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American College of Rheumatology 2015 Annual Meeting
This year’s American College of Rheumatology (ACR) annual meeting, held from November 6 to 10 in San Francisco, California, was host to a record of more than 13,300 scientific attendees and more than 16,800 total attendees. We review key scientific sessions on the effects and relationships of early remission, weight, corticosteroids, and anti-tumor necrosis factor (TNF) agents in rheumatic diseases.
Intra-Articular Corticosteroids Are Safe and Have No Major Effect on Structural Progression Of Synovitic Knee OA: A 2-Year Randomized Controlled Trial of 3-Monthly Triamcinolone Hexacetonide
Synovitis, which is common in patients with osteoarthritis (OA), is associated with structural progression. Intra-articular corticosteroids are widely used, but whether they reduce cartilage damage in knee OA or have adverse effects on cartilage health and periarticular bone is uncertain.
“Recent insights into the role of inflammation on osteoarthritis raise the possibility that suppressing those processes may reduce progression of structural damage in the joint,” Dr. McAlindon said. “However, there are also theoretical concerns that corticosteroids may have deleterious effects on articular cartilage.”
Dr. McAlindon’s study tested the potential for disease modification of synovitic knee OA with triamcinolone hexacetonide (THA), taking comprehensive measurements of the effects on cartilage using the cartilage damage index (CDI) and on subchondral bone using magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DEXA). The two-year, National Institutes of Health–funded, randomized, placebo-controlled, double-blind clinical trial of intra-articular THA (40 mg) versus saline included 140 participants (54% female; 65% white; mean body mass index [BMI], 31.2 kg/m2) with symptomatic OA (Kellgren and Lawrence grade 2 or 3) and ultrasonic evidence of synovitis. Patients received intra-articular THA every 12 weeks for two years (eight doses).
Dr. McAlindon reported that after two years of treatment, there were no significant differences between THA and placebo in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain (–2.2 versus –2.8, respectively; P = 0.3), function (–7.1 versus –9.2; P = 0.4), chair stand (–1.1 versus –1.6; P = 0.8), or walk time (–0.5 versus –0.3; P = 0.5). Differences were observed in the CDI scores and in the fraying of cartilage, with more cartilage loss in the steroid-injection group (saline, –17.8 per year; triamcinolone, –52.1 per year; P = 0.03) and more fibrillation in the placebo group (THA, 11%; placebo, 24%; P = 0.04).
Dr. McAlindon concluded: “This study did not find any long-term benefit of intra-articular corticosteroids for either patient-reported outcomes or progression of structural damage, nor did the injections cause more damage in the two years they were studied. There did appear to be slightly more cartilage loss in the treated arm, but the difference was small in magnitude and did not appear to be clinically meaningful.”
In the Multicenter Randomized Controlled Rotation or Change Trial, a Non-TNF Targeted Therapy Has a Higher Efficacy Than a Second Anti-TNF at 3, 6, and 12 Months
It is common practice in patients with rheumatoid arthritis (RA) to prescribe an alternate anti-TNF agent if they don’t respond to a first one. About a third of RA patients do not respond to initial anti-TNF therapy. Dr. Gottenberg and his colleagues compared this strategy with prescribing a non–TNF-targeted biologic in 292 RA patients in a randomized 48-week rotation of anti-TNF or change of class of biologic (ROC) trial (NCT01000441). “Recently, the European League Against Rheumatism recommendations acknowledged the absence of evidence to guide the choice of a second biologic in TNF-IR [inadequate responder] patients, which further confirmed the need for studies like this one,” Dr. Gottenberg said.
In the multicenter, investigator-initiated, open-label, parallel-group, randomized controlled trial, the choice between biologics and anti-TNF agents (i.e., adalimumab, certolizumab, etanercept, or infliximab as the second anti-TNF and abatacept, rituximab, or tocilizumab in the non–TNF-targeted biologic group) was left to the discretion of the participants’ physicians. Good or moderate responses, according to European League Against Rheumatism (EULAR) criteria, were assessed at six and 12 months. Among patients receiving a second anti-TNF agent at three months, 48% achieved good or moderate responses compared with 64% of patients receiving a non–TNF-targeted biologic. At six months, the respective response rates were 43% and 60% (P = 0.003). In addition, the results on the Disease Activity Score, 28 Joints–Erythrocyte Sedimentation Rate (DAS28-ESR) were lower in the non–TNF-targeted biologic group, with 41% and 24% of patients in the non–TNF-targeted biologic and second anti-TNF groups, respectively, achieving low disease activity, and 27% and 14% experiencing remission (P = 0.004).
“Superiority [for non–TNF-targeted biologics] was consistent throughout the study period and across numerous outcome criteria in a setting nearing common practice, with no significant difference in the safety of the two treatment strategies evaluated,” Dr. Gottenberg said. He also noted that at least 40% of the patients failed to respond to their second-line biologic. “That emphasizes the unmet need to continue to increase the number of treatment options and to develop personalized medicine for people with rheumatoid arthritis,” he remarked.
In a Two-Year Double-Blind Randomized Controlled Multicenter Study, Chondroitin Sulfate Was Significantly Superior to Celecoxib At Reducing Cartilage Loss With Similar Efficacy At Reducing Disease Symptoms in Knee Osteoarthritis Patients
The usefulness of chondroitin sulfate as a treatment for OA has long been a subject of debate, according to Dr. Pelletier. Investigators used quantitative magnetic resonance imaging (qMRI) to determine the effect of chondroitin on the progression of knee OA and to compare it with celecoxib, a commonly used first-line symptomatic treatment for OA.
In this double-blind study, 194 patients with knee OA and inflammation of the synovial membrane were randomly assigned to two groups, one taking 1,200 mg daily of a pharmacological preparation of chondroitin and the other taking 200 mg of celecoxib daily for a period of two years. MRIs at baseline and at one and two years evaluated cartilage volume loss, changes in bone marrow lesions, and thickening of the synovial membrane. In addition, patients were evaluated for joint swelling and effusion and for overall symptoms.
Cartilage loss in the whole knee was reduced in patients receiving chondroitin compared with those receiving celecoxib at 12 months (P = 0.017) and 24 months (P = 0.034). Synovial thickness and bone marrow lesion size were similar in the two groups, but some patients receiving chondroitin had reduced synovial membrane thickness. The incidence of joint swelling plus effusion was markedly reduced in the chondroitin and celecoxib groups from baseline to 24 months, and overall disease symptoms were similarly reduced in the two groups over time. Visual Analogue Scale (VAS) pain scores were reduced by 48% and 55%, respectively, with both chondroitin and celecoxib. Moreover, the two treatments (at 584 mg per day and 472 mg per day, respectively) reduced the daily consumption of rescue acetaminophen. Adverse events were similar in both treatment groups.
“These findings are most important as they demonstrate that chondroitin, in contrast to celecoxib, can reduce the loss of cartilage, at least in part by reducing synovial inflammation,” Dr. Pelletier said. He warned, however, that pharmaceutical-grade chondroitin was used in the study and that results for other chondroitin products, such as food supplements, may not be similar.
High Body Mass Index Negatively Impacts Time to Achieving Sustained Remission in Early Rheumatoid Arthritis: Results From a Multicenter Early Arthritis Cohort Study
For patients with early RA, achieving a sustained remission has important implications for preventing progressive disease and disability, and for preserving quality of life. Prior research has indicated that being overweight or obese increases the risk of developing RA, and of having more-severe disease activity and pain. In addition, overweight and obese patients respond less well to medications.
In a retrospective analysis of data from the CATCH (Canadian Early Arthritis Cohort) study, Dr. Schulman’s team divided 1,066 patients with early arthritis (symptoms present for one year or less) into three groups according to their BMI (normal, 18.5 to 24.9 kg/m2; overweight, 25.0 to 29.9 kg/m2; and obese, greater than 30.0 kg/m2) and examined the relationship between BMI and the likelihood of achieving sustained remission, defined as at least two consecutive DAS28 measurements.
Within three years, 48% of subjects in the normal BMI range achieved sustained remission compared with 38% of overweight individuals (hazard ratio [HR], 0.75; P = 0.03) and 28% of obese individuals (HR, 0.63; P = 0.0008). Factors conferring a greater likelihood of achieving sustained remission included a DAS28 of 3.2 or less by six months (HR, 4.209; P < 0.01); higher education (HR, 1.608; P = 0.05), and the use of methotrexate during the first three months (HR, 1.401; P = 0.02). Factors for a reduced likelihood of achieving sustained remission included a higher BMI, more comorbidities (HR, 0.911; P < 0.01), and steroid use during the first three months (HR, 0.761; P = 0.01).
The differences persisted even after adjustments for age, sex, race, smoking, education, comorbidities, achieving remission by six months, steroid use, and early use of methotrexate.
Dr. Schulman concluded: “This study suggests that excess body weight is an important factor that affects how well rheumatoid arthritis medications work. Because excess weight is a potentially modifiable risk factor, clinicians should consider whether excess body weight is contributing to suboptimal disease control and outcomes in their patients.”
Effect of Weight on Efficacy of Certolizumab Pegol in Patients With Axial Spondyloarthritis
Concerns over potentially reduced responses to anti-TNF therapy in high-BMI patients with axial spondyloarthritis (axSpA) were allayed in a trial of 24 weeks’ treatment with certolizumab pegol.
Prior research by Gremese and colleagues1 in patients with active axSpA treated with the anti-TNF agent adalimumab, etanercept, or infliximab showed that when outcomes were divided according to the baseline BMI, higher weight and female gender were associated with lower success rates. A second study by Gremese et al. in RA patients2 found that poorer outcomes with anti-TNF treatment were associated with increased weight. In an interview, Dr. Deodhar pointed out that among the five anti-TNF agents available for patients with axSpA, infliximab and golimumab have intravenous formulations that are given with a milligrams-per-kilogram dose, so heavier patients would receive higher doses. “In contrast, certolizumab pegol, etaneracept, and adalimumab have fixed doses, and this has been a question in physicians’ minds whether some heavier patients might fail to respond because they need a higher dose.”
The phase 3 RAPID-axSpA (NCT01087762) study of certolizumab pegol (200 mg or 400 mg administered every four weeks) was double-blind and placebo-controlled until the 24th week, and was then open-label to week 204. Dr. Deodhar’s post hoc analysis focused on 24-week efficacy data (Assessments in Ankylosing Spondylitis 20% [ASAS20]) with respect to baseline weight. The mean age among the 325 patients was 39.6 years; 61.5% of the subjects were male; and the mean BMI was 27.6 kg/m2 (overweight). More men than women weighed 80 kg or more, and C-reactive protein levels were higher in heavier patients. BMI categories at baseline were as follows: less than 25 kg/m² (n = 114); 25 to less than 30 kg/m² (n = 111); and 30 kg/m² or more (n = 94).
At week 12, ASAS20 and ASAS40 response rates were similar regardless of baseline weight. The improvements in ASAS20 for certolizumab pegol compared with placebo, for example, were 22.2% for the less-than-80-kg group, 22.9% for the 80-kg-or-more group, and 21.0% for the 100-kg or more group. According to BMI status, these improvements were 18.0% for the less-than-25-kg/m² group; 30.5% for the 25-to-less-than-30-kg/m² group; and 19.7% for the at-least-30-kg/m² group. For ASAS40, the improvements with certolizumab pegol versus placebo were 24.1% in the less-than-80-kg group; 31.8% in the 80-kg-or-more group; and 37.8% in the 100-kg-or-more group. According to BMI status, these improvements were 25.7% for the less-than-25-kg/m² group; 27.1% for the 25-to-less-than-30 kg/m² group; and 34.1% for the at-least-30-kg/m² group.
Dr. Deodhar also reported that efficacy was maintained to week 24 in all weight groups. While efficacy responses tended to be numerically lower in patients weighing 100 kg or more compared with those weighing less than 80 kg, the treatment difference between certolizumab pegol and placebo was maintained.
Dr. Deodhar concluded: “In clinical practice, at least when this agent is used in axSpA, you don’t have to be concerned so much about the patients’ BMIs or weight. All appear to have a good response.”
Early Response As a Predictor of Long-Term Remission in DMARD-Naïve Patients With Active, Severe, Progressive Rheumatoid Arthritis Treated With Certolizumab Pegol in Combination with Methotrexate
A lack of response to treatment with the anti-TNF agent certolizumab pegol in patients with established RA has been shown to indicate a low probability of achieving future target responses. Dr. Weinblatt’s analysis of the phase 3 C-EARLY study looked at whether that relationship holds true in patients with active, severe, progressive RA with poor prognostic factors who are naïve to disease-modifying antirheumatic drugs (DMARDs). All of the included patients had severe, active rheumatoid arthritis for less than one year since diagnosis.
A total of 879 patients were randomly assigned to receive certolizumab pegol (400 mg at weeks 0, 2, and 4, and then 200 mg every two weeks to week 52 plus methotrexate (n = 660) or placebo plus methotrexate every two weeks (n = 219). Methotrexate was initiated at 10 mg per week and was increased to 25 mg per week by week 8. The maximum tolerated dose per patient (the optimized dose) was maintained to week 52. The primary outcome was the association between week-12 clinical responses and week-52 outcomes, as measured by the DAS28-ESR. Sustained remission was defined as a DAS28-ESR score of less than 2.6 at weeks 40 and 52.
“The question was,” Dr. Weinblatt said in an interview, “can we identify those patients who would be remitters or have low disease activity?”
The mean baseline DAS28-ESR scores were 6.8 and 6.7 in patients receiving placebo plus methotrexate and in those receiving certolizumab pegol plus methotrexate, respectively.
At week 12, 12.2% of the patients in the placebo/methotrexate group achieved remission, compared with 18.9% in the certolizumab pegol/methotrexate group. At week 52, 26.8% and 42.6% of patients in the placebo and certolizumab pegol groups, respectively, were in remission. Patients in the placebo/methotrexate group who responded after three months had a 29% chance of remission at 12 months. Among those responding to certolizumab pegol plus methotrexate at three months, 49% were in remission at 52 weeks. In both cases, failure to achieve a DAS28-ESR response after 12 weeks was associated with a low chance of remission at week 52.
“What we found is that if you don’t achieve at least a 1.2-point improvement in your disease activity score by week 12, you have a more than a 90% probability of not being in remission at week 52. That means you can use the 12-week data to tell patients whether or not it makes sense to stay on therapy.” The cost implications, he added, are high.
A range of alternate therapies include a second anti-TNF drug, an interleukin-6 blocker, co-stimulation, B-cell depletion, and kinase inhibitors. “It’s a huge challenge that we haven’t identified biomarkers to tell us which drug they should get next,” Dr. Weinblatt commented.
Regarding safety, Dr. Weinblatt said that while the C-EARLY trial was not powered for safety, extensive 15-year experience with anti-TNF blockers should be reassuring to patients. An increased risk for malignancy, he said, appears to pertain only to nonmelanoma skin cancers. Previous reports of an increased lymphoma risk with anti-TNF agents can be attributed to an increased lymphoma incidence related solely to the immunological dysfunction inherent in RA, Dr. Weinblatt said.
Reduction of Disease Burden on Workplace and Household Productivity Following 52 weeks Of Treatment With Certolizumab Pegol in Combination With Methotrexate in DMARD-Naïve Patients With Active, Severe, Progressive Rheumatoid Arthritis
Workplace and household productivity are strongly affected in DMARD-naïve patients with early severe RA and poor prognostic factors, just as they are in patients with established RA. Moreover, the improvements in workplace and household productivity achieved with treatment with certolizumab pegol plus methotrexate in patients with established RA (the RAPID 1 and 2 trials3) were shown to extend to patients with early, active, severe, progressive RA receiving certolizumab pegol plus methotrexate in the C-EARLY trial.
Dr. Bykerk noted that workplace disability occurs in 20% to 30% of RA patients during the first three years after diagnosis and in up to 40% to 50% of patients during the first 10 years after diagnosis.3 As stated previously, the phase 3 C-EARLY trial compared certolizumab pegol plus methotrexate with placebo plus methotrexate in DMARD-naïve patients with early (one year or less), severe RA. This study revealed significant increases in symptom remission at 52 weeks in the patients receiving certolizumab pegol plus methotrexate compared with those given placebo (42.6% versus 26.8%, respectively).
For this analysis, investigators assessed participants’ employment status as well as workplace and household productivity over a 52-week period using the validated arthritis-specific Work Productivity Survey (WPS). The investigators also evaluated the economic burden of early and established RA using the WPS at study baseline in the C-EARLY trial and in the pooled RAPID 1 and RAPID 2 studies.
Among employed patients in the C-EARLY (n = 446) and RAPID 1 and 2 trials (n = 615), the absenteeism rates were 6.9 days and 7.8 days per month, respectively, and the “presenteeism” rates (being at work with RA, with a reduction of 50% or more in productivity) were 4.3 days and 3.7 days per month, respectively.
Subjects experienced a 100% reduction or at least a 50% reduction in household work productivity for 9.2 days and 9.7 days per month, respectively, in the C-EARLY trial, and for 7.6 days and 10.5 days per month, respectively, in the RAPID 1 and 2 trials.
In the C-EARLY comparison between certolizumab pegol plus methotrexate and placebo plus methotrexate, the numbers of baseline absenteeism days were 4.4 and 4.0 in the certolizumab pegol and placebo groups, respectively. At week 52, absenteeism accounted for 0.6 and 0.9 days, respectively (no significant difference). Presenteeism, reported at baseline as 6.4 days and 8.8 days in the certolizumab pegol and placebo groups (P < 0.05), respectively, accounted for 1.0 days and 1.8 days (P = 0.05), respectively, at week 52.
The levels of arthritis interference with paid work productivity per month, as measured on a 10-point scale (0 = no interference), were 5.5 and 5.8 for the certolizumab pegol and placebo groups, respectively, at baseline. At week 52, the levels were 1.4 and 1.9 (P = 0.05), respectively.
A similarly high burden of disease on workplace and household productivity was seen in both DMARD-naïve patients with early, severe RA and poor prognostic factors, and those with established RA. “This could lead to a large financial burden for both patients and society as a whole,” Dr. Bykerk said. The one-year improvements with certolizumab pegol plus methotrexate could reduce this burden, she added.
“The important thing to highlight here is the need to achieve early remission because this provides the highest opportunity to ensure patients regain full function and the ability to work,” she said. Once a person has been out of work for six months, she continued, the likelihood that they will be unable to return to work and that they will risk losing their job (and benefits) is very high. “For patients with early rheumatoid arthritis, there is an opportunity to minimize the impact this disease has on their lives in the first few months after diagnosis. Rheumatoid arthritis, if treated inadequately, is devastating and life altering.”
- Gremese E, Bernardi S, Bonazza S, et al. Body weight, gender and response to TNF-α blockers in axial spondyloarthritis. Rheumatology (Oxford) 2014;53:875–881.
- Gremese E, Carletto A, Padovan M, et al. Obesity and reduction of the response rate to anti-tumor necrosis factor alpha in rheumatoid arthritis: an approach to personalized medicine. Arthritis Care Res 2013;65:94–100.
- Kavanaugh A, Smolen JS, Emery P, et al. Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis. Arthritis Rheum 2009;61:1592–1600.