Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study

This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Eighty-six patients entered a 12-week open-label run-in phase (1 mg/kg anakinra daily, ≤100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N = 44). Due to low enrollment, the primary endpoint was changed from efficacy to safety. The incidence and nature of adverse events were similar across all study phases, with the exception of injection site reactions, which were mild to moderate and decreased with time. Anakinra produced a nonsignificant (P = 0.11) reduction in disease flares compared with placebo. When normalized to 1 mg/kg dose, anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis. These results indicate that anakinra 1 mg/kg once daily (≤100 mg/day) is safe and well tolerated in patients with JRA.     

Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-1

Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Although joint swelling is a major clinical feature, destruction of bone and cartilage may be dissociated from inflammation. It is therefore important to understand fully all elements of the destructive process. Tumour necrosis factor (TNF) and interleukin-1 (IL-1) are considered pivotal cytokines in the process of human rheumatoid arthritis (RA), with a claimed cascade of TNF inducing most of the IL-1 production. Studies in experimental models have revealed that TNF is indeed a pivotal cytokine in acute joint swelling, yet IL-1β is the dominant cartilage destructive cytokine and its production may occur independently of TNFα. This was found with anti-TNF/IL-1 neutralising antibodies and the observations were recently supported by similar findings in arthritis models in TNF and IL-1 knock-out mice. In RA, early clinical studies suggested a correlation between levels of IL-1β and measures of joint damage. In vitro studies have also demonstrated regulatory effects of IL-1β on both cartilage degradation and cartilage invasion by synoviocytes. A randomised clinical trial has suggested a significant reduction in the rate of joint damage following IL-1β inhibition by IL-1 receptor antagonist. Clinical trials of TNFα blockade have demonstrated a marked reduction in the clinical manifestations of inflammation but, to date, an effect on the rate of joint damage awaits confirmation.     

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     

Lateral collapse of the tarsal navicular in patients with rheumatoid arthritis: Implications for pes planovarus deformity

Objectives: In patients with rheumatoid arthritis (RA), the talonavicular joint is commonly involved and midfoot collapse can lead to progressive flattening of the arch. Despite a general awareness of the important structural role of the talonavicular joint in rheumatoid foot disease, details of its destructive pattern have not been elucidated.

Methods: We cross-sectionally investigated 176 RA patients (342 feet) and classified their feet into the following five groups according to radiographic findings: arthritis (RA changes with normal navicular shape), Müller–Weiss Disease (MWD) (collapse of the lateral aspect of the tarsal navicular), flat (flattened navicular), ankylosis (ankylosis of the talonavicular joint), and normal. We compared medical histories and radiographic measurements among all five groups.

Results: The arthritis group comprised 91 feet, 36 in the MWD group, nine in the flat group, 12 in the ankylosis group, and 194 classified as normal. The MWD group demonstrated a trend towards pes planovarus deformity in contrast to pes planovalgus deformity in the arthritis group. Corticosteroid use and the mean daily dosage were the highest in the MWD group.

Conclusions: This report revealed a high prevalence of MWD-like changes to the navicular in RA patients and its association with pes planovarus deformity and corticosteroid usage.     

Long-term safety and effectiveness of adalimumab for the treatment of Japanese patients with rheumatoid arthritis: 3-year results from a postmarketing surveillance of 552 patients

Objectives: To determine the safety and effectiveness of and identify associated factors in long-term adalimumab (ADA) treatment of Japanese patients with rheumatoid arthritis (RA).

Methods: Of 7740 patients participating in the all-case postmarketing surveillance study, 552 were enrolled in the present study and observed for 3 years. The safety and effectiveness of ADA were analyzed in 509 and 430 patients, respectively.

Results: Adverse drug reactions (ADRs) were reported in 34.2% of patients (23.3/100 person-years [PYs]); serious ADRs (SADRs) were reported in 10.6% (5.9/100 PYs). The most common ADRs and SADRs were infection (16.5%) and serious infection (6.1%), respectively. Seven patients (1.4%) developed malignancies. Multivariate analysis revealed that the risk factors for SADRs were age ≥65 years and respiratory disorder at baseline. The proportion of patients who achieved remission (28-joint count Disease Activity Score based on four erythrocyte sedimentation rates <2.6) increased from 3.3% at baseline to 49.2% at 36 months. Significant predictors of failure to achieve remission were female sex, age ≥65 years, blood disorders and advanced structural change at baseline.

Conclusions: Overall, no unknown safety issues were noted during the 3-year treatment with ADA in Japanese patients with RA.     

Genotyping for disease associated HLA DR β1 alleles and the need for early joint surgery in rheumatoid arthritis: a quantitative evaluation

OBJECTIVE: To determine the value of HLA DR beta 1 disease associated epitope (DAE) and erythrocyte sedimentation (ESR) in predicting the need for major joint replacement in rheumatoid arthritis (RA). METHODS: Sixty five RA patients who had undergone hip, knee or shoulder arthroplasty within 15 years of disease onset and 65 who had not. HLA DR beta 1 genotype was determined by polymerase chain reaction. ESR at first hospital visit was noted. RESULTS: Significantly more patients with two DAE required surgery, (32% v 9%), chi 2 = 13.9, p = 0.001, odds ratio = 5.4 (95% CI: 1.8, 16). Sensitivity was poor, 32%, specificity high, 91%. Presentation ESR was higher in surgery patients compared with non-surgery patients, 52 mm 1st h v 25 mm 1st h, p < 0.001, but was independent of DAE status. Sensitivity of an ESR of 30 mm 1st h was 75%, specificity 53%. CONCLUSION: The presence of two DAE is a risk factor for major joint surgery in RA and is independent of ESR, whereas in those with one or no DAE, a high ESR is an important predictor.     

Supplementation of 1,25 dihydroxy vitamin D3 in patients with treatment naive early rheumatoid arthritis: a randomised controlled trial

Aim: 1,25 dihydroxy vitamin D3 has immunomodulatory functions in rheumatoid arthritis (RA) and is an anti‐osteoporotic agent. No studies exist to assess its pain‐relieving action in RA. Methods: An open‐labeled randomized trial comparing triple disease‐modifying anti‐rheumatic drug (DMARD) therapy and 500 IU 1,25 dihydroxy vitamin D3 + calcium combination versus triple DMARD and calcium alone was conducted. The primary outcome was the time to pain relief by patients’ visual analogue scale (VAS). Changes in VAS after first achievement of pain relief and after 3 months were noted. 25 hydroxy‐vitamin D levels were correlated with disease activity scor (DAS‐28), adjusting for sun exposure. Comparisons between the groups were done by Mann–Whitney test and independent samples test. Results: Patients on the vitamin D group (n = 59) had higher pain relief than the control group (n = 62) (50%vs. 30%, P = 0.006). There was no significant difference in the time taken for initial pain relief between the two groups. Occurrence of hypovitaminosis D in RA patients (68.1%) is comparable to published normal Indian prevalence. There was no correlation between 25 hydroxy vitamin D levels and disease activity. Conclusions: Supplementation of 500 IU of 1,25 dihydroxy vitamin D3 daily to previously DMARD‐naïve patients with early RA along with triple DMARD therapy results in a significantly higher pain relief at the end of 3 months. The number needed to treat for this additional pain relief was 5. The prevalence of vitamin D deficiency in the study population was 68.1%.     

Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA): A multicenter RA ultrasound prospective cohort in Japan

We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. “PD responder” was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response.     

Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story

This review highlights the story of how methotrexate (MTX), a drug discovered for the treatment of childhood leukemia, became the mainstay of treatment and the standard‐of‐care for rheumatoid arthritis (RA) and was also found useful for several additional related rheumatological diseases. As against several synthetic disease‐modifying antirheumatic drugs (csDMARDs) for treating RA that were discovered serendipitously, the use of low‐dose MTX (LD‐MTX) was based on sound reasoning and astute observations made in the 1940s and 1950s. The difference between high‐dose MTX (HD‐MTX) used in the treatment of childhood leukaemia and other malignancies as against LD‐MTX used in rheumatology is emphasized.     

Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series

Abstract

Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60–96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.     

Assessing joint destruction in the knees of patients with rheumatoid arthritis by using a semi-automated software for magnetic resonance imaging: therapeutic effect of methotrexate plus etanercept compared with methotrexate monotherapy

Objectives: To evaluate the prevention of knee joint destruction and clinical efficacy of methotrexate (MTX) plus etanercept (ETN) compared with MTX monotherapy in patients with rheumatoid arthritis (RA) by using semi-automated software for magnetic resonance imaging (MRI) scan analysis.

Materials and methods: This study enrolled patients with active moderate-to-severe RA who displayed an inadequate response to oral MTX at screening. Patients were assigned to receive either MTX plus ETN or MTX monotherapy (≥10?mg/week). The primary endpoint was the quantitative knee cartilage volume using our software developed for MRI scan analysis.

Results: A total of 18 female patients were enrolled in this study and allocated to the MTX?+?ETN group (n?=?9) or the MTX monotherapy group (n?=?9). At 52 weeks, the quantitative knee cartilage volume was significantly reduced compared with baseline in both groups (MTX plus ETN group: 2.3?±?2.3?cm³; MTX monotherapy group: 2.4?±?1.6?cm³); however, the difference was not significant.

Conclusion: The semi-automated software for MRI scan analysis can reveal useful and potentially clinically important information about the characteristics of knee joint destruction in patients with RA.