A Double-Blind, Double-Dummy, Randomized Controlled, Multicenter Trial of 99Tc-Methylene Diphosphonate in Patients with Moderate to Severe Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterized by synovial hyperplasia and joint damage, eventually leading to damage of articular cartilage and subchondral bone, joint destruction, and substantial loss of function. The arthritis in RA is typically bilateral and symmetrical, with the small joints of the hands being the most common initial presentation. Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), leflunomide, and sulfasalazine are generally used as a first-line treatment based on low costs and prominent efficacy in China. When patients fail to respond to initial treatments, biologic (b) DMARDs and targeted synthetic DMARDs (such as Janus kinase [JAK] inhibitors) are usually considered. Although these drugs effectively control the disease activity of patients with RA, there is still a significant unmet need in the field of RA, especially for those at high risk of bone structural damage.
99Tc-methylene diphosphonate (99Tc-MDP), a chemical compound of technetium-99 conjugated with methylene diphosphonate, is an anti-inflammatory and anti-bone destruction drug patented in China. It has long been widely used and has shown good efficacy for the treatment of RA and osteoporosis in China since 2000. Clinical observational studies revealed that 99Tc-MDP could notably and quickly reduce joint pain and swollenness in RA patients. Previous studies found that 99Tc-MDP could increase the proportion of γδ T cells and CD4+ CD25+ Foxp3+ Tregs, leading to a decrease in rheumatoid factors (RF). However, whether 99Tc-MDP could act as a DMARD requires a randomized controlled clinical trial (RCT) for evaluation.
This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. The study was conducted in accordance with the good clinical practice (GCP) guidelines and the Declaration of Helsinki. Ethical committees of all participating centers approved the protocol, and written informed consent was obtained from each participant before entering the study.
A total of 178 patients with moderate to severely active RA were recruited between September 2010 and March 2012 from six study sites across four provinces in China. The eligible patients were 18 to 80 years of age with RA for at least 3 years according to the revised 1987 American College of Rheumatology criteria. Active RA was defined as having at least four swollen joints and six tender joints plus one of the following three criteria: morning stiffness ≥45 min, erythrocyte sedimentation rate (ESR) ≥28 mm/h, or C-reactive protein (CRP) ≥10 mg/L, with the disease activity score of 28 joints counted by ESR (DAS28-ESR) being at least ≥3.2. Participants were randomized to receive 99Tc-MDP plus MTX, MTX alone, or 99Tc-MDP alone for 48 weeks.
The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score (mTSS) at week 48. Secondary endpoints included the proportion of participants with ACR70 and ACR50 responses and changes in DAS28-ESR at week 24. Treatment failure was defined as not reaching the ACR20 response, premature withdrawal due to disease progression, or concomitant treatment with DMARDs other than MTX. Radiographs of both hands and both feet were assessed by an independent radiologist to evaluate changes in bone erosion and joint space narrowing.
At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX plus 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%). The ACR20 response rate was not significantly different between the MTX and 99Tc-MDP groups. The ACR50 responses at week 24 were 35.6% for the MTX plus 99Tc-MDP group compared with 33.9% for the MTX group and 11.9% for the 99Tc-MDP group. At week 24, 20.3% of the participants in the MTX plus 99Tc-MDP group achieved an ACR70 response compared to 11.9% in the MTX group and 6.8% in the 99Tc-MDP group.
The participants in the MTX plus 99Tc-MDP group and the 99Tc-MDP group had significantly less radiographic progression than the participants in the MTX group over the 48 weeks. The cumulative percentage of change in the mTSS score was significantly lower in the MTX plus 99Tc-MDP and 99Tc-MDP groups than that in the MTX group. The radiographic scores at baseline and changes from baseline to week 48 showed that a significantly greater proportion of participants in the MTX plus 99Tc-MDP group (72.2%) and the 99Tc-MDP group (60.0%) did not have an increase in the total Sharp score compared with the participants in the MTX monotherapy group (36.4%).
No serious adverse events (AEs) were observed during the study. There were no significant differences in AEs among the three groups. Eleven participants withdrew from the study due to AEs, including four in the MTX plus 99Tc-MDP group, five in the MTX group, and two in the 99Tc-MDP group. The most common AEs were decreased white blood cell (WBC) count and elevated liver enzymes in the three groups. WBC decrease occurred in two of the 59 participants in the MTX plus 99Tc-MDP group, five of the 59 participants in the MTX group, and one of the 59 participants in the 99Tc-MDP group. Elevation of liver enzymes occurred in one of the 59 participants in the MTX plus 99Tc-MDP group, five of the 59 participants in the MTX group, and two of the 59 participants in the 99Tc-MDP group.
The study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. The bone protective role of 99Tc-MDP is probably, at least in part, due to its chemical structure as technetium-99 conjugated with methylene diphosphonate. Therefore, it has potential anti-resorptive effects as a bisphosphonate derivative to target osteoclasts, slow down bone turnover, and prevent bone resorption. An in vitro study revealed that 99Tc-MDP could suppress the expression of bone destruction factors, such as TNF-α, and inhibit the viability and differentiation of osteoclasts. When 99Tc-MDP enters the joint cavity and reaches an area of synovitis or abnormal bone, it binds to immature collagen or is absorbed by hydroxyapatite crystals, thereby persisting and exerting a long-lasting therapeutic effect. In animal models of RA, 99Tc-MDP was shown to promote bone repair and increase joint space. A previous clinical trial also found that short-term treatment of 99Tc-MDP could significantly suppress serum markers of the bone turnover biomarkers Dickkopf-related protein 1 and tartrate-resistant acid phosphatase in RA patients.
The study results proved that 99Tc-MDP has significant effects on preventing and slowing down the bone destruction process in RA patients. The combination of 99Tc-MDP with MTX could improve disease activity in RA, with the MTX plus 99Tc-MDP combination group showing a quicker ACR response than MTX monotherapy in the first 16 weeks. At week 24, the ACR20 response rate was significantly higher in the MTX plus 99Tc-MDP combination group than in the MTX and 99Tc-MDP monotherapy groups. At the end of week 48, although there was a trend toward higher ACR20 and ACR70 in the MTX plus 99Tc-MDP combination group than in the MTX monotherapy group, the difference did not reach statistical significance.
Preliminary clinical trials also suggested that 99Tc-MDP had anti-inflammatory and immune modulation properties. A previous report indicated that 99Tc-MDP could increase the frequency of both γδ T cells and CD4+CD25+Foxp3+ Tregs in the peripheral blood of active RA patients, paralleled with decreased serum levels of TNF-α and interleukin (IL)-6 and increased levels of serum transforming growth factor-β. 99Tc-MDP also has been reported to inhibit the mitogen-activated protein kinase signaling pathway, thus reducing the production of TNF-α, IL-1β, and IL-6 by macrophages. Given that bisphosphonate agents and receptor activator of nuclear factor-κB ligand (RANKL) inhibitor denosumab only regulate bone metabolism with no effect on disease activity, 99Tc-MDP has a broader impact in RA treatment. It has anti-inflammatory properties, controlling disease activity, and anti-bone resorption properties, preventing structural damage. The exact mechanism of 99Tc contributing to the clinical effects upon that of methylene diphosphonate is yet to be elucidated.
The present study also suggested that 99Tc-MDP had a good safety profile. There were no serious adverse events in the trial. Most of the adverse events were mild and reversible. 99Tc-MDP did not increase the adverse events compared to MTX treatment. In a real-world experience, 99Tc-MDP is not associated with any serious side effects and has been safely used in China for two decades.
This trial has limitations. Only Chinese patients with moderately to severely active RA were enrolled, limiting the generalizability of the results. It is unknown whether 99Tc-MDP with MTX could benefit patients with milder or early RA.
In conclusion, this study’s results demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of adverse events. Future clinical studies are needed to optimize the dosage and course of 99Tc-MDP therapy in patients with an early and advanced stage of RA.
doi.org/10.1097/CM9.0000000000001527
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