Lessons learned in the use of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis

Tumor necrosis factor-alpha (TNFα) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are cur-rently three available anti-TNFα agents for the treatment of RA—adalimumab, etanercept, and infliximab. These tar-geted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFα inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often char-acterizes RA disease progression. Although anti-TNFα drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFα inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.     

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20 mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.     

Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year outcome of joint destruction (RECONFIRM-2J)

The anti-TNF-α chimeric monoclonal antibody infliximab is the first biologic to be approved for rheumatoid arthritis (RA) in Japan, and post-marketing surveillance of all of the Japanese cases treated with infliximab has been conducted to explore the safety of infliximab therapy. In addition, a retrospective clinical study on the notable efficacy and related factors of infliximab therapy in an RA management group in Japan (RECONFIRM and RECONFIRM-2) has demonstrated clinical responses. However, information on the effect of infliximab on joint destruction in Japanese RA patients remains insufficient. In this study, we retrospectively analyzed X-ray data from 67 patients in whom both hand and foot X-rays at baseline and at 54 weeks had been available among the 410 cases in the RECONFIRM-2 study. By scoring the X-rays according to the modified van der Heijde (vdH)–Sharp method, we found that the total vdH–Sharp score in the RA patients before infliximab therapy was 104.40 ± 87.34 and the yearly progression was 21.33, indicating relatively rapid progression. After infliximab therapy for 54 weeks, the total vdH–Sharp score at 54 weeks was 104.37 ± 86.87 and the estimated yearly progression was −0.03, indicating the almost complete inhibition of progression. The RECONFIRM-2J study confirmed the significant ability of infliximab to halt joint destruction in Japanese RA patients, and showed that joint destruction was significantly associated with disease activity and the dose of MTX in the patients with moderate and advanced disease durations, respectively, before infliximab therapy.     

A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.     

Influence of cyclosporin A on radiological progression in early rheumatoid arthritis patients: a 42-month prospective study

The aim of this study was to evaluate whether cyclosporin A (CsA) influences the radiological disease progression in early rheumatoid arthritis (RA) patients in comparison with other disease-modifying drugs (DMARDs). A total of 103 early RA patients, without prior use of DMARDs, were randomized to receive CsA (3 mg/kg per day) or methotrexate (MTX) (0.15 mg/kg per week). In addition, all patients received prednisone (7.5 mg/day). After 42 months of treatment, pairs of hand and wrist radiographs of 41 patients treated with CsA and 42 treated with MTX were evaluated blindly and separately by two investigators, using reference radiographs for scoring. A scale scoring similar to Larsen's standard radiographs with minor modifications was used. The studied radiographs were obtained at the beginning and 42 months after therapy in both groups. Patients in both groups responded beneficially to the above treatment regimens. In the CsA group, 37 patients (71%) remained radiographically stable and 4 worsened, while in the MTX group 39 patients (76%) remained stable and 3 deteriorated. No significant radiological worsening was found in the CsA-treated patients as compared to those treated with MTX. Early immunointervention in RA patients appears to be crucial for the future development of joint damage. CsA can delay radiological disease progression and may inhibit joint damage deterioration in early RA patients. Received: 28 August 1999 / Accepted: 3 December 1999     

Inhibition of joint destruction by methotrexate

Methotrexate (MTX) plays an important role in treatment of rheumatoid arthritis (RA). It significantly reduce expected radiographic progression. Comparing with other traditional disease-modifying anti-rheumatic drugs (DMARDs), MTX slow radiographic progression during the first 2 years. Since combination with anti-tumor nectosis factor alpha (TNF-alpha) therapy has been shown to be effective for the early supression of disease activity, it could be usefull to minimize bone destruction in RA.     

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.     

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.     

Therapy of rheumatoid arthritis: New developments and trends

The medical therapy of rheumatoid arthritis (RA) has been influenced strongly during the past decade by the recognition that many patients develop joint damage within the first year of disease. This observation has motivated rheumatologists to initiate disease-modifying antirheumatic drugs (DMARDs) early in the disease course. This trend has been matched by the increased use of combinatio DMARD therapy, with the aim to maximize control of the signs and symptoms of RA and limit the development of joint damage. The results from controlled clinical trials generally have supported the concept that early, aggressive treatment with DMARDs is superior to less intensive strategies. In addition, certain DMARD combinations are more effective than the individual components of these regimens, but the evidence is strong for only a few DMARD combinations such as methotrexate and cyclosporine A. Three new drugs have been recently approved for the treatment of RA. Celecoxib, a selective cyclooxygenase-2 inhibitor, has similar clinical efficacy as conventional nonsteroidal anti-inflammatory drugs, and in short-term studies causes no more gastric and duodenal ulcers and erosions than patients treated with placebo. Treatment with leflunomide, an inhibitor of pyrimidine synthesis, has been shown in controlled clinical trials to produce significant clinical improvement in 50% to 60% of patients with RA and delay radiologic progression of disease. The era of biologic therapy has dawned with the apparent success of tumor necrosis factor (TNF)-a blockade using etanercept, a recombinant TNF receptor:Fc fusion protein, and infliximab, a chimeric anti-TNF monoclonal antibody. These new agents expand our treatment options in RA and should lead to innovative and more effective treatment approaches.     

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis

Abstract

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20?mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.     

Efficacy of tacrolimus in infliximab-refractory progressive rheumatoid arthritis

We report a Japanese male patient with intractable rheumatoid arthritis (RA), in whom tacrolimus was effective ultimately. Five years before the admission he was diagnosed as RA, which was resistant to various disease-modifying anti-rheumatic drugs (DMARDs). Two years before, administration of infliximab was initiated although the medicine failed to control RA. In spite of the multiple joint replacement, the RA disease activity worsened. Tacrolimus (1.5 mg/day) was administered. Twenty-four weeks of tacrolimus treatment reduced the disease activity score for 28 joints-erythrocyte sedimentation rate from 7.44 to 3.65. Herein, we present a patient with RA, who was successfully treated by tacrolimus, and in whom infliximab was not effective. Tacrolimus may be one of the drugs for RA patients refractory to the conventional treatments including methotrexate or tumor necrosis factor inhibitors.     

Disease activity and functional changes of RA patients receiving different DMARDs in clinical practice

The aim of this study was to compare the effectiveness of different disease-modifying anti-rheumatic drugs (DMARDs) in improving disease activity and functional status in patients with rheumatoid arthritis (RA). One hundred and fifty-two Thai RA patients treated with at least one DMARD were enrolled in this 1-year cohort. Demographic characteristics, baseline and end-of-study data on disease activity and Health Assessment Questionnaire (HAQ) Disability Index of the subjects were compared among different DMARD options. Predictors of HAQ score were investigated using regression analysis. The results showed that the studied patients had established RA with mild to moderate activity. More than 85% were prescribed methotrexate (MTX) as single or combined DMARDs. At 1 year, improvement in most activity measures was experienced. However, all patients had functional declines. Patients taking antimalarial agents had the maximal rate of functional deterioration. Patients taking MTX-based DMARDs had significantly lower rate of functional decline than patients taking DMARDs without MTX (p=0.018). Only patients receiving MTX-based DMARDs had clinically meaningful improvement in HAQ score. The predictors of HAQ score at 1 year included baseline HAQ score and patient global assessment at end of study. In conclusion, although DMARD treatment was shown to improve disease activity in RA patients, functional deterioration was evident in our cohort. Thus, measures of functional status are more appropriate than measures of disease activity to evaluate treatment effects of DMARDs in established RA in clinical practice. MTX-based DMARDs should be prescribed where possible in RA patients with persisting activity due to their ability to delay functional deterioration.     

Krankheitsmodifizierende Effekte bei der rheumatoiden Arthritis durch Glukokortikoide

Drugs used for managing rheumatoid arthritis (RA) are designated disease-modifying antirheumatic drugs (DMARDs) if they reduce inflammation and pain, limit joint destruction, and improve long-term disease outcome. Glucocorticoids have long been known to have anti-inflammatory, immunosuppressive, and pain-reducing effects. Moreover, they have been shown in recent clinical trials, and also very recently in a systemic analysis of the results of these studies, to contribute to inhibition of the radiographic progression of RA. For these reasons, glucocorticoids can be considered DMARDs if they are used to treat patients suffering from early RA and, according to the current knowledge, are used in combination with other DMARDs.     

类风湿关节炎患者血清软骨寡聚基质蛋白水平及意义的研究

目的 探讨检测软骨寡聚基质蛋白(COMP)水平对类风湿关节炎(RA)患者疾病活动性及早期软骨破坏的临床意义.方法 采用酶联免疫吸附试验(ELISA)法,检测94例RA患者及40名健康人血清中COMP的水平.同时测定RA患者的其他实验室及临床指标:类风湿因子(RF)、红细胞沉降率(ESR)、C反应蛋白(CRP)、抗环瓜氨酸肽抗体(抗CCP抗体)、压痛关节数、疼痛关节数、肿胀关节数、晨僵时间及双手X线,分析它们与COMP的相关性.结果 RA患者血清COMP水平(11.3±5.2)U/L明显高于正常对照组的(9.2±1.7)U/L;两组差异有统计学意义(p=0.017).64例RA活动期患者血清COMP水平为(14±6)U/L,30例缓解期患者为(9±4)U/L,组间比较差异有统计学意义(p=0.005).COMP水平与RA思者的ESR、CRP、晨僵时间、压痛关节数、疼痛关节数、肿胀关节数、X,线分期呈正相关(P<0.05),与年龄、病程、RF、抗CCP抗体水平、功能分级无明显关系(p＞0.05).30例RA患者完成2年放射学随访,18例COMP值大于健康者,16例X线有递增现象,2例无递增现象;而12例COMP值正常/低于健康者,有递增5例,无递增7例,两组间差异有统计学意义(p=0.013).结论 RA患者血清中COMP高水平存在提示RA疾病活动性和早期关节软骨破坏.COMP可以作为反映RA疾病急性活动程度与软骨破坏的血清学指标.     

Fatigue in rheumatoid arthritis reflects pain, not disease activity

Objective. We determined the amount of fatigue experienced bypatients with RA, and its relationship to synovitis, pain andother common clinical features. We also examined to what extentRA fatigue is improved by disease-modifying antirheumatic drugs(DMARDs) and anti-tumour necrosis factor (TNF) therapy. Methods. We studied two cohorts of 238 and 274 RA patients cross-sectionallyand examined treatment responses in 30 RA patients startinganti-TNF and 54 starting DMARDs followed for 3 and 6 months.We measured fatigue using visual analogue scores (VAS) and MedicalOutcomes Study Short Form 36 (SF-36) vitality scores. We recordedthe disease activity score for 28 joints and its components(tender/swollen joint counts, patient global assessment, ESR),morning stiffness, health assessment questionnaire, physicianglobal assessment, erosive disease, nodules, rheumatoid factor,concomitant medications and illnesses, and the SF-36 questionnaire. Results. Fatigue was common in RA patients; over 80% had clinicallyrelevant fatigue (VAS     

Overestimation of serum levels of rheumatoid factor caused by the presence of an incorrect calibrator in the Dade Behring kit

Abstract

The anti-TNF-α chimeric monoclonal antibody infliximab is the first biologic to be approved for rheumatoid arthritis (RA) in Japan, and post-marketing surveillance of all of the Japanese cases treated with infliximab has been conducted to explore the safety of infliximab therapy. In addition, a retrospective clinical study on the notable efficacy and related factors of infliximab therapy in an RA management group in Japan (RECONFIRM and RECONFIRM-2) has demonstrated clinical responses. However, information on the effect of infliximab on joint destruction in Japanese RA patients remains insufficient. In this study, we retrospectively analyzed X-ray data from 67 patients in whom both hand and foot X-rays at baseline and at 54 weeks had been available among the 410 cases in the RECONFIRM-2 study. By scoring the X-rays according to the modified van der Heijde (vdH)–Sharp method, we found that the total vdH–Sharp score in the RA patients before infliximab therapy was 104.40 ± 87.34 and the yearly progression was 21.33, indicating relatively rapid progression. After infliximab therapy for 54 weeks, the total vdH–Sharp score at 54 weeks was 104.37 ± 86.87 and the estimated yearly progression was ?0.03, indicating the almost complete inhibition of progression. The RECONFIRM-2J study confirmed the significant ability of infliximab to halt joint destruction in Japanese RA patients, and showed that joint destruction was significantly associated with disease activity and the dose of MTX in the patients with moderate and advanced disease durations, respectively, before infliximab therapy.     

Discontinuation of infliximab in rheumatoid arthritis patients in clinical remission

Biologic drugs are effective but are also expensive, and it is difficult to evaluate the duration of treatment. Infliximab, an anti-TNFα antibody, suppresses arthritic activity and inhibits bone destruction in patients with rheumatoid arthritis (RA). Here, we document that infliximab could be discontinued after clinical remission in RA patients. Among 172 patients with RA who reached clinical remission following infliximab (3 mg/kg) and methotrexate (MTX, >6 mg/w), nine patients with sustained remission discontinued it. Clinical assessment was based on a disease activity score (DAS) that included a 28-joint count/erythrocyte sedimentation rate (DAS28-ESR). The disease was assessed before and after the start of infliximab treatment, and concomitant drug treatment—in the order of corticosteroid, nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying anti-rheumatic drugs (DMARDs) other than MTX—was gradually discontinued. We considered patients for discontinuation of infliximab treatment after remission (DAS28-ESR < 2.6) had been sustained for more than 24 weeks. The nine patients able to discontinue treatment were all females, with a mean age of 53.8 years; eight patients were at stage I or II. The mean duration of disease was 28.7 months, and these patients were on corticosteroid treatment equivalent to a mean of 2.28 mg prednisolone (PSL). These nine patients all met the remission standard—that DAS28-ESR < 2.6 for ≥24 weeks) —and so their treatment with concomitant drugs was discontinued. After the discontinuation of infliximab, the mean period of sustained remission was 14.2 months and the longest period was 29 months. The duration of disease was significantly shorter and the points from Steinbrocker’s stage-classification were significantly lower in the infliximab-discontinued group than in the infliximab-continued group. Strategic reductions and/or discontinuations of concomitant treatment were performed in RA patients who attained clinical remission (DAS28 < 2.6) through treatment with infliximab and MTX. Nine patients successfully discontinued infliximab after maintaining clinical remission for more than 24 weeks. After infliximab was discontinued, clinical remission and suppression of joint destruction were maintained with MTX alone, especially in early RA patients.     

A two year randomised controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease modifying antirheumatic drugs

BACKGROUND: In rheumatoid arthritis (RA), intramuscular (IM) pulsed depomedrone expedites an immediate response to disease modifying antirheumatic drugs (DMARDs). Although IM depomedrone is also widely used to treat disease flares in patients treated with DMARDs, its effect on radiological progression has not been assessed. OBJECTIVE: To evaluate the benefits of 120 mg IM depomedrone versus placebo in patients with established RA whose disease was inadequately controlled by existing DMARDs. METHODS: In a 2 year prospective randomised controlled trial patients were assessed using the ILAR/WHO core dataset, disease activity score (DAS28), x ray examination of hands and feet scored by Larsen's method, and bone densitometry. RESULTS: 291 patients with RA were screened, 166 were eligible, and 91 consented and were randomised. Disease activity improved more rapidly in the steroid treated patients than with placebo, but after 6 months no difference remained. A small but significant reduction in erosive damage in the steroid group compared with placebo was also found. More adverse reactions occurred in the steroid treated group than in the placebo patients (55 v 42), especially those reactions traditionally related to steroids (16 v 2), including vertebral fracture, diabetes, and myocardial infarction. Hip bone density fell significantly in steroid treated but not placebo patients. CONCLUSIONS: IM depomedrone improved disease activity in the short term and produced a small reduction in bone erosion at the cost of a significant increase in adverse events. Despite the initial benefit of IM depomedrone, when patients respond suboptimally to a DMARD they should not be given long term additional steroids but should be treated with alternative or additional DMARDs.     

Prevention of joint destruction by tacrolimus in patients with early rheumatoid arthritis: a post hoc analysis of a double-blind, randomized, placebo-controlled study

Abstract

Objectives A multicenter, randomized, double-blind, placebo-controlled study of the oral calcineurin inhibitor tacrolimus was performed in patients with early rheumatoid arthritis who had responded poorly to disease-modifying antirheumatic drugs (DMARDs), and factors related to suppression of joint destruction were investigated.

Methods The change in the total Sharp score (?TSS) was assessed by univariate analysis in patients with X-ray films to identify the main determinant of a ?TSS of <0.5 in week 52. Patients with this factor were then investigated further.

Results Univariate analysis showed that a baseline C-reactive protein (CRP) level of <1.5 mg/dL was the major determinant of ?TSS <0.5 at week 52 in the tacrolimus group. Detailed analysis of patients with a baseline CRP of <1.5 mg/dL revealed no significant differences in background factors between the two groups. In week 52, ?TSS was significantly smaller in the tacrolimus group than in the placebo group (2.67 ± 5.40 vs. 8.05 ± 10.32, respectively, p = 0.017). Both groups had a similar incidence of adverse reactions.

Conclusions Adding tacrolimus to DMARDs significantly suppressed disease activity and joint destruction in patients with early rheumatoid arthritis, a disease duration ≤3 years, a CRP <1.5 mg/dL, and a poor response to oral DMARDs.     

Life expectancies of Japanese patients with rheumatoid arthritis: a review of deaths over a 20-year period

We investigated trends in life expectancy in rheumatoid arthritis (RA) patients, reviewing records for 286 patients (204 female, 82 male) who had died over the past 20 years. The average age at death was 68.8 years before 1990, increasing to 72.1 years after 2001. Trends in disease modifying anti-rheumatic drugs (DMARDs) saw gold preparations (45.2%) predominate before 1990, sulphydryl donor agents (53.6%) from 1991 to 2000, then methotrexate (43.0%) after 2001. The most common causes of death were infectious diseases up to 1995, rheumatic disease 1996–2000, and cardiovascular events and malignancies after 2001. Major advances in surgical interventions, such as joint replacement surgery, occurred after 1990. Surgical intervention followed by a period of rehabilitation maintained a favourable level of activities of daily living (ADLs), The requirements for favourable life expectancy are control of RA inflammation and maintenance of a favourable level of ADLs. Although recently developed DMARDs and biological agents show promise, caution is required to avoid serious adverse reactions. Optimum care of patients with RA will require preventive measures and early intervention for infections and rheumatic diseases, as well as for lifestyle diseases, osteoporosis and malignancies.