In the Literature - December 2016

VBCR - December 2016, Vol 5, No 6 - In the Literature

In This Article

Pregnancy Outcomes in Ankylosing Spondylitis

Results from a large population-based study showed that pregnancies among mothers with ankylosing spondylitis (AS) were associated with higher rates of Cesarean sections, more preterm births, and a higher rate of small-for-gestational-age births compared with the general population (Jakobsson GL, et al. Ann Rheum Dis. 2016;75:1838-1842). These results suggest an influence of disease severity and comorbidities, according to the investigators.

The case-control study was based on 388 deliveries among women with AS identified in the Swedish National Patient Register and Medical Birth Register, and deliveries among 1082 matched controls from the general population.

A total of 1470 singleton births were included in the analysis; 388 occurred in 301 women with AS and 1082 in 698 women in the control group. Women with AS were significantly older at delivery (P <.0001), and had higher body mass index, greater frequency of smoking, lower levels of education, and less parity compared with the general population.

Women with AS also had a higher rate of comorbidities, including diabetes, renal disease, and hypertension, which can affect birth outcomes. Before giving birth, women with AS were diagnosed with inflammatory bowel disease (6%), psoriasis (4%), and peripheral arthritis (10%). In the 12 months before delivery, women with AS took more drugs, including nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, corticosteroids, and tumor necrosis factor (TNF) inhibitors compared with the controls.

The rate of Cesarean section was higher among women with AS compared with matched controls. Emergency Cesarean sections were performed in 16.5% of women with AS compared with 6.5% of controls, and elective Cesarean sections were performed in 9.8% versus 6.9%, respectively. Odds ratios were 3.00 for emergency Cesarean section and 1.66 for elective Cesarean section.

Preterm births occurred more frequently in women with AS (9.0% vs 4.9% in matched controls; odds ratio, 1.92), and small-for-gestational-age births occurred in 3.1% versus 1.5%, respectively (odds ratio, 2.12).

Findings were similar after adjusting for confounders such as age, smoking status, educational level, parity, and the exclusion of women with comorbidities.

More extensive antirheumatic therapy was associated with greater risks for elective Cesarean sections and small-for-gestational-age births.

Subgroup analysis suggested that complex mechanisms underlie these adverse outcomes, including a more severe phenotype of AS, increased rate of preeclampsia, and other undetermined factors.

There are few previous reports of pregnancy outcomes in patients with AS, the investigators said. They were prompted to initiate the study because inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, are known to carry an increased risk for premature birth and restricted infant growth.

Limitations of the study include potential invalid diagnosis of AS, a lack of information regarding disease activity and severity during pregnancy, and incomplete information regarding congenital ab­norm­alities.

Strengths of the study include comprehensive, registry-based data, and inclusion of representative populations.

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Prescribing Patterns for JIA in the United Kingdom

An observational study of biologic prescribing patterns found that etanercept is still the most common biologic prescribed to children and adolescents with juvenile idiopathic arthritis (JIA), but strong trends were evident toward the use of alternative biologics without a strong evidence base for treatment selection in this age-group (Kearsley-Fleet L, et al. Rheumatology. [Oxford] 2016;55:1556-1565). Physicians are prescribing biologics other than etanercept partly because of the wider availability of different biologics, and treatment decisions appear to be driven by disease subtype and history of chronic anterior uveitis, according to the investigators.

The researchers sought to determine disease characteristics among children and adolescents recently initiating different first-line biologics for JIA; describe changes in characteristics over time among patients in this age-group starting etanercept in light of an expanded evidence base on the efficacy of other biologic therapies for JIA (eg, tocilizumab, canakinumab, and anakinra); and describe patterns of prescribing a second biologic among children and adolescents who are intolerant of, or whose disease failed to respond to, their first biologic treatment.

The analysis was based on 2 JIA biologic registers that are ongoing, prospective, and observational cohorts collecting data on patients starting biologic therapy for JIA—the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study, and the Biologics for Children with Rheumatic Diseases study.

The investigators compared first biologics in patients starting treatment who were registered from January 1, 2010. Patients starting etanercept from January 1, 2003, were included to analyze changes in etanercept prescribing. The pathway to starting a second biologic was recorded for all patients.

From January 1, 2010, to August 26, 2014, a total of 931 patients starting a first-line biologic were recruited. Starting in 2010, patients with systemic JIA were almost exclusively prescribed tocilizumab or anakinra. The choice between anti–tumor necrosis factor (TNF) therapies was largely determined by the patient’s history of chronic anterior uveitis.

Recent evidence suggests that ana­kinra is effective in treating systemic JIA, which may have influenced physician prescribing. Moreover, patients with chronic anterior uveitis were more often prescribed monoclonal antibody TNF inhibitors than etanercept. This shift appears to be based on small studies and case reports suggesting that adalimumab and infliximab are superior to etanercept in patients with a history of chronic anterior uveitis.

Evidence supporting the shift toward the use of monoclonal antibody TNF inhibitors is limited, but 2 ongoing, randomized controlled trials (MTX ADUVITE and SYCAMORE) in the treatment of patients with JIA with chronic anterior uveitis should shed some light on this issue.

Results also showed that etanercept is now being prescribed earlier in the course of disease in children with lower levels of disease activity and severity. Fewer children and adolescents with systemic JIA or a history of chronic anterior uveitis are now being initiated with etanercept. Similar patterns were observed in children and adolescents switching to a second biologic.

“This is the first description of biological therapy prescribing patterns in CYP [children and young people] with JIA in all of the biological therapies currently available in the UK [United Kingdom],” the investigators said. The existence of the 2 prospective registers will enable analysis of patient outcomes in various drug cohorts, and will address which is the best choice of biologic therapy.

“This channeling of children towards specific therapies should be considered carefully in future studies and in clinical guidelines and ongoing research,” they concluded.

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Sifalimumab Is a Potential New Treatment Approach for Patients with Systemic Lupus Erythematosus

Sifalimumab demonstrated encouraging results in the treatment of adults with active systemic lupus erythematosus (SLE) in a phase 2b, double-blind, placebo-controlled trial (Khamashta M, et al. Ann Rheum Dis. 2016;75:1909-1916). Sifalimumab met all the primary end points of the trial for response, including a 4-point improvement in the SLE Disease Activity Index−2000 score; no clinically significant worsening on the Physician’s Global Assessment; and no new British Isles Lupus Assessment Group 2004 severe scores, or ≥1 new moderate organ system scores, showing significant superiority over placebo for SLE responder index response at week 52.

Sifalimumab is a fully human monoclonal antibody that binds to and neutralizes the majority of interferon (IFN)-α subtypes, suppressing INF-α–induced genes. SLE is a chronic, multisystem, autoimmune disease primarily seen in women of childbearing age. SLE is challenging to treat because standard-of-care medications have limited efficacy, and their use has been associated with serious adverse events.

Previous studies suggested a role for IFN-α in the pathogenesis of SLE, indicating a potential need for a treatment that blocks the type I IFN pathway, and giving rise to the present study of sifalimumab.

The study evaluated the efficacy and safety of 3 fixed intravenous doses of sifalimumab given monthly to 431 adults with moderate-to-severe active SLE and inadequate responses to standard-of-care treatments.

Patients were randomized as follows: 108 to placebo; 108 to sifalimumab 200 mg; 108 to sifalimumab 600 mg; 107 to sifalimumab 1200 mg. Baseline characteristics were similar between the 4 groups, with the exception of shorter disease duration in the placebo group and fewer patients in the 600-mg group receiving mycophenolate. Disease scores were similar across groups, between the IFN-high and IFN-low groups, and between patients from different geographic regions.

At week 52, the number of patients achieving the primary composite end point was greater in the sifalimumab group than in the placebo cohort (P = .053), and improvement was consistent for all doses of sifalimumab compared with placebo.

The primary composite end point was met as follows: for the 200-mg group, 58.3%; for the 600-mg group, 56.5%; and for the 1200-mg group, 59.8%, compared with placebo, 45.4%.

Secondary effect measures at week 52 assessing decreased prednisone dosages and effects on individual organ systems were improved with sifalimumab compared with placebo. These included assessments in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician’s Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in SLE Disease Activity Index−2000 score, and reductions in counts of swollen and tender joints.

The percentages of patients with ≥1 adverse events, serious adverse events, or adverse events leading to treatment discontinuation were similar across all of the groups. Worsening of SLE, urinary tract infections, headaches, upper respiratory tract infections, and nasopharyngitis were the most common adverse events. Five deaths occurred during the double-blind period; 2 patients in the placebo group (both septic shock), 1 in the 600-mg group (cardiopulmonary arrest/sepsis), and 2 in the 1200-mg group (stab wound, cardiopulmonary arrest/transient ischemic attack). Serious adverse events were reported in 17.6% of patients receiving placebo, and in 18.3% of patients taking sifalimumab.

Herpes zoster infections were more common in the sifalimumab-treated group (5.9%) than in the placebo cohort (0.9%), with the highest incidence in the sifalimumab 1200-mg group (9.3%).

These are promising early results on broad-based improvement measures with sifalimumab, but studies are needed that show significant improvement in SLE.

“Our observations demonstrate that blocking the type I IFN pathway is a promising approach for the treatment of moderate to severe active SLE,” the investigators concluded.

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