Bryant Furlow

Recent advances in rheumatoid arthritis (RA) genetics research show great promise for the future personalization of treatment-but diagnostic and prognostic gene tests are probably still several years away from clinical validation, regulatory approval and routine use, cautioned authors of a review published in 

Gene tests for rheumatoid arthritis face a “long and winding road” to FDA approval and widespread adoption, they concluded. Despite impressive advances in the study of rheumatoid arthritis genetics and gene/drug interactions, and the growing availability of rapid gene-sequencing technologies like Next Generation Sequencing, the use of gene tests for rheumatoid arthritis will likely continue to lag behind clinical oncology, they wrote.

Progress is being made at an “astonishing” rate, but much has yet to be discovered about the genetic underpinnings of rheumatoid arthritis, they wrote. Genome-wide association studies have identified more than 100 candidate rheumatoid arthritis-susceptibility genes to date, many of them involved in T-cell activation and signaling gene pathways. “Somewhat surprisingly, these susceptibility loci account for less than 50% of the total genetic heritability [of rheumatoid arthritis], suggesting that there is a significant portion of the genetic architecture of RA that remains to be discovered,” they wrote.  [[{"type":"media","view_mode":"media_crop","fid":"47602","attributes":{"alt":"Â©Watchara/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_9829038905157","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5621","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Â©Watchara/Shutterstock.com","typeof":"foaf:Image"}}]]

Risk genes could one day help with early detection and treatment decisions for patients. However, the genes thus far identified each play a small role in a patient’s overall rheumatoid arthritis risk, meaning that when gene tests are developed, they will likely be panel tests that assess numerous genes at one time.

“While these applications are largely not refined to the point of clinical utility in RA, it seems likely that multi-parameter datasets including genetic, clinical, and biomarker data will be employed in the future care of RA patients,” wrote lead study author George N. Goulielmos, M.D., of the Laboratory of Molecular Medicine and Human Genetics, Medical School of Crete, in Greece, and co-authors from the University of Leeds in England and the 

“In RA, although there is not yet any guidance about which treatment will be the most suitable for any particular patient, it seems likely that genetic variation will be useful in predicting treatment response,” the authors wrote.

Advances in other areas-including RNA, protein, and epigenetic testing--might also yield new tools for the early identification of rheumatoid arthritis phenotypes, they wrote. For example, recent epigenetics research has tied epigenetic modifications to an aggressive, intrinsically activated form of rheumatoid arthritis, the researchers wrote. “Linking genetic and epigenetic data with gene expression and proteomics/metabolics is certainly the biggest challenge we are facing, and novel tools need to be developed to this end.”

Goulielmos GN, Zervou MI, Myrthianou E, et al. "Genetic data: the new challenge of personalized medicine, insights for rheumatoid arthritis patients." 

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Genetics research shows great promise for personalized treatment in rheumatology - but diagnostic and prognostic gene tests are years away.

A Long and Winding Road Ahead in Personalized Medicine

Tofacitinib and adalimumab improve physical function, pain, fatigue, well-being, emotional health and overall disease activity in patients with rheumatoid arthritis, a study shows.

The study is based on an analysis of the phase III ORAL Standard trial, a 12-month, randomized controlled trial of rheumatoid arthritis patients who had an inadequate response to methotrexate, but when tofacitinib or adalimumab was added to the treatment regime, patients experienced improvements in outcomes across the board, researchers wrote in the Feb. 29 online issue of 

“Patients with moderate to severe RA and inadequate responses to methotrexate reported improvements across a broad range of patient reported outcomes with tofacitinib 5 and 10 mg twice daily and adalimumab (40 mg once every two weeks) that were significantly superior to placebo,” the authors wrote.

The ORAL Standard trial (NCT00853385) enrolled 717 patients (75-83 percent female with mean disease range from 6.9 to nine years) of which 77.5 percent completed the 12-month trial. Patients were randomly assigned to one of four study arms:  (1) methotrexate plus tofacitinib 5 mg twice daily (2) tofacitinib 10 mg twice daily (3) placebo or (4) an active control group that received the tumor necrosis factor inhibitor adalimumab (40 mg once every 2 weeks).

Led by Gene Wallenstein, Ph.D., of Pfizer, researchers found significant differences in improvements in all patient reported outcomes at three months with tofacitinib 10 mg twice daily - and, these were sustained for 12 months.

Like tofacitinib, adalimumab was associated with improved patient-reported outcomes versus placebo. The study was not designed to test tofacitinib vs. adalimumab, the authors wrote. [[{"type":"media","view_mode":"media_crop","fid":"47219","attributes":{"alt":"(Â©PHOTOCREO/Shuttersstock.com)","class":"media-image media-image-right","id":"media_crop_2385547646672","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5544","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"(Â©PHOTOCREO/Shuttersstock.com)","typeof":"foaf:Image"}}]]

“In this randomized controlled trial, treatment with tofacitinib 5 and 10 mg twice daily, or adalimumab, all resulted in statistically significant and clinically meaningful improvements versus placebo in patient reported outcomes that approached maximal at month 3, with further smaller improvements until month 6,” the authors wrote.

“These results indicate that tofacitinib not only improves physical function, global assessments of disease activity, pain and fatigue, but also other aspects of HRQoL (health-related quality of life), particularly well-being and emotional health of patients with RA,” the authors wrote.

The ORAL Standard study was designed by Pfizer and academic partners, and was entirely funded by Pfizer, and study authors disclosed consulting fees and research funds from Pfizer and numerous other pharmaceutical firms. Dr. Wallenstein and four other study coauthors are employees and shareholders of Pfizer, they disclosed in the 

Strand V, van Vollenhoven RF, Lee EB, et al. 

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis

2016;299:53. Published online ahead of print Feb. 29, 2016. doi: 10.1093/rheumatology/kev442.

Tofacitinib and adalimumab improve physical function, pain, fatigue, well-being, emotional health and overall disease activity in patients with rheumatoid arthritis.

Overall Well-Being in RA Achieved with Tofacitinib

Both bone erosion and joint space narrowing are important indicators of physical disability in patients with rheumatoid arthritis (RA), but measuring soft tissue damage with subluxation (SLUX), which is a consequence of long-term RA, doesn’t seem to be relevant.

Writing in the March 11 issue of the journal 

RMD Open: Rheumatic & Musculoskeletal Diseases

, Ana Maria Gherghe, M.D., of Leiden University Medical Center in the Netherlands, and colleagues found that cartilage loss, measured by joint space narrowing, is important in assessing physical function. But in examining joints separately, erosive damage of the wrist and joint space narrowing of the metacarpophalangeal joints (MCPs) - together - are the best indicators for measuring disability. 

“These data indicate that the comprehensive assessment of joint damage is needed to reliably reflect disease-related damage,” the authors wrote. “In clinical practice, an aggregated score, such as Sharp van der Heijde, is needed to reliably reflect disease-related damage.”

Using three-year follow-up data from two randomized controlled trials, Rheumatoid Arthritis Prevention of structural Damage (RAPID 1) and RAPID 2, researchers evaluated the effects of bone erosion, cartilage loss associated with joint space narrowing, and soft tissue damage in patients with rheumatoid arthritis. Patients in the RAPID trials were randomized into one of two groups:  certolizumab pegol (200 or 400 mg) with methotrexate or placebo with methotrexate. Researchers included 847 patients from the 52-week RAPID 1 trial and 567 from the 24-week RAPID 2 trial.

Radiographs of patients’ hands and feet were acquired at baseline, weeks 24 and 52. For open label extensions of the trial beginning at week 16, radiographs were obtained at weeks 76, 100 and 148 among patients completing 52 weeks of treatment. Physical function was assessed using Health Assessment Questionnaire (HAQ) and radiographic damage assessments were conducted using the van der Heijde modified Sharp scoring, which allows separate scoring for bone erosions, joint space narrowing, and subluxation.

Researchers found that erosion and joint space narrowing were each more strongly associated with physical functioning as compared to subluxation. In combined models, joint space narrowing was the only type of lesion associated with HAQ when all joints were included. When separate joint groups were analyzed, erosion in the wrist and cartilage loss in the metacarpophalangeal joints (MCPs) were most strongly associated with function.

When all types of radiographic measures were included in a single combined multivariate analysis, only joint space narrowing was associated with physical function. The authors could not identify an independent contribution of SLUX to explain the variation in HAQ score.

“In accordance with other studies, we found ‘real JSN’ to be most contributory to explaining the HAQ score. That does not mean that SLUX (or erosion) is not important; in fact, there was a numerical association between subluxation score and HAQ score that was not statistically significant. It only indicates that the contribution of erosions and SLUX is appropriately captured by JSN. In other words: erosions and SLUX in this cohort rarely occur as the only phenomena, but, usually - if not always - in conjunction with JSN. An alternative explanation could be that erosions and SLUX are rare phenomena in comparison with ‘real’ JSN. That is definitely not true for erosions, which occur as often as ‘real’ JSN, but likely true for SLUX that were indeed rare in these trials. Since SLUX is a known late consequence of long-term RA, and the effects of SLUX are captured by JSN, the inclusion of SLUX in the scoring method for radiographic damage does not seem to be very relevant. However, there is also no indication that SLUX jeopardizes the performance of the modified Sharp score, and it does not make sense to remove SLUX from the current score,” the authors wrote.

Limitations of the study included the high number of statistical tests performed and the sensitivity of methods such as GEE that make use of all data available.

Association of the different types of radiographic damage with physical function in patients with rheumatoid arthritis: analysis of the RAPID trials."

. 2016;2:e000219. doi: 10.1136/rmdopen-2015-000219.

Both bone erosion and joint space narrowing are important indicators of physical disability in rheumatoid arthritis (RA), but measuring soft tissue damage not as relevant.

Best Tools to Measure Joint Damage in RA

 find that a simple walking test can help assess the status of pulmonary disease in patients with systemic lupus erythematosus.

More than half of patients with lupus experience pulmonary involvement, commonly including pleural disease (thickening, fibrosis or effusions on CT imaging), interstitial lung disease (ILD), pulmonary manifestations (pulmonary infarction, pulmonary hypertension and pleural fibrosis), abnormal pulmonary function tests (PFTs), or the presence of shrinking lung syndrome (SLS).

For patients with lupus, pulmonary disease can impact their ability to walk longer distances without necessarily affecting other patient reported outcomes, such as dyspnea, cough, shortness of breath, sleep or fatigue. So, the researchers, led by Shikha Mittoo, M.D., of Mount Sinai Hospital in Toronto, decided to assess the use of the six-minute walk test in evaluating pulmonary disease.

The cross-sectional study included 110 patients with lupus of which 62 (56 percent) had pulmonary disease:  54 (49%) abnormal pulmonary function test; 13 (12%) pleural disease; 12 (11%) interstitial lung disease; 11 (10%) shrinking lung syndrome and five (5%) pulmonary hypertension. Dyspnea was the only PRO found to be significantly associated with pulmonary disease (P = 0.0004).  [[{"type":"media","view_mode":"media_crop","fid":"46987","attributes":{"alt":"Â©arka38/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_411549834527","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5496","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Â©arka38/Shutterstock.com","typeof":"foaf:Image"}}]]

Researchers found that patients with pulmonary disease were able to walk significantly shorter distances (P = 0.00015, 95% CI for mean 39–125 m) and a predicted distance (P = 0.00001, 10%–26%) based on the six-minute walk test as compared to participants without pulmonary disease. Patients with pulmonary disease had a significant reduction in six-minute walk test six-minute walking distance compared to those without:  486 (17) m vs 569 (14) m (P = 0.0002) and 85.0 (3.0)% vs 103.1 (2.7) % (P = 0.000010), respectively.

The “six-minute walk test holds promise as an inexpensive, reproducible and feasible Patient Performed Outcomes test to detect or assess pulmonary disease in SLE patients while patients are in the que for PFTs (Plumonary Function Tests) and imaging,” the researchers wrote in the Feb. 3 issue of 

The authors suggest a need to explore testing strategies for pulmonary disease that include expanding patient performed outcomes.

The study’s limitations included its cross-sectional design and the small sample of patients

 Impact of pulmonary disease on patient-reported outcomes and patient-performed functional testing in systematic lupus erythematosus.

2016. (In press.) DOI: 10.1177/0961203316630818.

Researchers reporting in the journal Lupus find that a simple walking test can help assess the status of pulmonary disease in patients with systemic lupus erythematosus.

Author | Bryant Furlow

Articles

A Long and Winding Road Ahead in Personalized Medicine

Overall Well-Being in RA Achieved with Tofacitinib

Best Tools to Measure Joint Damage in RA

Walking Test Can be a Measure of Lung Disease in Lupus