) and adverse events (interstitial pneumonia: n = 2 [7.7%] and skin rash: n = 1 [3.8%]). There were also no significant differences in the proportion of the patients with lack of efficacy and with adverse events between the 2 groups (17 [43.6%] of 39 patients versus 10 [38.5%] of 26 patients; P = 0.68 and 3 [7.7%] of 39 patients versus 3 [11.5%] of 26 patients; P = 0.46, respectively) (Table 2). The interstitial pneumonia and skin rash were not severe and improved promptly after discontinuation of adalimumab and administration of prednisone without further exacerbation.

Table 2. Comparison of the causes of discontinuation or switching of adalimumab treatment*
 With renal insufficiency (n = 39)Without renal insufficiency (n = 26)P
  • *

    Values are the number (percentage). There was no significant difference in the duration of adalimumab treatment between the 2 groups (median 31.0 weeks [interquartile range (IQR) 28.6 weeks] vs. median 23.4 weeks [IQR 25.2 weeks]; P = 0.27).

Inefficacy17 (43.6)10 (38.5)0.68
Adverse events3 (7.7)3 (11.5)0.46
 Skin rash3 (7.7)1 (3.8) 
 Interstitial pneumonia0 (0)2 (7.7) 
Total20 (51.3)13 (50.0)0.53

The mean ± SD changes of eGFR at the start and end of followup after adalimumab treatment were from 41.6 ± 13.3 to 43.4 ± 17.9 ml/minute/1.73 m2 in patients with renal insufficiency and from 83.6 ± 17.5 to 83.0 ± 16.8 ml/minute/1.73 m2 in patients without renal insufficiency, and the differences were also not statistically significant in each group (P = 0.92 and P = 0.78, respectively) (Figures 1A and B). No severe infections or other severe adverse events were observed in either group during adalimumab treatment.

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Figure 1. The changes of the estimated glomerular filtration rate calculated from the Cockcroft-Gault formula (CG-eGFR) at the start and end of followup after adalimumab treatment. A, Rheumatoid arthritis (RA) patients with renal insufficiency (n = 39). B, RA patients without renal insufficiency (n = 26). The mean ± SD differences of the CG-eGFR changes in each group were not statistically significant (41.6 ± 13.3 vs. 43.4 ± 17.9 ml/minute/1.73 m2; P = 0.92 and 83.6 ± 17.5 vs. 83.0 ± 16.8 ml/minute/1.73 m2; P = 0.78, respectively).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Although renal insufficiency is known as a common comorbidity in patients with RA, few studies have investigated the therapeutic strategies for RA patients with renal insufficiency, much less for those undergoing hemodialysis. In this study, we demonstrated no significant differences of the proportion of patients who discontinued or switched adalimumab and the mean changes of eGFR during the treatment between patients with and without renal insufficiency, defined as an eGFR less than 60 ml/minute/1.73 m2. No severe infections or adverse events were observed in those with renal insufficiency during the treatment.

Decreased renal function is a major limiting factor for the use of RA-related drugs such as NSAIDs and DMARDs (3). When renal function is decreased, the RA-related drugs frequently require dose reduction or drug cessation to avoid serious toxic effects. For instance, MTX is one of the most commonly used and established main drugs for the treatment of RA, and is eliminated primarily by the kidneys. Therefore, compromised renal function can result in increased serum levels of MTX leading to life-threatening toxicity, such as pancytopenia (8–10). Dose adjustment and cessation of RA-related drugs for patients with renal insufficiency, however, may sometimes lead to undertreatment and inadequate control of RA.

Anti-TNFα agents have proven to be a major advance in the treatment of RA, and their efficacy and safety have been established in patients with RA. However, they are limited only for those with normal renal function, and no pharmacokinetic data are available in patients with renal insufficiency. Recently, several reports have demonstrated the efficacy and safety of anti-TNFα agents, even in RA patients with renal insufficiency (3, 4). Hueber et al reported 11 patients (9 patients with RA, 1 patient with psoriatic arthritis, and 1 patient with juvenile rheumatoid arthritis) with impaired renal function (serum creatinine level ≥1.1 mg/dl) who were treated with infliximab, etanercept, or adalimumab. During the followup period up to 24 months, no significant increases in serum creatinine could be detected, compared with baseline, and no severe infections or other serious adverse events were observed. No differences were observed among the anti-TNFα agents (3). Adalimumab, however, was only given to 2 patients for a relatively short period during the study.

There have also been some reports of anti-TNFα treatment for RA patients with ESRD undergoing hemodialysis (11–14). Don et al reported the safety of etanercept in 6 patients with ESRD receiving hemodialysis during a 3-month treatment phase and subsequent 6-month followup period. They showed that the pharmacokinetics of etanercept in patients with ESRD receiving hemodialysis was similar to that in patients with normal renal function (11). Sugioka et al administered etanercept to a patient with RA receiving hemodialysis and demonstrated a significant clinical improvement without any side effects after 12 weeks of treatment (12). Infliximab has also been reported to be a safe and effective treatment for patients with RA receiving hemodialysis (13).

There are few reports regarding the use of adalimumab in the treatment of RA patients with renal insufficiency, and no data are available regarding the treatment of those patients undergoing hemodialysis. Kobak demonstrated the efficacy and safety of adalimumab during 12 weeks of treatment in a 65-year-old male patient with active ankylosing spondylitis who was undergoing peritoneal dialysis. They also reported the pharmacokinetics of adalimumab and mentioned that it had no effect on renal function and could be safely administered even to patients undergoing dialysis, since adalimumab is hydrolyzed in lysosomes similar to other anti-TNFα agents, such as etanercept and infliximab (14). Indeed, adalimumab is a recombinant, fully human IgG1 monoclonal antibody composed of heavy and light chain variable regions and IgG1:κ constant regions. It consists of 1,330 amino acids and has a molecular weight of approximately 148 kd. It is structurally and functionally indistinguishable from naturally occurring human IgG1 (15). As for the antibody elimination, renal elimination, which is the primary pathway for the clearance of small-molecule drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the glomerulus. The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor-mediated endocytosis. Therefore, although no data are available regarding dialyzability of adalimumab, significant drug removal by conventional hemodialysis techniques is unlikely based on the physicochemical characteristics of the drug, such as the molecular size or volume distribution.

These data strongly suggest that adalimumab, a fully human IgG1 monoclonal antibody, is not affected by renal function and could be administered without dose reduction, even to RA patients with renal insufficiency and including those undergoing hemodialysis. Needless to say, since renal insufficiency is characterized by impairment of host defenses, treatment with anti-TNFα agents could lead to unpredictable immune responses resulting in serious infection. Therefore, close monitoring and followup are required when administering adalimumab to RA patients with renal insufficiency.

There are a number of limitations of this study that should be acknowledged. This study is a single-center retrospective cohort study with a small number of patients that cannot be interpreted without considering selection bias and generalizability, and the followup period was variable between patients. It also lacked a detailed evaluation of the efficacy of adalimumab treatment using the Disease Activity Score for 28 joint count or the Health Assessment Questionnaire score, etc. Further clinical studies in larger patient populations are required to confirm the safety and efficacy for RA patients with renal insufficiency.

In conclusion, in this study, we demonstrated that adalimumab does not worsen renal function and has no serious adverse events in RA patients with renal insufficiency, including those undergoing hemodialysis. These results strongly suggest that adalimumab could be a potential therapeutic option for RA patients with renal insufficiency, including hemodialysis, as well as those patients without renal insufficiency.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Sumida had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Sumida, Ubara, Suwabe, Hayami, Hiramatsu, Hasegawa, Yamanouchi, Hoshino, Sawa, Takaichi.

Acquisition of data. Sumida, Ubara, Suwabe, Hayami, Hiramatsu, Hasegawa, Yamanouchi, Hoshino, Sawa, Takaichi.

Analysis and interpretation of data. Sumida, Ubara, Suwabe, Hayami, Hiramatsu, Hasegawa, Yamanouchi, Hoshino, Sawa, Takaichi.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES