Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatment of rheumatoid arthritis

OBJECTIVE: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. METHODS: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. RESULTS: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. CONCLUSIONS: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage.     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Abstract

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Kidney involvement in rheumatoid arthritis

Rheumatoid Arthritis (RA) is a widespread disease and its renal involvement, relatively common, is clinically significant because worsens course and mortality of the primary disease. There is still no agreement on the prevalence of renal disorders in RA: data analysis originates from different sources, as death certificates, autopsies, clinical and laboratory findings and kidney biopsies, each with its limitations. Histoimmunological studies on bioptical specimens of patients with RA and kidney damage, led to clarify prevalent pathologies. In order of frequency: glomerulonephritis and amyloidosis (60-65% and 20-30% respectively), followed by acute or chronic interstitial nephritis. Kidney injury during RA includes secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs and nephropathies as extra-articular manifestations (rheumatoid nephropathy). Amyloidosis affects survival, increases morbidity and is the main cause of end stage renal disease in patients with RA and nephropathy. Strong association between RA activity and amyloidosis needs the use of immunosuppressive and combined therapies, to prevent this complication and reduce risk of dialysis. Long-lasting and combined RA pharmacotherapy involves various renal side effects. In this review we describe NSAIDs and DMARDs (Disease-Modifying Antirheumatic Drugs) nephrotoxicity, particularly by gold compounds, D-penicillamine, cyclosporine A and methotrexate. Rare cases of IgA glomerulonephritis during immunomodulating therapy with leflunomide and TNF blocking receptor (etanercept) are reported; real clinical significance of this drug-related nephropathy will be established by development of RA treatment. In RA nephropathies, mesangial glomerulonephritis is the most frequent histological lesion (35-60 % out of biopsies from patients with urinary abnormalities and/or kidney impairment), followed by minimal change glomerulopathy (3-14%) and p-ANCA positive necrotizing crescentic glomerulonephritis.     

Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis

OBJECTIVE: The efficacy of biological therapies in rheumatoid arthritis (RA) is well known, but their hypothetical benefit in amyloid A (AA) amyloidosis secondary to RA still remains to be considered. We evaluated the efficacy and safety of etanercept in serum amyloid A (SAA) 1.3 allele Japanese patients with AA amyloidosis secondary to RA. METHODS: Seven RA patients with histologically confirmed AA amyloidosis and renal involvement who were treated with etanercept were enrolled. They all had the SAA1.3 allele, which has been shown to be a risk factor not only for the association of AA amyloidosis but also for a poor prognosis in Japanese RA patients. Efficacy was assessed as a sustained decrease in RA inflammation and an amelioration of renal function. RESULTS: RA inflammation and AA amyloidosis were improved and stabilized after 43.4 +/- 16.5 weeks. At week 20 the number of tender (p = 0.017) and swollen (p = 0.017) joints, and levels of serum C-reactive protein (p = 0.018) and albumin (p = 0.045) had improved. The values for SAA, serum creatinine, calculated creatinine clearance, and proteinuria also ameliorated. No severe adverse events were observed. One patient eventually had to go on hemodialysis but her tolerance of etanercept remained stable. CONCLUSION: Etanercept can be used safely and effectively in AA amyloidosis secondary to RA with renal involvement, and is of clinical benefit in the short-term, even in patients on hemodialysis. It appears that SAA1.3 allele may be used as a clinical parameter for the introduction of etanercept in Japanese RA with AA amyloidosis.     

TNF inhibitors induce discoid fibrosis in the sublining layers of the synovium with degeneration of synoviocytes in rheumatoid arthritis

We determined the characteristic features of synovial tissues of rheumatoid arthritis (RA) patients treated by TNF inhibitors in order to delineate their mechanism of action. Synovial tissues were obtained during the joint surgical operations from 12 RA patients who had been treated with TNF inhibitors in addition to disease modifying antirheumatic drugs (DMARDs) for at least 5 months (5–25 months) (RA-TNFinh), and from 12 RA patients who had been treated with DMARDs alone (RA-DMARD), and were evaluated under light microscopy. There were no significant differences in disease duration, serum CRP levels, DAS28, Steinbrocker’s stages on X-ray and treatment regimen except for TNF inhibitors between RA-TNFinh and RA-DMARD. The most prominent changes in the synovium from RA-TNFinh were discoid fibrosis in the subliming layers of the synovium with degeneration and detachment of synoviocytes and marked decrease in vasculatures. There was no significant difference in these synovial features between RA patients with infliximab and those with etanercept. Interestingly, appearance of osteoclasts was observed in RA-TNFinh (3 out of 12 patients) and in RA-DMARD (1 out of 12 patients). These results indicate that not only infliximab, but etanercept might have direct actions on synovial cells in the deep lining layers of the synovium, leading to the discoid fibrosis thereof. Moreover, the data confirm that the deep lining or sublining layers of the synovium are the most important portions that steer the disease process of RA synovitis.     

Efficacy and safety of tacrolimus treatment for rheumatoid arthritis patients undergoing hemodialysis

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.     

Efficacy and safety of tacrolimus treatment for rheumatoid arthritis patients undergoing hemodialysis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.     

Life-threatening reversible bone marrow toxicity in a rheumatoid arthritis patient switched from leflunomide to infliximab

SIR, As a result of the introduction of new disease-modifyinganti-rheumatic drugs (DMARDs) for the treatment of rheumatoidarthritis (RA), patients with refractory RA tend to be treatedwith an increasing number of different DMARDs, alone or in combination.This improves the chances of achieving good disease controlbut also risks triggering adverse reactions. We report the case of a 66-yr-old man with RA in whom treatmentwith some recently marketed DMARDs was responsible for life-threateningbone marrow toxicity. The patient's clinical history includedRA (since 1992), type II diabetes, essential arterial hypertension,chronic urate nephropathy and mild renal failure. No historyof abnormal blood cell     

Successful leukocytapheresis therapy in a patient with rheumatoid arthritis on maintenance hemodialysis

Abstract

We report the case of a 44-year-old female undergoing maintenance hemodialysis in whom early-phase rheumatoid arthritis (RA) was successfully treated by leukocytapheresis (LCAP). The effects of prednisone, tacrolimus, and etanercept were limited, but LCAP was highly effective and its efficacy continued even after cessation of LCAP. Moreover, remission was maintained for 2 years after discontinuation of medication. LCAP may be an important treatment option for RA patients with end-stage renal failure who are on hemodialysis.     

Prediction of DAS28-ESR remission at 6?months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.     

Efficacy and safety of adalimumab in a patient with ankylosing spondylitis on peritoneal dialysis

The most commonly used treatments in patients with ankylosing spondylitis include nonsteroidal anti-inflammatory and disease modifying anti-rheumatic drugs (DMARDs), but most of these have nephrotoxic effects. In patients who undergo chronic hemodialysis, DMARDs are not widely preferred due to the chance of increased adverse effect incidence and the risk on patient survival, in addition to already present immunosuppression. The efficacy and safety of anti-TNF alpha drugs for the treatment of renal dysfunction that develops associated to secondary amyloidosis in inflammatory rheumatic diseases have been reported in various studies. In this report, the efficacy and safety of adalimumab was shown in patients with active ankylosing spondylitis who undergo peritoneal dialysis because of chronic renal failure.     

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

Abstract

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.     

Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab

TNF-alpha is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis. TNF-alpha blockers such as infliximab and etanercept are currently used in the treatment of active rheumatoid arthritis (RA) when traditional DMARDs have failed and are effective in a significant proportion of patients. However, about one third are non-responders to anti-TNF-alpha.The aim of this study was to verify whether rheumatoid patients, after failing infliximab, can benefit from etanercept.We analysed 18 patients with active RA with no response to at least 3 DMARDs and where infliximab therapy had failed. The patients had received infliximab associated with methotrexate: eleven of them did not show any significant response, while seven patients, after a good response, relapsed. Etanercept was then started. EULAR criteria of response were used with calculation of activity index DAS28 at baseline, after 2 weeks, 3 months and every third month until last follow-up. A moderate or good response was achieved with etanercept in 13 out of 18 patients. From our experience, etanercept can be considered as a good alternative choice when infliximab has failed.     

The efficacy and safety of etanercept in patients with rheumatoid arthritis and spondyloarthropathy on hemodialysis

We aimed to evaluate the efficacy and safety of long-term use of etanercept therapy in patients with spondyloarthropathy (SpA) and rheumatoid arthritis (RA) on hemodialysis (HD). Selected RA or SpA patients treated with etanercept under HD were retrospectively evaluated. Etanercept-related adverse events were closely recorded for all patients. At the follow-up, erythrocyte sedimentation rate and C-reactive protein levels were monitored. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for SpA patients and Disease Activity Score (DAS28) for RA patients were measured at every 3 or 6 months. In total five end-stage renal disease (ESRD) patients were enrolled to the study. The causes of ESRD in the study subjects were amyloidosis (n = 2), analgesic nephropathy (n = 2), and nephrolithiasis (n = 1). Three were diagnosed as SpA and two were RA. All patients used etanercept. The median age was 39 years (range 22–72 years). The median disease duration was 12 years (range 2–20 years). The median follow-up after etanercept therapy was 18 months (range 5–33 months). DAS28 score decreased after the treatment and did not increase during follow-up in RA patients. BASDAI score decreased after the treatment during follow-up in three patients with SpA. At the follow-up, only one patient was diagnosed with septic arthritis. As a result of our study, etanercept treatment in RA and SpA patients on HD seems to be safe, well tolerated, and effective in most of the patients. Above all, due to impaired host defense in patients with ESRD, enhanced risk of infections should be kept in mind during follow-up period and larger trials are needed to prove the safety of etanercept in HD patients.     

Transcatheter arterial chemotherapy with miriplatin for patients with hepatocellular carcinoma and chronic renal failure

Miriplatin is a novel lipophilic platinum complex developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, there is no reliable data regarding clinical toxicity of miriplatin in HCC patients with chronic renal failure. We retrospectively evaluated the safety and efficacy of transcatheter arterial chemotherapy with miriplatin in 67 HCC patients with chronic renal failure (estimated glomerular filtration rate [GFR] by the Cockcroft-Gault equation <60ml/min). Estimated GFR within 2 months after miriplatin administration did not decrease significantly by the Wilcoxon signed rank test (pretreatment;46ml/min, 1 month;48ml/min;P=0.019, 2 months;45ml/min;P=0.619 [P<0.003 was significant by the Bonferroni correction]). Complete response in terms of tumor necrosis was achieved in 14 of 67 patients and no serious adverse events were observed. These results suggested that transcatheter arterial chemotherapy with miriplatin can be used safely for HCC patients with chronic renal failure.     

Effectiveness, predictive response factors, and safety of anti-tumor necrosis factor (TNF) therapies in anti-TNF-naive rheumatoid arthritis

OBJECTIVE: To evaluate the effectiveness and safety of anti-tumor necrosis factor (anti-TNF) therapies in rheumatoid arthritis (RA), and to identify the factors involved in this response. METHODS: Dynamic prospective cohort study of patients with RA treated with anti-TNF under clinical practice conditions. Effectiveness was evaluated using Disease Activity Score (DAS) 28, European League Against Rheumatism (EULAR) response, Health Assessment Questionnaire (HAQ), and time to treatment failure. Prior adherence was evaluated retrospectively and safety was evaluated by adverse events (AE). The analysis was restricted to anti-TNF-naive patients. RESULTS: The study included 161 patients treated for RA during 6 years (60 infliximab, 79 etanercept, and 22 adalimumab). At 6 months, 15% reached a good EULAR response and 38% a moderate response. A mean decrease of -1.5 (p < 0.0001) was observed in the DAS28 and of -0.34 in the HAQ (p < 0.0001); however, women showed poorer progress in terms of DAS and HAQ. In the first year, 64.3% did not experience treatment failure and this figure was 50.5% after 2 years. In one-third, glucocorticoids were withdrawn and in the remainder the dose was reduced by 50%. Adherence to treatment, selection of etanercept, and intensification of infliximab were associated with a lower probability of premature failure in the multivariate model. AE were similar to other those in studies and no outstanding differences in safety were found between the 3 anti-TNF therapies. CONCLUSIONS: Anti-TNF treatments are effective and safe, reducing the activity of the disease, disability, and the need for corticosteroids. Patients who displayed good adherence prior to the anti-TNF treatment and were treated with etanercept or with increasing doses of infliximab had the best chance of displaying a response.     

Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis

OBJECTIVE: To evaluate safety and efficacy of etanercept treatment in elderly (age > or = 65 yrs) and younger adult subjects (age < 65 yrs) with rheumatoid arthritis (RA). METHODS: Subset analyses were used to describe the safety and efficacy of etanercept in elderly and younger subjects treated for early and disease modifying antirheumatic drug-resistant or late-stage RA (ERA and LRA) in one of 4 randomized controlled clinical studies (N = 1353) or 2 longterm extensions (N = 1049). RESULTS: Rates of serious adverse events tended to be higher in elderly than younger subjects; however, rates of safety events observed in elderly etanercept-treated subjects did not exceed rates in elderly placebo or methotrexate (MTX)-treated subjects. With regard to efficacy measures [American College of Rheumatology 20% response (ACR20), ACR50, and ACR70], elderly subjects tended to have somewhat less robust responses to treatment than younger subjects. However, for both age groups, treatment with etanercept resulted in improved efficacy and function compared with control treatment, and combination therapy with etanercept plus MTX resulted in greater efficacy than either etanercept or MTX used alone. Efficacy responses of elderly subjects were sustained for up to 6 years. Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups. CONCLUSION: Consistent with responses in younger subjects, elderly subjects with RA treated with etanercept experienced significant improvement in disease activity and function without incurring additional safety concerns.     

改善病情抗风湿药治疗类风湿关节炎167例临床分析

目的 比较使用改善病情抗风湿药(DMARD)治疗类风湿关节炎(RA)的临床效果及对RA转归的影响,提高对DMARD治疗RA的认识和评价.方法 回顾性总结了1999年1月至2003年4月门诊有随访病历RA患者一般情况、临床症状及治疗情况.通过统计学分析比较单用、二联、三联治疗组(一联组、二联组、三联组)疾病临床缓解的差异;3组间远期疗效、双手正位X线的变化;队列比较各组中不同病程的疗效;同时比较各组药物不良反应.结果 共有256例患者初治选择了DMARD,除外89例合用激素者,共167例作为研究对象.3组近期疗效比较:红细胞沉降率和(或)C反应蛋白、缓解晨僵差异无统计学意义;对关节肿、痛,二联组和三联组优于一联组.3组近期疗效比较差异有统计学意义(X2=9.858,P=0.002).3组远期疗效比较差异有统计学意义(p=0.048);远期疗效与联合治疗有关(Spearman等级相关系数rs=0.228 43,P=0.0132;CMH非零相关统计量为6.059,P=0.014).初诊时不同病程的远期疗效比较差异有统计学意义(p=0.019).3组药物副作用差异无统计学意义.结论 早期联合使用DMARD治疗RA远期与近期疗效,均优于单一药物治疗.     

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.