Vanessa Caceres

A newly published small prospective observational study shows that rheumatoid arthritis patients who have had a malignancy and are receiving a TNFi or rituximab (RTX), do not appear to have an increased risk of cancer recurrence.

Chronic inflammation, such as inflammation associated with rheumatoid arthritis, has been shown to predispose patients to cancer. It leads to increased cell proliferation, mutagenesis, oncogene activation and angiogenesis. “The longer the inflammation persists, the higher the risk of associated carcinogenesis,” in particular, lymphoma, leukemia and lung cancer, write the authors of a study published in the Aug. 22 online issue of 

The study, led by Kimme L. Hyrich, Ph.D., of the University of Manchester, U.K., explores the influence of rituximab on the incidence of cancer in patients with rheumatoid arthritis and a prior malignancy.

Hyrich and colleagues identified 425 patients with a prior malignancy from 18,000 rheumatoid arthritis patients. Of these, 101 patients developed a new malignancy. The rates of incident malignancy were 33.3 events/1,000 person years in the TNFi cohort; 24.7 events/1,000 person years in the rituximab group and 53.8 events/1,000 person years in the DMARD group. 17.0% of patients in the DMARDs group had a recurrence of the same cancer as compared to the 12.8% and the 4.3% in the TNFi and rituximab groups, respectively.

The authors compared the rates of first incident malignancies that were diagnosed after the first dose of the biologic agent or after the study registration date for the sDMARDs group. They found that after five years, patients with rheumatoid arthritis and a prior malignancy who received TNFi or rituximab treatment, did not seem to have an increased risk of recurrence or develop a new malignancy.

How this study add to our current knowledge about biologics and cancer risk:

The current findings are consistent with previous findings in which patients with a prior malignancy, who were on TNFi therapy, did not have an increased risk of cancer recurrence. The current study extends the mean follow-up by three years.

“Nevertheless, attending to the wide confidence interval of the HR in the RTX group, we cannot firmly rule out a clinically important increased or decreased risk of IM in patients receiving RTX,” the authors wrote.

Although this was among the largest and longest studies to address the question of cancer risk in this group of patients, the authors cited a number of concerns, including the non-randomization of treatment in the study which could threaten the validity of the results.

The authors suggest that the results be “interpreted in the context of an observational study of routine clinical practice.”

Silva-Fernandez L, Lunt M, Kearsley-Fleet L, et al. 

“The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.”

. Published online Aug. 22, 2016. DOI:  10.1093/rheumatology/kew314

Dixon WG, Watson KD, Lunt M et al. “Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register,” 

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Rheumatoid arthritis patients who have had a malignancy and are receiving a TNFi or rituximab (RTX), do not appear to have an increased risk of cancer recurrence.

Another Study Shows No Malignancy after Biologics

Rheumatoid arthritis patients prescribed a combination therapy of tofacitinib and a disease-modifying anti-rheumatic drug, reported significant improvements in their condition, a phase III randomized controlled trial shows. The study was published as a brief report in the Aug. 26 online issue 

Patient-reported outcomes can help assess the impact of disease and quality of life and are often more important to patients than what is revealed from laboratory results or joint counts.

The trial, called ORAL Sync, took place over 12 months and included 795 adult patients with rheumatoid arthritis. In the trial, patients were randomized to receive tofacitinib 5 mg or 10 mg twice daily; or a placebo of 5 mg or 10 mg twice daily in combination with a DMARD.

By month three, non-responders in the placebo group were advanced blindly to receive 5 mg or 10 mg of tofacitinib twice a day; by month six, all placebo patients were advanced blindly to receive tofacitinib. Patients in the tofacitinib groups who were nonresponders continued with the same treatment.

At month three, there were statistically significant improvements in the tofacitinib 10 mg and 5 mg groups using six assessments, with slightly better results in the tofacitinib 10 mg cohort. The improvements continued through 12 months. One key factor that improved was sleep quality, as measured by the MOS Sleep. “Sleep disturbance is associated with disease activity and pain in RA…it is encouraging, therefore, that in this trial, reported improvements in [health-related quality of life] and fatigue were accompanied by similar changes in MOS sleep,” the authors wrote.

The study results are similar to those of previous phase III randomized controlled trials of tofacitinib with rheumatoid arthritis in patients who did not adequately respond to methotrexate and biologic DMARDs, the authors reported.

Studies that utilize patient-reported outcomes are valuable because they reflect the actual needs and desires of patients, the authors wrote.

“PROs assessing HRQoL and fatigue are considered important in RCTs of RA treatments because, in addition to being incorporated into composite disease activity measures, they reflect aspects of disease impact (such as physical function, physical and emotional wellbeing, pain, and fatigue) that are likely more important to patients than joint counts or laboratory tests,” the authors wrote.

The study limitations included a short duration of placebo exposure because advancement from placebo occurred in two stages at months three and six, the authors wrote. Another limitation was that the study did not stratify patients by background DMARD therapy, which varied among patients. Still, the results provide further evidence that tofacitinib can help improve pain, physical function, health-related quality of life, fatigue and sleep, the authors concluded.

At three months, treatment with tofacitinib 5 mg BID and 10 mg BID resulted in significantly greater improvements from baseline in PtGA, Pain, and HAQ-DI compared with placebo (P < 0.0001). The proportion of patients reporting improvements greater than the minimum clinically important differences in PtGA, Pain, and HAQ-DI at Month 3 was significantly greater with both doses of tofacitinib versus placebo (P < 0.0001).

Treatment with tofacitinib 5 mg BID and 10 mg BID resulted in significant improvements (P < 0.05) compared with placebo at Month 3 in SF-36 physical component and mental component scores, and seven of eight SF-36 domains with 5 mg BID and all eight SF-36 domains with 10 mg BID.

At three months, significantly greater mean improvements from baseline (P < 0.001) in FACIT-F and MOS Sleep were reported by patients treated with both doses of tofacitinib versus placebo.

Vibeke Strand MD, Joel M. Kremer MD et al

. "Tofacitinib in Combination with Conventional DMARDs in Patients with Active Rheumatoid Arthritis: PROs from a Phase 3 Randomized Controlled Trial

Brief report in the journal Arthritis Care and Research shows that patients report favorable outcomes with a tofacitinib/DMARD combo therapy.

Tofacitinib Ranks High in Patient-Reported Outcomes

Glucocorticoid use in patients has long been associated with osteoporosis, but new studies show that some patients are still not being screened or treated for glucocorticoid-induced osteoporosis (GIOP).

In a recent study, published in the July 7 issue of 

, French researchers write that GIOP management is inadequate, particularly among primary care physicians who prescribe glucocorticoids more frequently than other physicians.

This finding is particularly important because .5 – 1.2% of adults in the United States and United Kingdom are on long-term glucocorticoid therapy. Even at low dosages, glucocorticoids have been associated with increased risk of fractures. Glucocorticoids decreases bone formation and increases bone resorption and within three months can lead to bone fragility.

Led by Pierre Lafforgue, Hopital Sainte-Marguerite, France, researchers culled a national public health insurance database finding that of 32,812 patients (44 percent male, mean age 58 years) were prescribed at least 7.5 mg of prednisone per day for at least 90 days from 2009-2011 and 14,205 patients (43%) “met our definition of incident cases.” Of 14,205 cases, 6,311 (44%) were males and 7,894 (55%) were females, including 4,377 (31%) females older than 55 years old. The average glucocorticoid use was 11 mg/day of prednisone equivalent for an average of 206 days. [[{"type":"media","view_mode":"media_crop","fid":"50086","attributes":{"alt":"Â©Lightspring/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_3802932257625","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6092","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©Lightspring/Shutterstock.com","typeof":"foaf:Image"}}]]

"The bone loss induced by glucocorticoids occurs early and at a fast pace, being significant within 6âmonths. Consequently, an evaluation of bone risk and the implementation of prophylactic measures should take place at, or shortly after, the first prescription of glucocorticoid therapy," the authors wrote.

The majority of first-time prescriptions, 55%, were written by primary care physicians. Rheumatologists wrote 5%, pulmonologists 2%, gastroenterologists 2% and internists 1% (the prescriber’s specialty was unknown in 23% of cases). Patients were prescribed glucocorticoids for rheumatoid arthritis (20%), autoimmune disease such as systemic lupus erythematosus, polyarteritis nodosa or Sjogren’s syndrome (13%); chronic respiratory failure (13%), asthma (10%) or chronic inflammatory bowel disease (8%).

In patients using glucocorticoids, 18% used calcium and/or vitamin D, and 12% used bisophosphonates. Eight percent had bone mass measurement performed. That compared with only 3% who underwent bone mass measurement and 3% that used bisophosphonate therapy in a control population.

American College of Rheumatology recommends

 using the smallest dose of glucocorticoid for the shortest duration possible as an important strategy to minimize osteoporosis risk. “Since there may be no dose of glucocorticoids that does not accelerate bone loss or increase fracture risk, recommendations for counseling and assessment are extended to all doses of glucocorticoids used or expected to be used for at least three months,” according to the ACR’s updated 2010 recommendations.

 presented at the American College of Rheumatology annual meeting in 2015, showed that 53% of patients treated at a New York Hospital were not appropriately screened or treated for glucocorticoid-induced osteoporosis. Younger patients and male patients were not screened, and new studies show that they too are at higher risk of developing osteoporosis. This study was conducted with rheumatologists, which suggests that this group also underutilizes osteoporosis screening and preventative treatment measures. Better education regarding the screening and treatment of glucocorticoid-induced osteoporosis for both primary care physicians and rheumatologists may be helpful, the authors wrote.

1. Trijau S, de Lamotte G, Pradel V, et al. 

“Osteoporosis prevention among chronic glucocorticoid users: results from a public insurance database.”

 RMD Open 2016;2:e000249. doi:10.1136/rmdopen-20 16-00024.

2. Grossman JM, Gordon R, Ranganath VK, et al. 

“American College of Rheumatology 2010 Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.”

 Arthritis Care & Research Vol. 62, No. 11, November 2010, pp 1515–1526. DOI 10.1002/acr.20295.

3. Ogando S, Santana C, Blanco I, et al. 

“Osteoporosis Screening and Treatment of Rheumatoid Arthritis Patients at a Teaching Institution.”

Some patients are not being screened or treated for glucocorticoid-induced osteoporosis by primary care physicians or rheumatologists.

Screening is Lax in Glucocorticoid-Induced Osteoporosis

Researchers have found a subset of Treg cells that are more prevalent in the blood of patients with juvenile idiopathic arthritis and active inflammation, as compared to patients in remission.

The findings have a potential impact for both rheumatoid arthritis as well as oligoarticular and polyarticular juvenile idiopathic arthritis. The study, which was led by Maura Rossetti of the University of California Los Angeles and the SingHealth and Duke-NUS Graduate Medical School in Singapore, appears in the June 16 issue of the 

“Our work uncovers an easily accessible pool of synovial Treg cells in circulation that might be used as a novel non-invasive diagnostic tool, and proposes an innovative antigen-agnostic approach to shed light on pathogenic mechanisms of autoimmune disease and unresponsiveness to therapy,” researchers wrote.

The imbalance between regulatory T cells and effector cells is linked to the pathogenesis of autoimmune arthritis.

“Immune responses are often investigated in the blood because of its accessibility, but circulating lymphocytes are not representative of those found in inflamed tissues. This disconnect hinders our understanding of the mechanisms underlying disease. Our goal was to identify Treg cells implicated in autoimmunity at the inflamed joints, and also readily detectable in the blood upon recirculation,” the authors wrote.

In rheumatoid arthritis, regulatory T cells are believed to be lower in number and dysfunctional. Some therapies, such as anti-tumor necrosis factor, can help to reestablish normal regulatory T cell counts and function, the authors reported. Most studies agree that in juvenile idiopathic arthritis, regulatory T cells accumulate in the synovial fluid.  [[{"type":"media","view_mode":"media_crop","fid":"49680","attributes":{"alt":"Â©PuwadolJaturawutthichai/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_6009444552164","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6022","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©PuwadolJaturawutthichai/Shutterstock.com","typeof":"foaf:Image"}}]]

The authors compared regulatory T cells from patients with juvenile idiopathic arthritis who were or were not responding to therapy by using T cell receptor sequencing, FOXP3 regulatory T cell-specific demethylated region methylation assays, flow cytometry and suppression assays.

They found a subset of synovial regulatory T cells that recirculated into the bloodstream. “These inflammation-associated Treg cells, but not other blood Treg cells, expanded during active disease and proliferated in respond to their cognate antigens,” the authors wrote. The idiopathic arthritis regulatory cells were stably committed to their regulatory lineage, and they were fully suppressive.

“The consistency of our findings in two distinct autoimmune diseases highlights the clinical relevance of iaTreg cells in conditions where immune regulation is ineffective,” the authors wrote. “Further investigations of this subset may yield critical insights into the pathological mechanisms at play in human arthritis and, possibly, autoimmunity at large.”

Rossetti M, Spreafico R, Consolaro A, et al. 

“TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis.”

 Ann Rheum Dis. 2016 Jun 16. pii: annrheumdis-2015-208992. doi: 10.1136/annrheumdis-2015-208992. 

Treg cells are more prevalent in patients with juvenile idiopathic arthritis and active inflammation, as compared to patients in remission.

Author | Vanessa Caceres

Articles

Another Study Shows No Malignancy after Biologics

Tofacitinib Ranks High in Patient-Reported Outcomes

Screening is Lax in Glucocorticoid-Induced Osteoporosis

Treg Cells Implicated in JIA