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European League Against Rheumatism 2017
The annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR 2017) hosted more than 14,300 attendees from 130 different countries in Madrid from June 14–17. We review below sessions on rheumatoid arthritis and axial spondyloarthritis.
Little to No Placental Transfer of Certolizumab Pegol During Pregnancy: Results From CRIB, A Prospective, Post-Marketing, Multicenter Pharmacokinetic Study
Transfer of certolizumab pegol (Cimzia, UCB) across the placenta during the third trimester was absent or minimal in the CRIB trial, which was conducted in pregnant women remaining on active treatment for rheumatoid arthritis (RA).
Chronic inflammatory diseases, such as RA, often affect women of reproductive age. Because high disease activity is associated with increased risk of adverse pregnancy outcomes, adequate disease control is crucial, Dr. Mariette said. While RA activity improves spontaneously during pregnancy in some women, about half still need effective therapeutic intervention.
“Tumor necrosis factor [TNF] inhibitors represent one of the most significant advances in the treatment of inflammatory diseases like rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis/ankylosing spondylitis [axSpA/AS], but research suggests that most of these drugs cross the placenta, so they are usually discontinued during pregnancy,” he said.
The molecular structure of certolizumab pegol, however, should prevent placental transfer because it does not contain a fragment crystallizable (Fc) region. The Fc receptor is a protein associated with immune function found on some cell surfaces.
Using a highly sensitive and previously validated enzyme-linked immunosorbent assay with anti-certolizumab pegol antibody levels greater than 2.4 units/mL defined as positive, CRIB investigators assessed 16 women who were pregnant for 30 weeks or longer. The women decided to continue on or to start treatment with certolizumab pegol for an approved indication with their treating physician prior to participation in the trial. Blood samples were collected from the mothers and umbilical cords, and were also collected from the infants at delivery and again four and eight weeks after delivery. The CRIB primary analysis was of infant certolizumab pegol levels at birth. Secondary analyses were of mother and umbilical cord blood samples.
The mean age of the mothers was 31 years (range, 18–41 years). Eleven of them had RA, three had Crohn’s disease, one had psoriatic arthritis, and one had axSpA/AS. Mean infant birth weight was 3.3 kg.
Dr. Mariette reported that maternal certolizumab pegol plasma levels at delivery were within the expected therapeutic range (median, 24.4 mcg/mL; range, 5.0–49.4 mcg/mL). Samples were evaluable from 14 of the 16 infants delivered, and among these 14 infants, 13 had no quantifiable certolizumab pegol levels at birth (less than 0.032 mcg/mL). One infant whose mother had a certolizumab pegol level of 49.4 mcg/mL had a minimal level of 0.042 mcg/mL (infant/mother plasma ratio, 0.09%). At weeks 4 and 8, none of the infants had quantifiable levels of certolizumab pegol.
Levels of certolizumab pegol were quantifiable in three of 15 umbilical cord samples (maximum, 0.048 mcg/mL). The maximum cord/mother plasma ratio for these three cords was 0.0025. No anti-certolizumab pegol antibodies were detected in the mothers, umbilical cords, or infants.
Adverse events experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children. Their safety profiles were consistent with those of unexposed similar-age infants. Safety data in the mothers were in line with the known safety profile of certolizumab pegol.
Dr. Mariette concluded that the CRIB study “shows minimal to no placental transfer from mother to infant. This is very encouraging news for female patients who have an active inflammatory disease.” He added, “CRIB results support continuation of certolizumab pegol treatment during the third trimester of pregnancy if anti-TNF therapy is considered necessary.”
Four-Year Imaging Results Demonstrate Low Disease Progression and Long-Term Efficacy of Certolizumab Pegol in Patients With Axial Spondyloarthritis
In the first report of long-term imaging results for anti-tumor necrosis factor (TNF) treatment of patients with axial spondyloarthritis (axSpA), reductions in inflammation of the spine and sacroiliac joints were maintained with continuous certolizumab pegol treatment over four years.
“Objective information from imaging is important,” Dr. van der Heijde noted in an interview, “because, especially in axial spondyloarthritis, many of the outcome measures are purely patient reported, and few abnormalities can be found by physical investigation. The imaging data complete the clinical data, which by themselves do not give a full picture.” Magnetic resonance imaging (MRI) reveals objective signs of inflammation, and radiographs show structural damage, she explained.
Dr. van der Heijde’s imaging analysis was subsequent to an earlier presentation of data from the RAPID-axSpA trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled study of certolizumab pegol in patients with axSpA, ankylosing spondylitis (AS), and nonradiographic axSpA (nr-axSpA). That study had shown rapid clinical improvements after 12 weeks of treatment that were then sustained through four years of treatment in patients with both AS and nr-axSpA. MRI and spinal x-rays at 96 weeks had shown evidence, respectively, of reduced inflammation and limited progression.
The current study objective was to report both x-ray and MRI assessments over four years of certolizumab pegol treatment in a population of 315 axSpA patients (mean age, 39.7 years). The treated population, Dr. van der Heijde said in her oral presentation, included patients with AS and nr-axSpA. MRI assessments were available for 158 patients, and 198 had one or more modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) assessments. In addition, 273 patients had sacroiliac joint x-rays at baseline. Mean patient age was 41.5 years for those with AS (n = 174) and 37.5 years for those with nr-axSpA (n = 141).
Spinal progression over four years of treatment with certolizumab pegol in both AS (n = 113) and nr-axSpA (n = 83) patients was limited, Dr. van der Heijde reported. From baseline to 96 weeks, mSASSS scores increased in AS patients by 0.67 from 13.17 to 13.84, and at week 204 had increased by only 0.31 to 14.16 (an overall increase of 0.98 for weeks 0–204). The mSASSS scores in nr-axSpA patients decreased by 0.01 from 4.42 to 4.41 at week 96, and increased by 0.07 to 4.47 at week 204 (an overall increase of 0.05 for weeks 0–204).
Progression from nr-axSpA to AS over four years occurred in 4.5% of patients (n = 42). Over the same period, 4.3% (n = 89) improved from AS to nr-axSpA.
The percentage of AS patients in spinal remission (defined as a Berlin spine score of 2 or less) increased from 42.4% at baseline to 67.2%, 67.6%, and 76.0% at weeks 12, 96, and 204, respectively. The percentage of nr-axSpA patients in spinal remission increased from 62.3% at baseline to 76.2%, 69.6%, and 84.4% at weeks 12, 96, and 204, respectively. The percentage of patients in sacroiliac joint remission (defined as a Spondyloarthritis Research Consortium of Canada [SPARCC] score of less than 2) increased from 52.7% at baseline to 85.7%, 83.6%, and 75.6% at weeks 12, 96, and 204, respectively, for those with AS, and increased from 43.3% at baseline to 69.8%, 72.3%, and 80.6% for nr-axSpA patients at the same respective time points.
MRI improvements in Berlin spine score were sustained in both AS and nr-axSpA patients. The mean baseline score of 7.4 in AS patients decreased to 2.7, 2.7, and 2.6 at weeks 12, 96, and 204, respectively. In nr-axSpA patients, it decreased from 4.2 to 1.4, 1.6, and 1.4 at weeks 12, 96, and 204, respectively. Similarly, MRI assessments of SPARCC sacroiliac joint score revealed sustained improvements, with the baseline score of 8.5 in AS patients decreasing to 2.0, 1.3, and 1.8 at weeks 12, 96, and 204, respectively. In nr-axSpA patients, scores also decreased from a baseline of 7.7 to 2.3, 2.5, and 2.0 at weeks 12, 96, and 204, respectively.
“These imaging data confirm the good clinical outcome over four years during treatment with certolizumab,” Dr. van der Heijde concluded.
High Multibiomarker Disease Activity Score Is Associated With High Risk of Radiographic Progression in Six Studies
An analysis of six study cohorts that included more than 800 rheumatoid arthritis (RA) patients shows a strong correlation between the score on Vectra DA (12-biomarker blood test, Crescendo Bioscience, Inc.) and the risk of radiographic progression (RP). Included patients had received conventional disease-modifying antirheumatic drugs alone or with adalimumab, infliximab, or abatacept (Orencia, Bristol-Myers Squibb) for one year.
Joint inflammation and damage are important determinants of disability in patients with RA, Dr. Sasso noted. Vectra DA, a multibiomarker disease activity (MBDA) test, analyzes 12 serum protein biomarkers and uses a validated algorithm to generate a single score that represents the level of RA disease activity. RA disease activity is rated on a scale of 1 to 100 with categories of low (less than 30), moderate (30−44), and high (greater than 44). The Vectra DA assay has been tested and validated in more than 3,000 patients, Dr. Sasso said. The test is not currently approved by the Food and Drug Administration.
While MBDA scores have been shown previously to correlate with risk for RP in RA, the current meta-analysis of one registry (Leiden) and five randomized controlled trials (OPERA, SWEFOT [year 1], SWEFOT [year 2], AMPLE [year 1], and AMPLE [year 2]), each with more than 100 RA patients, was performed to more strongly establish this correlation. RP was defined via the threshold for change in modified total Sharp score (∆mTSS) specific to each study (i.e., 2 to greater than 5 mTSS units per year).
Positive predictive value (PPV) and negative predictive value (NPV) were determined for each study by comparing patients in a high MBDA category with those in a low/moderate category. The high disease activity category was defined by the parent study’s criteria, which included an MBDA score greater than 44; disease activity score 28-joint count C-reactive protein (DAS28-CRP) greater than 4.09 or greater than 5.1; and CRP greater than 3.0 mg/dL.
Dr. Sasso reported at his poster that in each of the six studies, there was a strong relationship between high Vectra DA scores (greater than 44) and RP relative risk (RR) (range, 3.6–9.5).
The superior predictive value of Vectra DA was underscored, Dr. Sasso said, by the meta-analysis of the Leiden, SWEFOT Year 1, and OPERA Year 1 studies. Patients with a high Vectra DA score were 5.1 times more likely to develop RP than those with low Vectra DA scores. In comparison, patients were 1.4 times more likely to develop RP than patients with risk assessed by DAS28-CRP (P = 0.23) and 1.6 times more likely than those measured by CRP alone (P = 0.01).
PPV for an MBDA score greater than 44 ranged from 18% to 31%, and the NPV ranged from 93% to 97% (RR, 3.6–9.5), which was considered highly significant. “Based on high NPVs (93% or greater), the MBDA score used alone has clinical value for identifying patients with little or no risk of radiographic progression,” Dr. Sasso said.
“We believe combining the Vectra DA score with conventional clinical measures will enable physicians to individualize treatment plans for their patients, improve outcomes, and reduce the burden of future health care costs associated with this disabling disease,” he concluded.