Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by persistent synovitis and systemic inflammation. Genetic predisposition as well as autoantibodies and environmental factors, such as smoking, are associated with an increased risk of RA. Traditionally RA has been treated with disease modifying anti-rheumatic drugs (DMARDs) but in the last 15 years or so the introduction of biological response modifiers has revolutionized the treatment of RA. Among these anti-tumor necrosis factor (TNF) agents were the first to be successfully used in treating RA. The goal in treating RA is to induce remission or very low disease activity; remission is now accepted as the ultimate therapeutic goal by adoption of a “treat to target” strategy to achieve tight disease control.
Tumor necrosis factor (TNF) has an extremely broad spectrum of biological activities. Cytotoxicity to tumor cell lines was one of the first functions to be discovered which led to its name, tumor necrosis factor. TNF-α is produced mainly by monocytes and macrophages, but also by B-cells, T-cells and fibroblasts. It is one of the key cytokine molecules that causes inflammation in RA. It is an autocrine stimulator as well as a potent paracrine inducer of other inflammatory cytokines, including interleukin-1 (IL-1), IL-6, IL-8 and granulocyte monocyte-colony stimulating factor (GM-CSF). TNF-α is also known to stimulate fibroblasts to express adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1).
TNF-α plays a dominant role in rheumatoid synovitis. In cultures of synovial cells from patients with RA, blocking TNF-α with antibodies significantly reduced the production of IL-1, IL-6, IL-8, and GM-CSF.4 Hence, the blockade of TNF-α may have a more global effect on inflammation than the blockade of other cytokines present in high concentration in synovial fluids, such as IL-1
To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying ant rheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. A group of researchers aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week. In a large-scale study (EXXELERATE Trial) with around 1,000 RA research volunteers, the research group from Vienna General Hospital) compared the two drugs certolizumab pegol and adalimumab (with methotrexate in each case). These drugs are two of the five TNF inhibitors currently in clinical use for treating rheumatoid arthritis.
This 104-week, randomized, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centers worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept blinded throughout the study and participants were blinded until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomized were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders.
The key findings of the trial were that between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of who 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67–1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82–1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. The switching from one drug to another was done without utilizing the generally recommended standard washout period between stopping of one anti-TNF regimen and starting a new regimen with a different drug in the same anti-TNF class of RA agents. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch.
These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor.
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- Curr Pharm Des. 2011;17(29):3141-54