Tocilizumab Vs. Adalimumab
The first study, a trial with 326 patients, was a head-to-head comparison of tocilizumab and adalimumab. Tocilizumab, given at a high dose of 8 mg/kg, performed better, with a reduction of 3.3 on the DAS28 after 24 weeks, compared with 1.8 for adalimumab.1
But Dr. O’Dell shared some important insight.
“The majority of the patients were not aggressively treated before being enrolled in this study,” he said. “Also, most patients had stopped methotrexate within a very short window leading up into the trial.”
“This was supposed to be a trial of people who didn’t tolerate methotrexate,” he added, “but with the long disease duration you really have to wonder about that, and that should color our interpretation. I have a hard time interpreting how this trial will contribute to my practice.”
He said the trial might be worth bearing in mind in certain cases, for example, those in which monotherapy is necessary.
Immunogenicity of TNF Inhibitors
Another study, a review of 2,082 studies, examined the immunogenicity of tumor necrosis factor (TNF) inhibitors—specifically adalimumab and infliximab. No appreciable antidrug antibodies were found with etanercept.2
Researchers found that antidrug antibodies decreased efficacy by 68%. Being on methotrexate, they found, helped protect against the development of these antibodies, not just for infliximab but for adalimumab, too.
“I have started to order antidrug antibodies in selected clinical situations, and I think they’ve been helpful to me,” Dr. O’Dell said. “And I’ll do it more now after this article.”
Infliximab Vs. Biosimilar
In another trial, infliximab was compared with its biosimilar, CT-P13. They were found to be similarly effective, with a drop in ACR20 of 59% at 30 weeks on infliximab and 61% on CT-P13. Safety and immunogenicity were also found to be similar.3
“To be a biosimilar, to even get into a trial, there’s a high bar for that,” he said. “We still need clinical studies, and this is a clinical study that should reassure us.”
Unfortunately, he has heard predictions from insurance companies that the emergence of biosimilars will only help keep costs close to what they are, but won’t lower them in the long term.
Tabalumab Better Than Placebo
Another study found that tabalumab, an anti-BAFF monoclonal antibody, performed better than placebo in patients on methotrexate who were naive to biologicals. He noted, though, that the methotrexate dose—as is common in studies—was, on average, 12 mg weekly, which is well below the optimal dose.4
The three doses used all produced similar results, Dr. O’Dell said.
“There needs to be more work done on dos[age], because we don’t understand the right dose,” he said. However, there might be a “new kid on the block with a new mechanism of action.”
RACAT Trial
Dr. O’Dell then reviewed the RACAT trial, a strategy trial that he helped lead, in which patients were started on either methotrexate plus sulfasalazine and hydroxychloroquine or methotrexate plus etanercept. In a scenario that mimics actual clinical practice, patients were switched to the other group if the DAS28 score didn’t improve by more than 1.2. Patients were kept on the same therapy if the DAS28 score did improve by that much.5
Researchers found no difference between the groups. Moreover, patients were switched to the other therapy group exactly the same amount in each starting group—27% of the time.
The bottom line, according to Dr. O’Dell: “In patients with active disease despite methotrexate, add triple [therapy] first, switch to etanercept or another TNF inhibitor at six months if the patients have not significantly improved. It’s much more economical and there are no clinical or radiographic penalties for doing that.”
TEAR
Dr. O’Dell also mentioned a subanalysis of data from the TEAR trial, in which researchers tried to determine whether there was some penalty for starting on methotrexate then ramping up to combination therapy. They found that, over time, DAS28 scores ended up at the same point and there was no radiographic benefit for starting combinations up front.6
Axial Spondyloarthritis: Current Aspects
There is too long a delay in the diagnosis of axial spondyloarthritis (axial SpA), but the problem could be helped by a change in how disease is assessed, said Muhammad Asim Khan, MD, Professor Emeritus of Medicine at Case Western Reserve University.
“We define AS [ankylosing spondylitis] when there is radiographic evidence of sacroiliitis,” Dr. Khan said. “But that has been one of the most important reasons why this disease is not diagnosed for about five to nine years. That delayed diagnosis is totally unacceptable.”
He said there’s a need for better recognition of axial SpA by rheumatologists in the U.S.
A 2013 study found that 124 out of 514 patients, or 24%, who were between 18 and 44 years old and were seen with chronic back pain, actually had axial SpA but were undiagnosed by rheumatologists even though they met the criteria of the Assessment of SpondyloArthritis International Society.7
A recent study using data from the National Health and Nutrition Examination Survey found an overall prevalence of axial SpA to be 0.9% to 1.4% in the U.S.8
“These diseases are at least as common, if not more common, than rheumatoid arthritis,” he said. “We see many more patients with rheumatoid arthritis [than] we see with spondyloarthritis. The reason is ascertainment bias. These patients don’t come to see us.”
Another, older study concluded that 5% of chronic back pain sufferers may have AS or a mild form of AS that might never progress to definite ankylosis, but for whom treatment as if they have AS would be of benefit.9
Dr. Khan said we need to develop different strategies, such as a simple referral model used in Germany. There, someone with chronic back pain, with the first symptoms arising at age 45 or earlier, and for whom there are signs that the pain is inflammatory is referred immediately to a rheumatologist. That way, patients at risk of AS get into the proper hands more quickly.
“Let the rheumatologist decide what kind of imaging should be done, when and if testing for HLA-B27 is needed,” Dr. Khan said.
In a Dutch model, more red flags are considered, and preselection by primary care providers is recommended if a combination of at least three features from a menu of symptoms are present.
The longer disease goes undiagnosed and untreated, the worse the prospects for a better outcome.
“In the individual patient the effect of anti-TNF therapy on radiographic progression depends on the relative number of ‘acute’ vs. ‘mature’ inflammatory lesions,” Dr. Khan said. “Early diagnosis is a prerequisite for advances in disease modification. The earlier you control the disease, the earlier you treat osteitis, then that transformation into the osteoproliferative phase may not occur, and, therefore, one would prevent spine fusion,” he said.
“At least 30 genes are associated with increased risk for axial SpA; HLA-B27 is the most important,” said Dr. Khan. “The newly described entheseal-resident naïve T cells, when activated by interleukin 23 (IL-23), can promote pathogenesis characteristic of spondyloarthritis. This has provided potential for new therapeutic approaches.”
He also said that ustekinumab (generic for Stelara), a monoclonal antibody that targets the common p40 subunit of IL-12 and IL-23, has been approved for the treatment of psoriasis and psoriatic arthritis. Moreover, a proof of concept open-label study (TOPAS) of 20 active axial SpA patients showed a 65% ASAS40 response (the primary study endpoint) at week 24.
Bone Erosion & Repair in RA
Ellen Gravallese, MD, chief of the Division of Rheumatology at the University of Massachusetts Medical School, said a growing understanding of bone erosion and repair in RA holds promise for better treatment approaches.
Her lab has been studying the effects of TNF alpha in bone remodeling.
“We’ve been thinking about the balance of resorption and formation and realizing that when bone is resorbed, what’s supposed to happen is osteoblasts are supposed to come in and make bone and fill in that area that’s been resorbed,” she said. “And it turns out that the proinflammatory cytokines, in particular TNF alpha, are inhibitory to this process. … There are a number of ways that TNF can regulate bone resorption independent of its effects on inflammation.”
Denosumab, which inhibits osteoclast differentiation by blocking RANK ligand, curbs bone erosion significantly, but presents an issue with “bone turnover,” she noted. “If you block resorption of bone really effectively, you also block formation of bone, because the two are coupled,” she said. “What you’d really like to do is block resorption in favor of formation.”
A potentially better alternative is cathepsin K inhibitors, which don’t block formation of osteoclasts, but rather their function. This means that this interruption of the bone turnover process isn’t a concern. These are now in Phase 3 trials.
Combinations of agents that block bone resorption, coupled with an anabolic agent, are probably going to get more attention in the future, she said. “This actually seems to be more effective than either agent alone.”
The role of inflammation in the repair of bone has also been generating increasing attention, she said. It’s not common that bone erosion-healing occurs; it’s only seen in about 10% of cases, but when it does occur, it’s usually at times of low disease activity.
In her lab, mouse models were given serum to induce arthritis. At the peak of inflammation, a high RANKL/OPG (osteoprotegerin) ratio was seen, which drove osteoclastogenesis. But this faded as inflammation waned.
Using fluorochromes, researchers were able to track the growth of new bone at erosion sites. At times of peak inflammation, there was no bone repair. But later, as inflammation dissipated, healing was seen. “Erosion repair can occur, but it occurs only when inflammation is almost completely resolved,” Dr. Gravallese said.
“What does this tell us about RA?” she said. “One of the things it might be telling us is that the reason that we don’t see healing more often is that there’s actual residual inflammation in the joint.”
An ongoing question, to be explored further, she said, is how important this residual inflammation is, including the significance in terms of the likelihood of later cardiovascular events.
Thomas R. Collins is a freelance medical writer based in Florida.
References
- Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541–1550.
- Garcês S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: A systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72(12):1947–1955.
- Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: The PLANETRA study. Ann Rheum Dis. 2013;72(10):1613–1620.
- Genovese MC, Bojin S, Biagini IM, et al. Tabalumab in rheumatoid arthritis patients with an inadequate response to methotrexate and naive to biologic therapy: A phase II, randomized, placebo-controlled trial. Arthritis Rheum. 2013;65(4):880–889.
- O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369(4):307–318.
- O’Dell JR, Curtis JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: Results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65(8):1985–1994.
- Strand V, Rao SA, Shillington AC, et al. Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res. 2013;65(8):1299–1306.
- Reveille JD, Witter JP, Weisman MH. Prevalence of axial spondylarthritis in the United States: Estimates from a cross-sectional survey. Arthritis Care Res. 2012;64(6):905–910.
- Underwood MR, Dawes P. Inflammatory back pain in primary care. Br J Rheumatol. 1995;34(11):1074–1077.
