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VBCR - February 2016, Vol 5, No 1 - In the Literature

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Secukinumab Effective in Ankylosing Spondylitis

An analysis of 2 double-blind phase 3 trials (MEASURE 1 and MEASURE 2) shows that secukinumab significantly reduced the signs and symptoms of ankylosing spondylitis. Results suggest that secukinumab is effective in patients naive to anti–tumor necrosis factor (TNF) treatment as well as those who have failed on previous anti-TNF treatment.

"Anti-TNF agents are the only approved biologic agents for ankylosing spondylitis, with a number of other therapies failing to show benefits. Although head-to-head trials would be required to fully assess the efficacy and safety of secukinumab versus TNF-inhibitors, the ASAS20 [20% improvement in Assessment of Spondyloarthritis International Society] response rates at week 16...are similar to those reported in phase 3 trials of anti-TNF agents in which most patients had not received previous anti-TNF therapy," the authors wrote, while noting that 30% to 40% of patients in the MEASURE 1 and MEASURE 2 studies had had no response to previous anti-TNF treatment.

The lead author was Dominique Baeten, MD, of the Academic Medical Center at the University of Amsterdam, the Netherlands.

These results from MEASURE 1 and MEASURE 2 extend the positive results of the phase 2 study. Approximately 60% of patients achieved the primary end point of an ASAS20 response.

Secukinumab is an interleukin-17A inhibitor approved by the US Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis.

In both MEASURE 1 and MEASURE 2, patients with ankylosing spondylitis were randomized to treatment with secukinumab versus placebo. In the MEASURE 1 study, 371 patients received intravenous secukinumab (10 mg/kg of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In the MEASURE 2 study, 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline, at weeks 1, 2, and 3, and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg.

In the MEASURE 1 study, the rates of ASAS20 at week 16 were 61% for subcutaneous secukinumab 150 mg, 60% for subcutaneous secukinumab 75 mg, and 29% for placebo (P< .001 for both comparisons with placebo). In the MEASURE 2 study, ASAS20 rates were 61% for subcutaneous secukinumab 150 mg, 41% for subcutaneous secukinumab 75 mg, and 28% for placebo (P< .001 for the 150-mg dose and P =.10 for the 75-mg dose). Significant improvements in patient clinical response were maintained through week 52. No incremental increase in efficacy was observed with intravenous loading compared with the subcutaneous loading regimen.

The safety profile of secukinumab in these studies was consistent with previous studies of secukinumab in ankylosing spondylitis and moderate-to-severe plaque psoriasis. Infections were more common with secukinumab compared with placebo (30% vs 12% in MEASURE 1 and 32% vs 27% in MEASURE 2). Pooled rates for both studies of grade 3 or 4 neutropenia, Candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years in patients treated with secukinumab.

These findings suggest that interleukin-17A is implicated in the pathogenesis of ankylosing spondylitis and validate inhibition of interleukin-17A as a potential approach in this disease.

Baeten D, et al. N Engl J Med. 2015; 373:2534-2548.

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Vitamin D Supplementation in Juvenile-Onset SLE

Six months of vitamin D supplementation decreased disease activity and improved fatigue scores in patients with juvenile-onset systemic lupus erythematosus (SLE), a recent study suggests.

At the end of the 24-week study, the mean serum level of 25-hydroxyvitamin D (25[OH]D) was higher in the group of patients receiving vitamin D supplementation than in the placebo group (31.30 ± 8.6 vs 16.56 ± 5.8, respectively; P<.001). Seventy percent of patients in the supplement group attained levels of 25[OH]D greater than 30 ng/mL; none of the patients taking placebo reached this level.

The vitamin D supplementation group showed significant improvement in the SLE Disease Activity Index (SLEDAI; P =.010) and the European Consensus Lupus Activity Measurement (ECLAM; P =.006 compared with the placebo group. The supplement group also achieved a lower score of fatigue related to social life than the placebo group (P =.008), and an improved global fatigue score by study end compared with the placebo group according to the Kids Fatigue Severity Scale (K-FSS): 3.15 ± 1.44 versus 4.30 ± 1.33, respectively; P =.012.

This double-blind, placebo-controlled trial randomized 40 juvenile-onset SLE patients 1:1 to vitamin D supplementation with cholecalciferol 50,000 IU/week or placebo. Both treatment arms were well-matched for age, body mass index, organ involvement glucocorticoid dose, use of immunosuppressive drugs, as well as baseline scores on SLEDAI, ECLAM, and K-FSS.

All patients had a 3-month washout of vitamin D prior to randomization. Evaluations occurred at baseline, and at 3 and 6 months.

The authors claim this is the first study of vitamin D supplementation in juvenile-onset SLE patients. The study was based on increasing evidence that, in addition to bone health, vitamin D plays an important role in the immune system. A previous study by this group of investigators showed an association between a vitamin D deficiency (<20 ng/mL) and higher SLEDAI scores.

Vitamin D supplementation was well-tolerated in this study. The authors conclude that "a therapeutic intervention may be recommended in patients with deficient levels of 25[OH]D," and call for larger multicenter trials to further assess their findings.

The study was carried out at the Hospital das Clinicas da Universidade de São Paulo, Brazil.

Lima GL, et al. Arthritis Care Res (Hoboken). 2016;68:91-98.

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Health-Related Quality of Life in Childhood-Onset Lupus

Decreased health-related quality of life (HRQOL) in patients with childhood-onset systemic lupus erythematosus (SLE) appears to be attributable more to psychological health factors than to disease activity, according to a recent cross-sectional study. The researchers found that achieving the best health outcomes depended on providing medical attention to address these factors, which included symptoms of fatigue, mood, pain, and anxiety.

The study enrolled 60 children and adolescents aged 8 to 20 years treated at a tertiary rheumatology clinic at Cincinnati Children's Hospital Medical Center. All participants met the revised American College of Rheumatology Classification Criteria for SLE by their 18th year.

Study participants completed the following instruments to assess components of HRQOL: visual analog scale (VAS) for pain intensity; Adolescent Sleep-Wake Scale; Pediatric Quality of Life (PedsQL) for fatigue; Pain Coping Questionnaire; Pain Catastrophizing Scale (PCS); Children's Depression Inventory-I (CDI-I); Screen for Child Anxiety Related Emotional Disorders (SCARED); and the PedsQL generic core (GC) and rheumatology module (RM). Results were compared to a reference population of healthy children and children with arthritis.

Patients in the study reported symptoms of fatigue, 65%; clinically relevant pain (pain-VAS >3), 40%; anxiety (SCARED ≥25), 37%; depressive symptoms (CDI-I >12), 30%; and high pain catastrophizing (PCS ≥26), 22%. Moderate pain catastrophizing was evident in most patients. The authors contend that this is the first study to report on pain catastrophizing in childhood-onset SLE.

PedsQL-GC and -RM scores of patients with childhood-onset SLE were lower on average than for healthy children or for those with arthritis, and highly correlated with increased levels of fatigue, anxiety, and depression. There was a low correlation with disease activity. When all factors were concurrently evaluated, regression analysis indicated that HRQOL was negatively affected most by fatigue and pain, and, to a lesser extent, anxiety.

"These results strongly suggest that drug therapy to improve childhood-onset SLE-associated inflammation and damage alone is insufficient to normalize HRQOL outcomes," the authors state.

Results of the study reinforce findings from previous reports that patients with childhood-onset SLE generally have significantly lower HRQOL scores than their healthy peers, despite the improved treatments and survival rates achieved in the past decade. The authors recommend the use of simple questionnaires to identify patients who may benefit from psychologists, psychiatrists, pain intervention, and other resources to improve the HRQOL scores of patients with childhood-onset SLE.

Jones JT, et al. Arthritis Care Res (Hoboken). 2016;68:73-80.

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Provider's Communication Style and Patient Self-Efficacy

It appears that how positively a provider communicates about a specific treatment affects patients' ability to control health behaviors (ie, "self-efficacy") and, in turn, influences outcomes. For example, if a provider communicates high expectations that a treatment will be effective, patients are more likely to believe that treatment will help, and the treatment is more likely to help.

The investigators sought to determine the mind–body relationship vis-à-vis the effect of a provider's style of communications (ie, high expectations or neutral expectations) on patient self-efficacy as a mediator of outcomes as a secondary analysis of a study originally designed to compare acupuncture to sham acupuncture for the treatment of knee pain in patients with knee osteoarthritis (OA).

The 3-arm study randomized 485 patients (63% female, mean age of 64.7 years, mean body mass index of 32.2 kg/m2) with painful knee OA to traditional acupuncture, sham acupuncture, or a wait list. Treatment was twice a week for 6 weeks.

Six licensed acupuncturists were trained to communicate with participants in either a high-expectation or neutral-expectation style regarding treatment success. Those trained in the neutral style conveyed uncertainty about treatment and outcomes, while those trained in high-expectation style conveyed positive, hopeful statements about treatment success.

In both acupuncture groups, patients were equally randomized to high–expectation-trained acupuncturists and neutral-expectation–trained acupuncturists.

A modified Arthritis Self-Efficacy Scale questionnaire and the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscale were administered at baseline and at 3 months, and linear regression analysis was used to examine whether patient self-efficacy mediated the relationship between the communication style of the provider and knee pain at 3 months.

In the primary analysis, true acupuncture was not superior to sham acupuncture. In the secondary analysis, high-expectation provider communication was associated with improved patient self-efficacy, and self-efficacy was associated with a reduction in WOMAC pain score, while controlling for provider communication style. Neutral provider communication style did not affect patient self-efficacy, supporting the assumption that patient self-efficacy mediates the relationship between provider- communicated expectations of treatment effects and knee pain.

Self-efficacy was strongly associated with WOMAC pain (P <.0001): those with greater self-efficacy at 3 months had a lower WOMAC pain score. Longitudinal change in self-efficacy was correlated with WOMAC pain levels, as those with an improvement in self-efficacy over time had reduced WOMAC pain.

High-expectation provider communication style was associated with greater patient self-efficacy at 3 months compared with those patients who received a neutral communication style from their provider.

"High clinician expectation of efficacy conveyed to patients for a given treatment, even a treatment that is not inherently effective, has an important effect on pain reduction in knee OA. This relationship is mediated by improved patient self-efficacy," wrote Grace Hsiao-Wei Lo, MD, Baylor College of Medicine, Houston, TX, and coauthors. "These findings suggest that clinician-conveyed expectations can enhance the benefit of treatments targeting the symptoms of knee OA."

"These findings underscore the importance of the mind-body relationship and potentially have important clinical implications as well as the importance of modeling pathways through which communication can contribute to improved health outcomes," the authors wrote.

The mind–body connection and the effect of provider communication style has also been found to play a role in other pain-related diseases that are difficult to treat, such as fibromyalgia, chronic low back pain, and headache, the authors said.

Lo GH-W, et al. Arthritis Care Res (Hoboken). October 27, 2015. doi: 10.1002/acr.22775.

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Postoperative Care Navigation for Total Knee Arthroplasty

A new study reports a counterintuitive finding–that postoperative care navigation with frequent follow-up following total knee arthroplasty (TKA) did not substantially improve functional improvement at 6 months compared with controls.

The parallel, randomized controlled study enrolled 308 subjects undergoing TKA for knee osteoarthritis (OA). Subjects were randomized 1:1 to 2 treatment arms: motivational interviewing–based postoperative care navigation with frequent follow-up by a care navigator versus usual care.

"Motivational interviewing (MI) is a technique for promoting behavior change by guiding individuals through the stages of change to achieve their goals," explained lead author Elena Losina, MD, Harvard Medical School, Boston, MA. The purpose of the study was to evaluate the efficacy of MI-based enhanced postoperative care navigation in improving outcomes following TKA and to identify patient groups that would derive the most benefit from such interventions. "To our knowledge, this is the first published randomized controlled trial to investigate the effectiveness of [this technique] on improvement in pain and function following TKA."

Navigators trained in the MI technique made a total of 10 calls to patients over the 6-month period. For the first month, navigators made calls more frequently. During the calls, the navigators asked open-ended questions to elicit the patient's objectives for recovery and to help the patient identify barriers to achieving his or her goals. The navigator gave positive feedback regarding progress and adherence to therapy. Navigators gave no medical advice, and encouraged the patient to contact a healthcare provider when appropriate.

The usual care arm underwent the standard rehabilitation protocol at Brigham and Women's Hospital in Boston, MA, for inpatient physical therapy for range of motion and gait therapy with a prescribed outpatient physical therapy regimen. Most patients received some form of outpatient therapy for 3 to 6 months following TKA.

The primary outcome measure was change in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) function scores from preoperative to 6 months postoperative. Mean age of patients was 66 years, 60% were female, and 50% had body mass index (BMI) 30 kg/m2. About two-thirds had the most severe form of knee OA. At baseline, average WOMAC function score was 41. Both groups were well an balanced for pain catastrophizing score, with average score of 11. (Pain catastrophizing is a significant predictor of outcome after TKA, the authors said.) The final sample for analysis consisted of 269 patients.

Mean change in WOMAC function score from baseline to 6 months was–30 in the navigator group and–27 in the usual-care group. Both arms improved from baseline. Both arms had similar range of motion 6 months after surgery. Improvements from baseline in WOMAC pain score followed the same pattern.

In a preplanned subgroup analysis, change from baseline to 6 months in the intervention group was–1 point for study participants with BMI <30 kg/m2,–2 points for those with BMI 30-35 kg/m2, and -3 points for those with BMI >35 kg/m2. Those with a moderate degree of pain catastrophizing (score of ≥20) had a detrimental effect from navigation of 7 points compared with those with a low degree of pain catastrophizing (–3 points).

Dr Losina and coauthors wrote, "Offering the intervention to all TKA recipients rather than those at risk for poor outcomes may have diluted the efficacy of the intervention."

A better approach, they suggested, might be to identify subgroups more likely to benefit, such as patients with higher BMI and low pain catastrophizing score. Patients with high levels of pain catastrophizing may not benefit from this type of intervention, unless they have received psychological counseling and learned coping strategies to reduce their levels of anxiety.

Losina E, et al. Arthritis Care Res (Hoboken). December 29, 2015. doi: 10.1002/acr.22829.

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