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HSS Rheumatology Research News

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HSS Authors:Yurii Chinenov, PhDRebecca GupteJana Dobrovolna, PhDJamie R. Flammer, PhDBill LiuFrancesco E. MichelassiInez Rogatsky, PhD

Inez Rogatsky, PhD, and her lab

discovered that without GRIP1,

glucocorticoids (GC) fail

to control inflammation.

The team found that without GRIP1, the GC

receptors on macrophages fail to repress NFkB

activity. Transcription is “on”, pro-inflammatory

cytokines keep being produced. Until now, the

key molecular mechanisms of how GC stop

inflamation had not been known.Inez Rogatsky, PhD, HSS Associate Scientist

Revealing How Steroids Work

GRIP1 Required

The Role of Transcriptional Coregulator

Glucocorticoid hormone Receptor Interacting Protein-1 (GRIP1)

in the Anti-inflammatory Actions of Glucocorticoids (GC)

Published in PNAS, July, 2012Full Details now on HSS.edu

previous next study

Full details on HSS.edu

AuthorsHSS:Anna Yarilina MD, PhDKai XuChunhin ChanLionel B. Ivashkiv MD

Rheumatoid arthritis prevents the immune system from

effectively using its “off switch” in the inflammatory

process. Cytokines – the messenger proteins that carry

action signals to cells – just can’t seem to communicate

“no”. The cells that are supposed to halt inflammation

don’t. The cells promoting inflammation continue

unstopped. Joints deteriorate, pain increases.

But now, for the first time, HSS scientists and rheuma-

tologists have pinpointed what seems to be a key

component of that crucial “no”: the immunoreceptor

tyrosine-based activation motif coupled receptors - the

ITAM pathway. The researchers observed the ITAM

pathway fully stopping the inflammatory process.

“It completely turns things off,” reports HSS Associate

Chief Scientific Officer Lionel Ivashkiv, MD, who led the

multi-center study. “What we saw was the ITAM pathway

triggering a complete inhibition of the inflammatory response.”

At the outset, the team knew the ITAM pathway was involved

in regulating inflammation. It had been shown to suppress

so-called Toll-like receptors on pathways that promote

inflammation. But no one knew exactly how. What’s more,

the ITAM pathway had never been established - or even

studied - as specifically involved in rheumatoid arthritis.

“

– Lionel Ivashkiv, MD,Associate Chief Scientific Officer,

David H. Koch Chair in Arthritis and Tissue Degeneration

New Discovery: A Pathway That Can Completely Stop Inflammation in Rheumatoid Arthritis

In the 20 years or so I have been studying regulation of inflammation, this seems to be

the most potent inhibitory mechanism we have ever seen.”

“

HSS RheumatologyClick here for more on HSS.edu

Next

How JAK InhibitorsStop Inflammation

in Rheumatoid Arthritis

Published in Arthritis & Rheumatism, (epub in advance of print)August, 2012.

Lionel B. Ivashkiv MDAssociate Chief Scientific Officer

It has not been completely understood exactly how JAK inhibitors

suppress inflammation in RA. Now, an HSS study of two JAK inhibitors (tofacitinib

and ruxolitinib) has revealed key mocleular mechanisms.

The drugs are able to suppress macrophage activation and attenuate tumor necrosis factor (TNF) responses.

Cytokine/chemokine production is diminished.

The research team also found thatJAK inhibitors partially interfered with

transcription factor NF-KB, blocking the expression of genes that encode pro-

inflammatory cytokines.

Regulation of

Inflammatory Responses in

Tumor Necrosis Factor-activated

and RA Synovial Macrophages by

Janus Kinase Inhibitors

HSS and Seoul National University College of Medicine:Kyung-Hyun Park-Min, MDEun Young Lee

Authors

Weill CornellMedical College:Chuanxin Huang, PhDAri M Melnick, MD

HSS:Neal K Moskowitz, MD, PhDElisha LimEdward Purdue, PhDSteven R Goldring, MDLionel B Ivashkiv, MD

University of Connecticut Health Center:Sun-Kyeong Lee, PhDJoseph A Lorenzo, MD

Negative Regulation of

Osteoclast Precursor Differentiation by CD11band

β2 integrin-BCL6 Signaling.

The molecular mechanisms that directly suppress osteoclastogenesis have not been well understood.

Now, a recent collaboration has uncovered a key finding

In the study, CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation

of RANK expression and induction of recruitment of the transcriptional repressor BCL6 to the NFATC1 gene.

CD11b was identified as a negative regulator of the earliest stages of osteoclast differentiation.

New Discovery: Key Mechanism of Negative Regulation

of Osteoclastgenesis

Steven A. Goldring, MDChief Scientific Officer

Richard L. Menschel Research Chair

Lionel B. Ivashkiv, MDAssociate Chief Scientific Officer

David M. Koch Chair

Edward Purdue, PhDHSS Associate Scientist

Director, HSS Osteolysis Lab

Published in Journal of Bone Mineral Research,

(Epub ahead of print) August, 2012

Coming Soon: Full details on

HSS.edu

Authors from HSS:Elana J. Bernstein, MDJessica K. Gordon, MD, MScRobert F. Spiera, MDLisa A. Mandl, MD, MPHEvelyn M. Horn, MD

Presented at the2012 ACR Annual Meeting

Full details on HSS.edu

New, Non-invasive Test May Help Diagnose

Pulmonary Hypertension in Scleroderma

A new, noninvasive stress test called SHAPE™ that uses a 5.5 inch high step on which patients step up and down

for 3 minutes has showed promising results for use in diagnosing pulmonary hypertension (PH) in scleroderma.

End tidal carbon dioxide monitored during SHAPE™ had significant negative correlation to the mPAP of right heart catherization (RHC), the current gold standard diagnostic

test. RHC is both expensive and invasive.

SHAPE™ stands for Submaximal Heart And Pulmonary Evaluation. Further, wider studies will help determine how SHAPE™ can help non-invasively diagnose PH,

a leading cause of death in SSc.

(left to right) Robert F. Spiera, MD Jessica K. Gordon, MD, MScLisa A. Mandl, MD, MPH

The presence of lupus anticoagulant (LAC) is the primary predictor of adverse pregnancy outcome after 12

weeks’ gestation in aPL-associated pregnancies. Other antibodies in the same family, thought to cause pregnancy

complications, do not put women at increased risk.

Anticardiolipin antibody and anti-β2 GPI – if LAC is not also present – do not predict adverse pregnancy

outcome. These findings are from the first clinical research publication of PROMISSE – the largest ever study of

pregnancy outcomes in women with lupus and/or aPL.

Published in Arthritis & Rheumatism, July 2012.

Full Details on study and PROMISSE on HSS.edu

Jane E. Salmon, MD

Collette Kean Research Chair;

Co-director, Mary Kirkland

Center for Lupus Research at HSS

Michael A.Lockshin, MDDirector, Barbara Volcker Center for Women and Rheumatic Disease; Co-director, Mary Kirkland Center for Lupus Research at HSS

PROMISSE Study OvERtuRnS COMMOn BElIEf

LAC Strongest Indicator of Advese Outcome in aPL-Associated Pregnancies

Full Details now on HSS.edu

Testing New Drugs to Treat SSc: Results of Open Label Trials of Imatinib Mesylate (Gleevec™)

Systemic sclerosis (SSc) – or scleroderma – has many debilitating manifestations and few reliably effective treatments. Research at HSS is hoping to help change that. Clinical trials at HSS have been testing the tyrosine kinase inhibitor (TKI) Imatinib Mesylate (Gleevec™) to treat SSc.

At the 2012 ACR Annual Meeting, HSS doctors are reporting on a 24-month trial extension involving 17 patients with early diffuse SSc. The patients had already completed an initial 12-month trial. The target daily dose of 400mg of Gleevec™ was the same in both trials.

The group started the extension with a median Modified Rodnan Skin Score (MRSS) score of 24, which reflected a 22% average improvement from the first 12 month trial.

At the end of the 24-month extension, the median group MRSS had improved to 18. Results must be interpreted cautiously, as patients with SSc can have spontaneous improvements in their skin scores, especially with longer duration of disease.

While both trials showed acceptable safety and tolerability, adverse events did occur. Imantinib is a powerful drug and is not for everyone. Testing at HSS has been a long, careful process. Further, wider testing is warranted on a drug that can provide some benefit for some people, especially when so few alternatives exist.

Robert F. Spiera, MD HSS Attending Rheumatologist Director, HSS Vasculitis and Scleroderma Program

HSS Authors:Jessica K. Gordon, MD

Morgana L. DavidsKamini Doobay

Jamie N. MerstenStephen L. Lyman, PhDMary K. Crow, MDRobert F. Spiera, MD

Recent collaborations of HSS physicians and surgeons using the extensive HSS Total Joint Replacement Registries have

revealed that patients with lupus and RA can experience pain relief and beneficial results from total joint arthroplasty (TJA).

Drug treatments for RA have changed dramatically in recent years, and the investigators wanted to see if that change affected

patient outcomes in joint replacement. Matching each of 159 contemporary patients with RA having total knee replacement

(TKR) to two patients undergoing TKR for osteoarthritis (OA), the collaboration demonstrated that patients with RA can expect

TKR benefits and outcomes similar to patients with OA.

HSS Rheumatologists & Orthopedic Surgeons Overturn Common Beliefs

New Findings on Joint Replacement for Patients with SLE or RA

Additonal Authors and Full Details on HSS.edu

Studies presented at the 2012 ACR Annual Meeting

Another investigation matched each of 101 patients with lupus undergoing either TKR or total hip arthroplasty (THA) to two similar patients having the same surgery for OA.

Patients with lupus experienced far fewer adverse events than previously expected. Two years after surgery, pain and function outcomes were similiar

for patients with and without lupus.

HSS Authors, Both Studies:Lisa A. Mandl MD MPH (right)Assistant Attending Physician

Susan M Goodman, MD (left)Assistant Attending Physician

Mark P. Figgie, MD (pictured on next page)

Chief, Surgical Arthritis Service

Morbid Obesity is Not a Risk Factor for Poor Pain and Function Two

Years After Total Knee Replacement

Almost 90% of referring physicians think obesity increases the likelihood of poor outcomes after total knee replacement (TKR).

However, current data are conflicting.

A recent collaboration of HSS rheumatologists and orthopedic surgeons found that although obese patients have worse pain and function at the time they elect TKR, their outcomes at 2 years are not clinically

significantly different than other patients. However, race and educational attainment were significantly associated with poor outcomes.

The study anaylzed data from 2524 patients in the HSS Total Joint Replacement Registry who underwent TKR between 2007 and 2009.

Findings showed that obese patients have similar expectations and are as satisfied as patients with lower BMI. While more research is needed on the effect of race and education on TKR outcomes, morbid obesity should not

be regarded as a risk factor for poor outcomes after primary TKR.

Authors HSS:Susan M. Goodman, MDMark P. Figgie, MD,Alejandro Gonzalez Della Valle, MDMichael M. Alexiades, MDLisa A. Mandl MD, MPH

Presented at 2012 ACR Annual Meeting

Full details on HSS.eduMark P. Figgie, MD

Chief, Surgical Arthritis ServiceAlejandro Gonzalez Della Valle, MD

Associate Attending Orthopaedic Surgeon

Pilot Nutrition Education Program

Receives High Marks from

Culturally Diverse Teens with Lupus and their Families

A recent HSS study shows promising results for a hospital-based education program specially designed for a culturally diverse group of teens with lupus and

their families to learn about healthy nutrition together.

The curriculum focused on learning about the nutritional benefits of whole grains/fiber, calcium/

vitamin D, fruits/vegetables, protein foods, and snacks/fast foods. Several key topics were included throughout

all 5 sessions, including portion control, food labels, sodium and culturally appropriate recipe examples.

94% of participants rated overall content as excellent. 94% of the participants reported that the program led

them to include more nutritious foods in their diet.

The benefits of this pilot series will be further expanded in future programs, which will consider

adding more communication tools and social media.

AuthorsHSS:Jillian A. Rose, LMSW (above left)Roberta Horton, LCSW, ACSW(above right)Dariana M. PichardoDana Friedman, MPHRobyn Wiesel, CHESSandra Goldsmith, MA, MS, RDSotiria Everett, MS, RD, CDN, CSSD

Morgan Stanley Children’s Hospital, New York-PresbyterianColumbia University Medical Center:Lisa F. Imundo, MD

Presented by Jillian Rose, LMSW, at 2012 ACR Annual Meeting

Full details on HSS.edu

Test of a Systematic Two Drug Regimen Shows Prolonged Improvement in Lupus

Full Details Coming Soon to HSS.edu

Thomas J.A. Lehman, MDChief, Pediatric Rheumatology

A carefully supervised, systematic regimen of twopowerful drugs was found to significantly reduce steroid dosage while improving a patient’s lupus condition.

15 patients, ranging in age from 10 to 22, with active lupus, who had been dependent on steroids for control of the condition, received a systematic regimen ofrituximab and cyclophosphamide administered at three intervals – at the start of the trial, then again at 6 months, and a third time at 18 months.

All 15 patients experienced improvements in 6 standard indicators of lupus disease level in their blood tests. Note these powerful drugs, used in chemotherapy, must not be administered without careful supervision from doctors familiar with the medications.

Study presented by Dr. Lehman at 2012 ACR Annual Meeting

Authors:HSS:Thomas J. A. Lehman, MDEmily BairdAnusha Ramanathan, MDRisa Alperin, MDEmma J. MacDermott, MDAlexa B. Adams, MD

Maimonides Medical Center:Laura V. Barinstein, MD

Robert Wood Johnson-UMDNJ:Lakshmi N. Moorthy, MD

Patient Self-Assessments and Patient Reported Outcomes May Reliably Identify Disease Flare in Early RA

AuthorsHSS:Vivian P. Bykerk, BSc, MD, FRCPC

Johns Hopkins University:Clifton O. Bingham III, MD

Cardiff University School of Medicine, UK:Ernest Choy, MD, FRCP

Mount Sinai Hospital, Toronto:Juan Xiong, PhD

CHUS - Sherbrooke University, Quebec:Gilles Boire, MD, MSc

University of Manitoba, Winnipeg:Carol A. Hitchon, MD, FRCPC, MSc

University of Western Ontario:Janet E. Pope, MD, MPH, FRCPC

Southlake Regional Health Centre, Ontario:J. Carter Thorne, MD, FRCPC

University of Montreal Hospital Research Centre: Boulos Haraoui, MD, FRCPC

University of Toronto: Edward Keystone, MD, FRCPC

McGill University, Montreal: Susan J. Bartlett, PhD

Patients reporting a rheumatoid arthritis (RA) flare have clinical indices reflecting worsening

disease activity. Using criteria of pain, function, stiffness, coping, participation, and fatigue, patient

reported outcomes (PROs) significantly discriminated between patients reporting flare vs. no flare.

These findings were uncovered in a recent investigation involving data from 512 patients in

the CATCH (Canadian early ArThritis CoHort) study, comparing patient and doctor assessment of

symptoms and clinical status in a flare.

There is modest agreement between patients and MDs regarding flare status. Flare patients

identify more swollen and tender joints than MDs.

PROs and patient joint counts may reliably identify

Study presented by Dr. Bykerk at the 2012 ACR Annual Meeting

Full Details With Chart of Patient/MD ConcordancesComing soon to HSS.edu

disease flare, but some ratings are higher inpatients than MDs. More research is

needed to identify predictors of concordance and discrepancy

between patients and providers in flare assessment.

Vivian P. Bykerk, BSc, MD, FRCPC

Hospital-Based Exercise Program

Shown to Decrease Pain

and Improve Life for Patients

with Arthritis

A recent HSS study has shown that a low-cost, hospital-based, exercise program of weekly classes significantly decreased pain and the severity and frequency of falls, as well as improved enjoyment of life and balance among the participants.

Of the 200 study participants, 53% indicated pain relief. Further analysis showed that in a subet of 66 participants who complete both pre and post program surveys, 62% experienced pain relief. Pain intensity dropped from 4.5 to 2.7 with 0 being “no pain” and 10 “worst pain imaginable.

Weekly classes, part of the HSS Osteoarthritis Wellness Initiative, included Tai Chi, yoga, mat and chair pilates, yoga-lates and dance fitness. Instructors tailored programs where necessary for patients with osteoarthritis.

AuthorsHSS:

Sandra Goldsmith, MA MS RDDana Friedman, MPHLinda Roberts, LCSW

Dana Sperber Laura Robbins, DSW, CSW, MSW

Linda Russell, MD

Low cost, community exercise programs can play an important role

in fighting OA with minimal resources.

Full details on HSS.edu

Presented at the 2012 ACR Annual Meeting

Testing New Drugs for SSc: A Single Group, Open Label,

Pilot Clinical Trial of Nilotinib (Tasigna™)

AuthorsHSS:Jessica K. Gordon, MDMorgana L. DavidsKamini DoobayStephen L. Lyman, PhDMary K. Crow, MDRobert F. Spiera, MD

Weill-Cornell Medical Center:Cynthia Magro, MDHoratio F. Wildman, MD

Presented by Dr. Gordon (pictured) at the 2012 ACR Annual Meeting

Second generation tyrosine kinase inhibitor (TKI) drugs aim to be more

efficacious with less side effects. A recent pilot study of one such TKI called nilotinib

(Tasigna™) was completed by 7 patients with diffuse cutaneous (dc) systemic sclerosis (SSc) for less than 3 years.

The twice daily 400 mg oral dose of nilotinib was tolerated by the majority

of patients in the study. Tolerability was limited primarily by mildly prolonged

QTc, which is a known side effect of nilotinib and an exclusion criterion for

continuation in this study.

Modified Rodnan Skin Score (MRSS) improved significantly with 6 months of

treatment in this very early and active group of patients.

Further testing in randomized placebo controlled trials will ultimately be necessary to determine whether the benefits seen were truly related to the

medication tested.

Full Details on HSS.edu

Stories of Health & Humanity

to HealRheum

Full Detailson HSS.edu

back to page 1

A New, Online, Narrative Journal By and For People Living with Rheumatic Conditions and their Physicians

and Caregivers

Rheum to Heal will use the power of words and images,

combined with the nurturing balm of community, to transform

all who share them. The frequently common emotional impact

of chronic rheumatic disease, once creatively expressed,

has the ability to unite and heal.

Stories, Poems, Artwork, Healingfrom patients, doctors & caregivers

Coming Soon from HSS