Rheumatology Connections - Cleveland Clinic

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Rheumatology
Connections
An Update for Physicians | Spring 2013
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12-RHE-1291

Rheumatology
Connections
An Update for Physicians | Spring 2013
Rituximab for GPA/MPA: Knowns and Unknowns 3 | A Link Among Aortitis Subclasses 4
Osteoarthritis and Obesity: Teachable Moments 6 | Multifront Scleroderma Research 8
RCVS: Profiling a Vasculitis Mimic 10 | Strengths and Limits of FRAX 12
CVID: A Case Study in Complexity 14 | New Adult Immunodeficiency Clinic 16
Defining a Novel Autoinflammatory Disease 18

From the Chair of Rheumatic
and Immunologic Diseases
Dear Colleague,
It is my pleasure to share the Spring 2013 issue of Rheumatology Connections
from Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases.
The breadth of clinical and research expertise of the physicians here is evident
in the diverse topics addressed in this issue.
Dr. Carol Langford’s review of rituximab for treating patients with granulomatosis
with polyangiitis or microscopic polyangiitis reflects the perspective that the
experienced staff in our Center for Vasculitis Care and Research bring to the complex
care of these patients. In Dr. Gary Hoffman’s discussion of the links between
isolated “idiopathic” aortitis and aortitis secondary to giant cell and Takayasu’s
arteritis, he and his co-authors share intriguing insights into the pathogenesis of
aortitis — and hope for an eventual noninvasive biomarker.
Dr. Elaine Husni’s article on outcomes research and interventions in patients with
obesity and osteoarthritis demonstrates the opportunities that result from the
collaboration across Cleveland Clinic’s Orthopaedic & Rheumatologic Institute. Dr.
Soumya Chatterjee shares exciting data on his wide-ranging scleroderma research,
much of which has stemmed from our interdisciplinary clinic for the evaluation and
treatment of patients who have lung disease associated with rheumatologic disease.
Dr. Qingping Yao’s description of NAID — NOD2-associated autoinflammatory
disease — represents exciting opportunities to utilize genomics in rheumatic
disease. Additionally, the case discussions on osteoporosis and common variable
immunodeficiency (CVID) and the profile of reversible cerebral vasoconstriction
syndrome as a mimic of CNS vasculitis further illustrate the diverse expertise
of our staff.
I am honored to work with the talented rheumatologists of Cleveland Clinic
whose broad expertise in patient care and research is represented in this issue
of Connections. I invite you to contact me with any questions or comments.
Rheumatology Connections, published by Cleveland
Clinic’s Department of Rheumatic and Immunologic
Diseases, provides information about state-of-the-art
diagnostic and management techniques as well as
current research for physicians.
Please direct any correspondence to:
Abby Abelson, MD
Chair, Rheumatic and Immunologic Diseases
Cleveland Clinic/A50
9500 Euclid Avenue
Cleveland, OH 44195
Phone: 216.444.3876
Email: abelsoa@ccf.org
Managing Editor: Glenn Campbell
Respectfully,
Abby Abelson, MD
Chair, Rheumatic and Immunologic Diseases
216.444.3876 | abelsoa@ccf.org
Graphic Designer: Irwin Krieger
Photography: Willie McAllister, Steve Travarca
To view the staff directory for the Department of Rheumatic
and Immunologic Diseases, visit clevelandclinic.org/rheum.
For a hard copy, contact Marketing Manager Beth Lukco at
216.448.1036 or lukcob@ccf.org.
Rheumatology Connections is written for physicians and
should be relied on for medical education purposes
only. It does not provide a complete overview of the topics
covered and should not replace the independent judgment
of a physician about the appropriateness or risks of a
procedure for a given patient.
© The Cleveland Clinic Foundation 2013
Cleveland Clinic’s Rheumatology
Program is ranked among the top 2
in the nation in U.S. News &
World Report’s “America’s Best
Hospitals” survey.
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Page 2 | Rheumatology Connections | Spring 2013
For referrals, call 800.223.2273, ext. 50096

Rituximab in Granulomatosis with Polyangiitis (Wegener’s)
and Microscopic Polyangiitis: Great Advance, Ongoing Questions
By Carol A. Langford, MD, MHS
The approval of rituximab by the Food
and Drug Administration for treatment of
granulomatosis with polyangiitis (Wegener’s)
(GPA) and microscopic polyangiitis (MPA)
represented a major therapeutic advance
for these diseases. As with all treatments,
though, the decision about whether to use
rituximab in GPA and MPA relies on both
physician and patient weighing the risks and
benefits. One of the most important lessons from the experience
with cyclophosphamide (CYC) is that fully understanding the safety,
efficacy and optimal use of a therapy in GPA/MPA takes time.
We know that rituximab is an effective treatment option for
severe active GPA/MPA, but many questions remain under active
investigation. This is therefore an appropriate time to review what
is currently known and unknown about the use of rituximab in
GPA/MPA and how to apply this to clinical practice in 2013.
Known: Rituximab is as effective as CYC for
inducing remission of severe active GPA/MPA.
In the randomized RAVE trial, 1 rituximab was compared with CYC
for remission induction in 197 patients who had severe active GPA
or MPA. Rituximab was found to be as effective as CYC in enabling
patients to reach the primary study endpoint of being in remission
and off prednisone at six months. In the randomized RITUXVAS
trial, 2 rituximab was not superior to CYC for remission induction,
but the two agents had comparable rates of remission induction,
providing further compelling evidence of the efficacy of rituximab.
Known: In relapsing patients, rituximab was
statistically superior to CYC for remission induction.
In a subgroup analysis of patients who were enrolled in the RAVE
trial at the time of relapse, rituximab appeared to be more effective
than CYC. Because the toxicities of CYC are known to rise as the
duration of exposure to the drug increases, this further favors
rituximab for patients relapsing with severe disease who have
previously received CYC.
Known: Disease relapse still happens after rituximab.
In the primary outcome analysis for the RAVE trial, 6 percent of
patients had already experienced disease relapse, and a relapse
rate of 15 percent was seen in the RITUXVAS trial. Longerterm
data from the RAVE trial presented at a recent American
College of Rheumatology annual meeting showed that further
disease relapses occur over time, although the flare rate was not
statistically different between rituximab and CYC.
The experience with cyclophosphamide
shows that fully understanding the safety,
efficacy and optimal use of a therapy in
GPA/MPA takes time.
Known: Adverse events still occur with
rituximab-based induction regimens in GPA/MPA.
While rituximab has a different side-effect profile than CYC,
the potential for toxicity of the overall induction regimen must
continue to be recognized. In both the RAVE and RITUXVAS trials,
the adverse event rate was comparable between the CYC and
rituximab arms. This is likely due to the role of glucocorticoids and
improved methods of minimizing CYC toxicity through close blood
count monitoring, use of uroprotection strategies and limiting CYC
exposure duration. Infection remains the most significant toxicity
during the induction period. Because Pneumocystis pneumonia has
been observed in rituximab-treated GPA/MPA patients, prophylaxis
remains important with rituximab-based regimens, just as it does
with induction regimens that include CYC or methotrexate.
Unknown: What is the optimal approach
to treatment after rituximab has been given?
Given that relapses still occur, the issue of how best to maintain
remission after treatment with rituximab must be considered in
each patient. For patients who do not have intolerances, some
physicians have used a conventional maintenance agent such
as azathioprine, methotrexate or mycophenolate mofetil after
rituximab, although published experience with this approach
remains limited. The option of continuing rituximab as a
maintenance agent has also been raised, with the challenge then
becoming at what intervals and for how long this should be done.
This issue is complicated by the observation that relapses have
occurred as early as five months following rituximab therapy while
other patients remain in remission for years following their initial
course. Until further data become available, this decision must be
individualized for each patient.
Unknown: Are there long-term toxicity issues
with rituximab in GPA/MPA?
The potential for long-term toxicity must be considered with
all therapies. The extended experience with rituximab in other
diseases has been encouraging, but caution is warranted when
generalizing across settings. While data are steadily being
generated with repeated rituximab infusions in GPA/MPA, more
time will be needed to fully assess long-term safety, particularly
in patients who have previously received immunosuppressive
therapies.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 3

Unknown: What about rituximab use in settings
other than severe GPA/MPA?
In the RAVE trial, patients with a serum creatinine greater than
4.0 mg/dL were excluded, as were those requiring mechanical
ventilation. In these most fulminantly ill patients, the comparative
effectiveness of rituximab vs. CYC has not yet been established.
At the other end of the severity spectrum, data have also been
limited on the use of rituximab in nonsevere disease, such as in
patients with sinonasal, skin, joint or other non-organ-threatening
manifestations.
Refining Rituximab Use: Where Do We Go from Here?
As experience with rituximab continues to accumulate, the optimal
means of using this therapy in GPA/MPA will be refined. New
studies will continue to explore rituximab in GPA/MPA. One such
study is an international randomized controlled trial comparing
rituximab with azathioprine as maintenance therapy in relapsing
ANCA-associated vasculitis (RITAZAREM). Cleveland Clinic will be
one of multiple sites in North America and Europe participating in
this study. More about this trial can be found at clinicaltrials.gov,
and physicians interested in referring patients to Cleveland Clinic for
the trial may contact us at 216.445.6056.
References
1. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus
cyclophosphamide for ANCA-associated vasculitis. N Engl J Med.
2010;363(3):221-232.
2. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus
cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med.
2010;363(3):211-220.
Dr. Langford is Director of the Center for Vasculitis Care and
Research as well as Vice Chair of the Department of Rheumatic
and Immunologic Diseases. She can be reached at 216.445.6056
or langfoc@ccf.org.
In Search of a Link Among Aortitis Subclasses:
Cleveland Clinic Research Points to Anti-14-3-3 Antibodies
By Ritu Chakravarti, PhD; Alison Clifford, MD; and Gary S. Hoffman, MD, MS, MACR
Idiopathic aortitis is an inflammation within the wall of the
aorta for which the cause is unknown. It is speculated to be
an autoimmune process. Aortitis may occur with or without
symptoms, resulting in aneurysm formation or dissection
or rupture of the aortic wall, with potentially devastating
consequences.
Aortitis may occur either as a focal isolated lesion or as part of
a primary systemic large-vessel vasculitis; the most well-known
forms of the latter are giant cell arteritis (GCA) and Takayasu’s
arteritis (TAK).
Three Forms of a Single Disease?
Traditionally, GCA, TAK and isolated aortitis have been
classified as separate diseases that are distinguished from one
another based on age at disease onset (young adulthood in
TAK vs. old age [mean age, 74] in GCA) and pattern of vessel
involvement (focal in isolated aortitis vs. multifocal in TAK
and GCA).
Yet these diseases may be more similar than previously thought.
All three subtypes preferentially affect women and share a
special predilection for the thoracic aorta. Involvement of large
vessels, which is required for diagnosis in TAK, is common
in GCA. In GCA, large-vessel disease is found in up to 83
percent of patients at diagnosis by PET imaging and has been
documented in 100 percent at postmortem examination.
The aortic pathology among subsets is indistinguishable.
Glucocorticoid therapy results in remission in GCA and TAK,
and relapses are frequent with treatment cessation in both
diseases.
The significant overlap observed among focal isolated aortitis,
GCA and TAK has raised a number of questions:
• May these separately defined clinical entities actually
represent a spectrum within the same disease, and might they
share a common etiology?
• If so, could differences be explained by genetic influences
or age-related changes in hormone status, tissue protein
content and functions, immune function or response to
environmental triggers?
Page 4 | Rheumatology Connections | Spring 2013
For referrals, call 800.223.2273, ext. 50096

Our finding of anti-14-3-3 antibodies in
the serum of aortitis patients may lead
to their use as a noninvasive biomarker
for diagnosis and disease activity.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
IgG
Findings Suggest a Role for a 14-3-3 Antigen
Developing an improved understanding of disease
pathogenesis and expression of large-vessel vasculitis may
lead to identification of safer and more effective therapies.
That is the principal goal of our current research.
In collaboration with the Aorta Center in Cleveland Clinic’s
Sydell and Arnold Miller Family Heart & Vascular Institute,
we have collected more than 120 aorta biopsies (as well as
patients’ blood and DNA). So far we have studied 24
digested tissue samples from aortitis patients and controls.
Although the results are preliminary, we have shown
that patients with each of the subclasses of aortitis
make antibodies to a protein from digested aorta tissue.
Using sophisticated protein analysis techniques (mass
spectroscopy), we identified the targeted protein (antigen)
to be a member of the 14-3-3 family that has important
cell signaling functions in health and disease (see figure).
We are hopeful that our novel initial finding of anti-14-3-3
antibodies in the serum of aortitis patients may lead to their
use as a noninvasive biomarker for diagnosis and disease
activity. This finding also adds to a growing body of evidence
that these three forms of vasculitis are likely to be part of
a shared spectrum of disease. We are also studying these
proteins in detail for alterations in composition that may
explain why they elicit a pathologic immune response.
30-kd
protein
Figure. Immunoblots of 15 aorta tissue homogenates: 1 to 9 are controls
(noninflammatory aortic aneurysms), and 10 to 15 are different forms of
aortitis (Takayasu’s arteritis, giant cell arteritis and focal isolated aortitis).
Each Western blot is probed with serum (antibodies) obtained from either
control patients (top) or patients with aortitis (bottom) to study whether an
autoantigen within the aortic tissue lysates is bound by antibody. Aortitis
patient sera react to a 30-kd protein (arrow at bottom) in tissue from both
controls and patients with aortitis. However, control sera do not contain
antibodies to this protein. Mass spectroscopy was used to characterize the
30-kd protein/antigen, which is in the 14-3-3 family.
IgG
Dr. Chakravarti is a project staff member in the Department
of Pathobiology, Lerner Research Institute. She can be
reached at 216.444.9174 or chakrar@ccf.org.
Dr. Clifford is a vasculitis fellow in the Center for Vasculitis
Care and Research, Department of Rheumatic and
Immunologic Diseases. She can be reached at cliffoa@ccf.org.
Dr. Hoffman is a staff member in the Center for Vasculitis
Care and Research as well as Professor of Medicine, Cleveland
Clinic Lerner College of Medicine. He can be reached at
216.445.6996 or hoffmag@ccf.org.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 5

A New Look at Obesity and Osteoarthritis:
Finding Teachable Moments in Healthcare
By M. Elaine Husni, MD, MPH
Percentage (%) with arthritis
The statistic is all
too familiar: More
than two-thirds of
the U.S. population
is overweight or
obese. Despite
the inescapable
evidence that this
is a public health
concern, little progress has been made in
treating obesity successfully.
Reasons for this lack of progress are
many. First, there is no “one size fits all”
approach to obesity. Similarly, there is a
diversity of points of view on the topic,
which makes obesity a highly complex
issue for healthcare providers (HCPs) and
patients alike. Additionally, behavioral
change is tough. How else can we explain
why many obese patients are willing to
undergo total knee replacement surgery
(TKR) for osteoarthritis (OA) rather than
modify lifestyle behaviors?
In response to these issues, Cleveland
Clinic is working to foster a broader
understanding of obesity, particularly as it
relates to knee OA. The author (Dr. Husni)
is leading a research team at Cleveland
Clinic in partnership with the DePuy
Synthes Companies to take a “whole
patient care” approach to evaluation and
treatment of knee OA in obese patients
considering TKR. To better understand
the complex relationships between
HCPs and obese patients with knee OA
seeking treatment for their knee pain, we
conducted extensive interviews with both
patients and HCPs in a first-of-its-kind
ethnographic study.
OA and Obesity:
Connections and Consequences
The multiple comorbidities related to
obesity affect almost every body system.
Our research team’s interest is the huge
impact of obesity on the musculoskeletal
system and associated conditions.
Figure. Prevalence of arthritis by weight in the National Health Interview
Survey of U.S. adults, 2007-2009.
35
30
25
20
15
10
5
0
Arthritis prevalence increases
with body weight
16.9%
Healthy
weight
19.8%
Overweight
29.6%
Obese
OA is one of the most prevalent
comorbidities of obesity, and obesity is
now recognized as an important modifiable
risk factor for OA (figure) — as well as
a factor that can accelerate knee OA.
Weight loss has been associated with real
improvement in pain and function in hip
and knee joints affected by OA.
Obesity increases the risk of knee OA by
a variety of mechanisms. These include
increased joint loading and changes
in body composition, with detrimental
effects stemming from adipose-related
inflammation and behavioral factors,
including diminished physical activity
and subsequent loss of protective muscle
strength. Interactions among these various
mechanisms can present a challenge to the
managing physician.
Beyond its associations with OA,
obesity has been linked with higher
rates of surgical complications and
early postoperative complications in
patients undergoing TKR, as well as
with longer hospital stays for these
patients. 1,2 Moreover, there is a direct
linear relationship between body mass
index (BMI) and operative time in TKR. 3
The implications of these findings will only
increase as the annual number of TKRs
performed in the United States rises from
already high levels (> 600,000 in 2008 4 )
to a projected 3.5 million by 2030. 5 TKR
revisions now account for 8.2 percent of all
Medicare dollars spent, and annual hospital
charges for TKR will approach $40.8
billion in 2015. 6
‘Whole Patient Care’ Program:
Objective and Methods
Our research team’s objective is to develop
qualitative insights, uncover new findings
and make patient-centric recommendations
to Cleveland Clinic’s Whole Patient Care
pilot program to improve outcomes for
obese patients with OA who undergo joint
replacement.
Source: Morbidity and Mortality Weekly Report. 2010;59(39):1261-1265.
Page 6 | Rheumatology Connections | Spring 2013
For referrals, call 800.223.2273, ext. 50096

Patients acknowledge that their weight is “unhelpful”
to their joints, but they generally believe their OA is
caused by heredity or injury.
Ours is a qualitative study using concepts
of ethnography, the branch of anthropology
that involves trying to understand how
people actually live their lives. Unlike
traditional researchers who ask specific,
highly practical questions regarding
patient care, anthropological researchers
visit patients in their homes or offices to
observe and listen in a nondirected way.
Our goal is to see people’s behavior on
their terms, not ours.
Key themes and concepts were extracted
and synthesized using ethnographic
research methods. A third-party research
company was hired to perform the
ethnographic research. Fieldwork was
conducted from April to October 2012,
and data collection included participant
observation, in-depth interviews and
informal talks with all HCPs who had
contact with these patients, including
rheumatologists, endocrinologists,
internists, psychologists, orthopaedic
surgeons, bariatric surgeons, physical
therapists and physician assistants.
Results: Polarized Perceptions
Data from our study suggest that HCPs
and patients are polarized in their views
of the relationship between obesity and
OA. When it comes to the cause of OA,
HCPs recognize a clear link and causality
between obesity and OA. Patients, on the
other hand, seldom recognize themselves
as morbidly obese and do not connect their
obesity to medical conditions, including
OA. Overcoming these gaps in perception
is a time-intensive and costly challenge for
most HCPs.
Our research showed that some HCPs
believe the cause of obesity is largely
metabolic, while others believe it is
predominantly behavioral/psychological.
Most agree it is a complex combination
of the two that requires a multifaceted,
multidisciplinary treatment approach.
Patients see obesity primarily as a lifestyle
issue and not as an issue that needs
medical treatment. They acknowledge
that their weight is “unhelpful” to their
joints, but they generally believe their OA
is caused by heredity or injury. They view
their OA and comorbidities such as high
blood pressure, heart disease, diabetes
and other ailments as reasons why they
are obese, not the other way around. For
many, comorbidities are also a barrier to
considering bariatric surgery.
Implications and Conclusions
Our findings have led us to identify six
priority actions that are needed to better
address obesity and improve outcomes
for obese patients who undergo TKR at
Cleveland Clinic:
1. Close the educational gap surrounding
the contributions of obesity to OA.
2. Design more individualized approaches
to weight loss.
3. Develop better and earlier interventions
for obesity.
4. Create and implement improved
education and tools for HCPs and patients.
5. Establish a single point of contact to
coordinate care of obese patients with OA
within Cleveland Clinic.
6. Implement protocols for moresystematic
referral to Cleveland Clinic’s
Bariatric & Metabolic Institute.
As we work to make these priorities
a reality, we recognize that because
every patient responds differently, it’s
important to take an individualized
approach to obesity and to view the
condition holistically, to promote treatment
of the whole patient. A holistic patient
assessment could include a medical
profile, a psychological evaluation, and
assessments of bariatric readiness,
dependency/addiction, education level,
support networks (family and friends),
nutrition literacy, attitudes toward diet and
exercise, and past weight-loss efforts.
OA and other comorbidities may represent
opportunities to teach and intervene
for obese patients in new ways. We are
committed to exploring how best to take
advantage of such opportunities and to
sharing our insights as broadly as possible.
References
1. Batsis JA, Naessens JM, Keegan MT,
et al. Body mass index and the impact on
hospital resource use in patients undergoing
total knee arthroplasty. J Arthroplasty.
2010;25(8):1250-1257.
2. Jackson MP, Sexton SA, Walter WL, Walter
WK, Zicat BA. The impact of obesity on
the mid-term outcome of cementless total
knee replacement. J Bone Joint Surg Br.
2009;91(8):1044-1048.
3. Liabaud B, Patrick DA Jr, Geller JA. Higher
body mass index leads to longer operative
time in total knee arthroplasty. J Arthroplasty.
2013;28(4):563-565.
4. Losina E, Thornhill TS, Rome BN, Wright
J, Katz JN. The dramatic increase in total
knee replacement utilization rates in the
United States cannot be fully explained
by growth in population size and the
obesity epidemic. J Bone Joint Surg Am.
2012;94(3):201-207.
5. Kurtz S, Ong K, Lau E, Mowat F, Halpern
M. Projections of primary and revision hip
and knee arthroplasty in the United States
from 2005 to 2030. J Bone Joint Surg Am.
2007;89(4):780-785.
Dr. Husni is Department Vice Chair for
the Arthritis and Musculoskeletal Center
and Director of Clinical Outcomes
Research for the Department of Rheumatic
and Immunologic Diseases. She can
be reached at 216.445.1853 or
husnie@ccf.org.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 7

Scleroderma Research: Taking on
Chronic Management Challenges of a Once-Fatal Disease
By Soumya Chatterjee, MD, MS, FRCP
Cleveland Clinic’s Scleroderma Program
integrates evidence-based care with clinical
and translational research exploring the
complex pathogenesis and management
of scleroderma. The program is currently
participating in several clinical trials
involving diverse aspects of scleroderma
management. This article profiles three of
those trials, focusing on the medical need
and scientific rationale behind each.
Ischemic Digital Ulcers
Medical need. Digital ulcers (Figure 1) are a major complication
of scleroderma, occurring in about 30 percent of patients
annually. They are associated with vasculopathy of the fingers
and toes, in which the intima of vessels is thickened and the
lumen occluded. As digital ulcers cause significant pain and
functional impairment, they have a major impact on quality of
life. They can become infected, resulting in osteomyelitis. Digital
gangrene may require amputation. Management of digital ulcers
in scleroderma involves nonpharmacologic and pharmacologic
interventions for treatment and prevention. The aim is to reduce
ulcer burden and impact on quality of life.
Several medications are available for use in the treatment and
prevention of digital ulcers. However, most regimens are empiric
and not based on randomized controlled trials. To date, no drug
has been approved outside Europe to treat digital ulcers in
scleroderma patients, although one agent — the dual endothelin
receptor antagonist bosentan — has been approved in Europe
for reducing the number of new digital ulcers in scleroderma
patients.
The need is clear for pharmacotherapy that would affect
the natural course of digital ulcers in scleroderma, improve
tissue integrity and viability, and prevent or reduce new ulcer
development. To address this need, our Scleroderma Program is
participating in the DUAL-1 study (Macitentan for the Treatment
of Digital Ulcers in Systemic Sclerosis Patients), as detailed in the
table on page 9.
Scientific rationale. In scleroderma, endothelial injury is thought
to precede loss of normal vasodilator response to nitric oxide and
prostacyclin, leading to abnormal responses to vasoconstrictive
mediators that include endothelin-1 and catecholamines.
Endothelin-1, the most potent naturally occurring vasoconstrictor,
is released as a result of endothelial damage. It also stimulates
fibroblast matrix biosynthesis and fibroblast and smooth
muscle cell proliferation. Because serum endothelin-1 levels are
Figure 1. Ischemic digital ulcer in a patient with scleroderma.
Figure 2. Diffuse swelling and induration of skin in a patient with
early diffuse scleroderma.
Page 8 | Rheumatology Connections | Spring 2013
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Table. The Scleroderma Program’s Active Clinical Trials
Objective Study name/sponsor Design Notes/details
Macitentan for digital ulcers:
Assess efficacy, safety, tolerability
of macitentan in patients with
ischemic digital ulcers associated
with systemic sclerosis
DUAL-1/Actelion
Prospective,
randomized, placebocontrolled,
double-blind,
multicenter, parallelgroup
study
Two-period study: Initial fixed 16-week
period 1 is followed by a period 2 of variable
duration. All patients completing period 1
continue on their original therapy into period
2 until last patient completes period 1.
Tocilizumab for skin tightness:
Assess efficacy and safety of
tocilizumab for improving skin
tightness in patients with systemic
sclerosis
faSScinate/
F. Hoffmann-La Roche
Phase 2/3 multicenter,
randomized, doubleblind,
placebo-controlled
study
Patients randomized to tocilizumab 162 mg/
wk subcutaneously or placebo for 48 weeks.
From week 49 to week 96, all patients
receive open-label tocilizumab. Anticipated
time on study treatment is 96 weeks.
Pomalidomide for ILD:
Assess pomalidomide in patients
with diffuse cutaneous systemic
sclerosis with interstitial lung
disease (ILD)
Not yet named/Celgene
Phase 2 multicenter
proof-of-concept study
with randomized,
double-blind, placebocontrolled
design
Evaluating safety, tolerability,
pharmacokinetics, pharmacodynamics and
efficacy of pomalidomide
increased in scleroderma patients, the use of endothelin receptor
antagonists may be justified in digital ischemia refractory to
conventional vasodilators since these agents also favorably affect
fibroproliferative vascular remodeling.
Macitentan is a novel dual endothelin receptor antagonist
that emerged from a tailored drug discovery process. It has a
number of potentially key beneficial characteristics, including
increased in vivo efficacy compared with existing endothelin
receptor antagonists, due to sustained receptor binding and
tissue penetration properties. In addition, macitentan has a low
propensity for drug-drug interactions.
Skin Tightness
Medical need. Management of skin tightness in scleroderma
(Figure 2) has been disappointing. Various immunomodulatory
agents have been empirically tried, based on anecdotal reports
and small clinical trials. Currently available agents used offlabel
to treat skin tightening include traditional DMARDs
such as hydroxychloroquine, methotrexate, azathioprine,
mycophenolate mofetil, thalidomide, cyclosporine, prednisone
and cyclophosphamide. Yet these agents have marginal effects at
best and often need to be discontinued due to adverse events or
inherent toxicity. No specific agent has been consistently effective
or has been approved by regulatory agencies for ameliorating skin
tightness in scleroderma patients.
To help meet this need for effective disease-modifying therapies
for skin tightness, our Scleroderma Program is enrolling systemic
sclerosis patients in a two-year multicenter study of tocilizumab, a
humanized monoclonal antibody against the interleukin-6 receptor
(IL-6R). Study details are outlined in the table.
Scientific rationale. IL-6 has been postulated to play a potentially
crucial role in the pathogenesis of scleroderma based on murine
models and data from patients with scleroderma. Elevated
levels of circulating IL-6 have been reported in patients with
scleroderma, particularly those with early disease. IL-6 is
overexpressed in endothelial cells and fibroblasts of involved
skin in patients with scleroderma, and elevated IL-6 levels are
detected in the bronchoalveolar lavage fluid. Dermal fibroblasts
from patients with scleroderma constitutively express higher
levels of IL-6 compared with those from healthy controls. In
addition, serum IL-6 levels correlate positively with skin sclerosis
and acute-phase proteins.
The multicenter trial in which we are participating is the first
randomized, controlled assessment of the benefit and safety of
IL-6R inhibition with tocilizumab in patients with scleroderma.
Interstitial Lung Disease
Medical need. Lung disease is the leading cause of death
in patients with systemic sclerosis. Nonspecific interstitial
pneumonitis is the predominant form of interstitial lung disease
(ILD). Cleveland Clinic’s combined Rheumatology/Pulmonary
Clinic evaluates and manages scleroderma patients with ILD
and/or pulmonary hypertension. Patients are evaluated by both
a rheumatologist and one of two pulmonologists with expertise
in scleroderma lung disease. This ensures optimal investigation
of complications and development of the most effective
management plan.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 9

Management of ILD in scleroderma has been a challenge. A
multitude of DMARDs have been tried unsuccessfully. Initial
optimism about cyclophosphamide’s success in stabilizing ILD in
scleroderma met with disappointment. The marginal beneficial
effects on lung function and quality of life in the NIH-sponsored
Scleroderma Lung Study were no longer apparent at the end of
the second year of follow-up after discontinuation of a one-year
trial of daily oral cyclophosphamide.
To help search for newer therapies to tackle this potentially fatal
complication, our Scleroderma Program is participating in a phase
2 proof-of-concept study of pomalidomide in patients with diffuse
scleroderma with ILD (see table).
Scientific rationale. Pomalidomide is a new immunomodulatory
agent and a chemical analog of thalidomide. Experience with
thalidomide has demonstrated beneficial effects in treating
patients with scleroderma. The rationale for using pomalidomide
in scleroderma arises from evidence of its immunomodulatory and
anti-fibrotic effects in both in vitro models and in vivo settings
that share immunopathologic mechanisms with scleroderma.
Prior studies suggest that pomalidomide has the potential to
achieve an anti-fibrotic effect in scleroderma patients through
an immunomodulatory mechanism involving inhibition of Th2
cytokines and enhanced production of anti-fibrotic Th1 cytokines
such as IFN-α, GM-CSF and IL-2. In addition to the Th2-to-Th1
phenotype shift, pomalidomide enhances endothelial progenitor
cell differentiation and has direct effects on the cytoskeletal
structure of fibroblasts.
The Quest Continues
Modern treatments have transformed scleroderma from a oncefatal
condition to a chronic illness. While that is immensely
rewarding, many challenges remain. We must find safer and
more effective therapies for this debilitating disease and its many
complications. This is best accomplished by research efforts to
identify the disease’s precise pathogenetic pathways — efforts
that will maximize our collective chance to manage this illness
more effectively.
Dr. Chatterjee directs the Scleroderma Program in the
Department of Rheumatic and Immunologic Diseases. He
welcomes comments and physician referrals of scleroderma
patients for participation in the ongoing clinical trials. He can be
reached at 216.444.9945 or chattes@ccf.org.
Reversible Cerebral Vasoconstriction Syndrome (RCVS):
Fleshing Out the Profile of a Leading Mimic of CNS Vasculitis
By Rula Hajj-Ali, MD
Reversible cerebral vasoconstriction
syndrome (RCVS) comprises a group
of diverse conditions characterized by
reversible multifocal narrowing of the
cerebral arteries heralded by sudden, severe
(thunderclap) headaches with or without
associated neurologic deficits and — most
important — by reversible angiographic
findings. RCVS predominantly affects
women and individuals in middle age.
Cleveland Clinic’s current work in RCVS, profiled here, extends
and draws on our more than 25 years of experience in caregiving,
research and education in the field of central nervous system
(CNS) vasculitis.
Why RCVS Matters
RCVS is of major importance to rheumatologists because it
is the leading mimic of CNS vasculitis. Early recognition and
diagnosis of RCVS can save patients the risks of unnecessary
immunosuppression. The pathophysiology of RCVS is unclear,
but perturbations in the control of cerebral vascular tone are
critical. The alteration in vascular tone observed in RCVS may
be spontaneous or evoked by various exogenous or endogenous
factors, such as exercise, emotional stress or drugs, among others.
Given the profound and long-term implications of a diagnosis of
CNS vasculitis, early recognition of its major mimic — i.e., RCVS
— is critical, as simple observation and support often may be
adequate.
Exploring RCVS on Multiple Fronts
At Cleveland Clinic’s R.J. Fasenmyer Center for Clinical
Immunology, our focus is to clarify the mechanisms and
pathogenesis of RCVS. We are building a repository of clinical data,
radiologic findings and biological samples from patients with RCVS
and CNS vasculitis. Our goals include the investigation of long-term
outcomes, discovery of biomarkers and exploration of radiologic
studies that may distinguish RCVS from CNS vasculitis and from
other mimics. By investigating biomarkers to aid in the diagnosis
of RCVS and the development of therapeutic targets against it, we
hope to better distinguish RCVS from other cerebral arteriopathies,
both inflammatory and noninflammatory. This, in turn, may lead
to reduced costs and morbidity, more effective diagnosis, and
ultimately identification of appropriate therapies.
Page 10 | Rheumatology Connections | Spring 2013
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Figure. High-resolution 3-tesla MRIs of the brain following gadolinium contrast in a patient with vasculitis (left) and a patient with
RCVS (right). Vessel wall enhancement and thickening (arrow) are present in the vasculitis patient, but minimal enhancement is
present in the RCVS patient.
Early recognition and diagnosis of RCVS can save patients the risks
of unnecessary immunosuppression.
One current project is the assessment of long-term outcomes of
patients with RCVS. We are assessing this cohort of patients with
validated instruments including the Headache Impact Test-6
(HIT-6), the Migraine Disability Assessment Test (MIDAS), the
Barthel Index (BI), the Patient Health Questionnaire (PHQ-9)
and the EQ-5D-5L. Data thus far indicate that the long-term
outcome of patients with RCVS is favorable. Half of the patients
continue to have headache, although it is decreased in severity
and frequency. Despite a large percentage of initial ischemic stroke
or hemorrhage in this surveyed cohort, all patients were living
independently with little disability. However, pain and anxiety
decreased quality of life among RCVS patients.
Pursuing Radiologic and Basic Science Insights
At the same time, we are partnering with our radiology colleagues
to explore the utility of high-resolution 3-tesla MRI (HR-MRI)
in distinguishing RCVS from CNS vasculitis. HR-MRI is a
noninvasive method that has added value to vascular imaging
by defining intracranial vessel wall characteristics (enhancement
and thickening). To date, 26 patients (13 with RCVS and 13 with
CNS vasculitis) have been included in our study. Interestingly, data
have revealed that enhancement of the intracranial vessel wall by
HR-MRI occurred mainly in the CNS vasculitis group as opposed
to the RCVS group, where enhancement was minimal (see figure).
HR-MRI appears to be a promising tool for differentiating RCVS
from CNS vasculitis in the acute setting.
We are also collaborating with scientists in Cleveland Clinic’s
Lerner Research Institute to examine biomarkers in RCVS to better
understand its pathophysiology and differentiate it from other
cerebral arteriopathies.
Dr. Hajj-Ali is a staff physician in the Center for Vasculitis
Care and Research and the R.J. Fasenmyer Center for Clinical
Immunology within the Department of Rheumatic and
Immunologic Diseases. She can be reached at 216.444.9643
or hajjalr@ccf.org.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 11

FRAX: Realizing Its Strengths
Depends on Recognizing Its Limitations
By Chad Deal, MD
Case Presentation
B.S. is a 65-year-old white woman who
presented for osteoporosis evaluation. She
had been treated with a bisphosphonate
for three years immediately following
menopause (ages 52 to 55). She had
a lumbar spine T-score of –2.3 and a
femoral neck T-score of –2.2. Her current
bone density showed a significant decline
of 8.6 percent in the spine and 7.0 percent in the hip when
compared with her bone density three years earlier. Laboratory
tests did not reveal a secondary cause for low bone mass and
bone loss. She was taking adequate calcium and vitamin D and
walked for exercise four times a week.
Her 10-year absolute fracture risk based on the FRAX ®
tool was 1.9 percent for hip fracture and 10.0 percent for
major osteoporotic fractures. Current National Osteoporosis
Foundation guidelines recommend treatment if the 10-year
fracture risk is 3 percent or greater for the hip or 20 percent
or greater for a major osteoporotic fracture (hip, spine, wrist or
humerus). Even though B.S.’s fracture risk was below treatment
thresholds, she was started on a bisphosphonate.
FRAX Caveats: The Devil’s in the Details
The appropriate use of FRAX as a tool for guiding treatment
decisions is important in the clinic. With FRAX, as with all
tools, understanding its strengths as well as its limitations
is essential to making appropriate treatment decisions. The
limitations are often called FRAX caveats. In the case of B.S.,
the most important limitation is that the FRAX model does not
adjust for patients with rapid bone loss. Allowing this patient
to continue losing bone at a rate of 7 to 8 percent every three
years would result in increasing fracture risk over time. This
is a case when treatment for prevention is appropriate in spite
of her FRAX-generated 10-year fracture risk being below the
National Osteoporosis Foundation treatment threshold.
The sidebar (above right) lists clinical risk factors considered in
FRAX. Many of these risk factors are dichotomous, involving
a yes/no response (see screen shot on next page), yet in the real
world these risk factors are more nuanced and complex. As a
result, the dichotomous nature of some variables can result in
either over- or underestimation of fracture risk. The risks for
fracture in the FRAX model are averages in a large population
of patients. Consider the following examples.
Risk Factors Considered in FRAX —
Not Always So Straightforward
History of previous fracture
Hip fracture in a parent
Current smoking
Glucocorticoid use (≥ 5 mg/d of prednisolone
[or equivalent] for ≥ 3 months at any time)
Secondary osteoporosis (used when risk is based on
body mass index, not bone mass)
Alcohol use ≥ 3 units a day
Femoral neck bone mineral density in g/cm 2
Confirmed diagnosis of rheumatoid arthritis
Race/ethnicity (used in U.S.)
Age, height, weight
Fracture history. A patient with one vertebral fracture has
a fivefold increase in fracture risk, while a patient with two
vertebral fractures has a twelvefold increase in risk. Despite this
difference, FRAX allows previous fracture to be reported only
as “yes” or “no” with no adjustment for multiple fractures or for
fracture site.
Smoking and alcohol use. FRAX assigns the same risk to a
patient regardless of whether she smokes one pack a day or two
packs a day or whether her alcohol use is three or six units daily.
Moreover, “no” is the technically accurate entry for “current
smoking” for a patient who quit a 40-year smoking habit six
months ago, yet this leaves the skeletal effects of decades of
smoking totally uncaptured.
Glucocorticoid use. The same increase in fracture risk is
assigned by FRAX for a patient on 60 mg of prednisone
for temporal arteritis as for a patient who was on 5 mg of
prednisone for three months five years ago.
Rheumatoid arthritis. The severity of rheumatoid arthritis
is likely to affect fracture risk (severe disease having a greater
effect than mild disease), yet FRAX does not account for
disease severity.
Page 12 | Rheumatology Connections | Spring 2013
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Family and personal fracture history. Family history of
osteoporosis is represented only by parental hip fracture, not
by spine fracture or other fracture types. Although personal
history is represented by both fracture types, many spine
fractures are asymptomatic and are thus not included in the
FRAX calculation unless X-rays are reviewed or ordered.
Other Limitations
Additionally, the FRAX model does not include some factors
that affect fracture risk, such as bone turnover and falls.
The model is also hip-centric; when lumbar spine density is
lower than hip density, the model will underestimate fracture
risk. “FRAX-hip” might be a more precise name for the tool.
Moreover, the model’s output — 10-year fracture risk — is
absolute, with no confidence intervals. Whereas FRAX may
assign a patient a risk of 19 percent, fracture risk (and life)
is not so exact, and a standard deviation around the estimate
would be welcome.
Still a Valuable Tool — If Used Appropriately
The purpose of reviewing all the limitations of FRAX is to help
the clinician wield this tool in an appropriate manner, not to
negate its importance. The FRAX tool is a significant advance
in global case finding of patients at increased risk for fracture
compared with other methods available for predicting fracture
risk before FRAX was introduced in 2008. FRAX is a great
starting point for assessing fracture risk, but its usefulness in
guiding treatment decisions for individual patients depends,
like the usefulness of all tools, on the knowledge and skill of
the user.
Dr. Deal is Director of the Center for Osteoporosis and Metabolic
Bone Disease as well as Vice Chair for Quality and Outcomes in
the Department of Rheumatic and Immunologic Diseases. He
can be reached at 216.444.6575 or dealc@ccf.org.
A final limitation, and one with relevance to our case
patient B.S., is that FRAX is designed for use in treatmentnaïve
patients, with no guidance for a patient who took a
bisphosphonate five or 10 years ago or who took estrogen but
discontinued two years ago.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 13

Managing Primary Immunodeficiencies:
A Case Study in Complexity
By James Fernandez, MD, PhD, and Leonard Calabrese, DO
Evaluation and Initial Management
Examination revealed an expressive
dysphasia, decreased sensation to pinprick
on the left side and mild splenomegaly.
Case Presentation
A 38-year-old woman presented to
Cleveland Clinic’s Rheumatology Clinic
with new-onset severe headache, left-sided
numbness and weakness, nausea, vomiting
and an expressive dysphasia.
Her long-term history included recurrent
sinopulmonary infections and a
subsequent diagnosis of common variable
immunodeficiency (CVID) based on
hypogammaglobulinemia and a lack of
specific vaccine responses. She was put on
intravenous immunoglobulin replacement
therapy at 400 mg/kg in 2004 and
switched to subcutaneous immunoglobulin
replacement (for greater convenience) in
2008. With regard to her CVID, a chest
CT showed granulomatous disease of the
lungs (Figure 1), but transbronchial biopsy
was nonspecific and there were no signs of
infection or other concerning signs.
One month before presenting at the
Rheumatology Clinic, the patient noted
two episodes of visual loss lasting
approximately 45 minutes each. On both
occasions, neuroimaging studies at a local
hospital were negative.
She described her recent headaches
as sharp, constant, bitemporal and
retro-orbital, eventually developing into
the “worst headache of my life,” with
associated difficulty speaking, left-sided
weakness, nausea and vomiting. Imaging
at this time (Figure 2) revealed a right
frontoparietal lobe hemorrhage. Cerebral
angiography was normal, and laboratory
results — including CBC, ESR, CRP and
BMP — were unremarkable.
The patient was started on 40 mg/day of
prednisone and experienced improvement
in symptoms. She fared well with physical
and speech therapy until two months later,
when she developed right-sided numbness,
hemianopsia and worsening dysphasia.
Repeat imaging of the head showed a large
hemorrhage at the left temporo-occipital
junction (Figure 3). Biopsy of the temporal
lobe showed a perivascular noncaseating
granuloma consistent with granulomatous
angiitis of the central nervous system
(Figure 4).
The patient was started on prednisone
and rituximab, with B-cell depletion
subsequently documented. After two doses
of rituximab, she experienced worsening
dysphasia and right-sided weakness, and
brain MRI showed progression of her
vasculitis. The rituximab was stopped and
infliximab was added to her regimen.
Follow-Up
The patient responded well to prednisone
and infliximab, as subsequent neuroimaging
showed no further progression. Her
weakness and dysphasia slowly improved
over months. She is currently receiving
prednisone 5 mg daily, infliximab 5
mg/kg every eight weeks and weekly
subcutaneous liquid immunoglobulin
therapy (Hizentra ® ). She remains free of
severe infections, and her neurological
deficits are slowly improving.
Figure 1. Chest CTs at the
patient’s presentation showing
ground-glass opacification and
interstitial thickening in both
lungs. Atelectasis or scarring is
present in the right middle lobe.
Page 14 | Rheumatology Connections | Spring 2013
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Figure 2. Brain CT at presentation showing
a hyperintensity in the subcortical white
matter underlying the right supramarginal
gyrus with separate patchy hyperintensity
in the overlying right frontoparietal lobe.
Abnormal hyperintensity is present along
the cortex of the right parietal operculum
and supramarginal gyrus. No significant
mass effect is present.
Figure 3. Brain CT two months
after presentation showing a large
hemorrhage at the left temporooccipital
junction with surrounding
edema. There is a moderate mass
effect on the left lateral ventricle.
A small subdural hematoma may
be present along the left lateral
frontotemporal region.
Comment
This case demonstrates the
complexity characteristic of primary
immunodeficiencies. Patients with CVID
are at risk for multiple complications,
including autoimmune disease, which
develops in 20 to 25 percent of cases. 1
These patients require continued
monitoring for not only infections but
also granulomatous disease of the lungs,
autoimmune disorders, lymphoma,
malabsorption and other complications.
For these reasons, a team approach is
vital to the overall care of our primary
immunodeficiency patients.
The Adult Immunodeficiency Clinic
within Cleveland Clinic’s R.J. Fasenmyer
Center for Clinical Immunology (see
following article, page 16) works closely
with pulmonologists, hematologists,
oncologists and gastroenterologists to
provide the best care for patients with
primary immunodeficiencies. We and
our colleagues frequently make decisions
about care as a team, and constant
communication among physicians and
with the patient is a necessity. In the end,
patients are better served and appreciate
a collaborative effort by multiple providers
with specific expertise in managing
their primary immunodeficiency and the
complications related to it. With a growing
number of adult immunodeficiencies being
identified, 2 our Adult Immunodeficiency
Clinic is fully committed to advancing the
care of patients and initiating new research
projects in this growing and exciting field.
References
1. Cunningham-Rundles C. Autoimmune
manifestations in common variable
immunodeficiency. J Clin Immunol.
2008;28(suppl 1):S42-S45.
2. Notararangelo LD, Fischer A, Geha
RS, et al, for International Union of
Immunological Societies Expert Committee
on Primary Immunodeficiencies. Primary
immunodeficiencies: 2009 update. J Allergy
Clin Immunol. 2009;124:1161-1178.
Dr. Fernandez is an associate staff
physician in the Department of Pulmonary,
Allergy and Critical Care Medicine in
Cleveland Clinic’s Respiratory Institute.
He can be reached at 216.444.6933
or fernanj2@ccf.org.
Dr. Calabrese is Director of the R.J.
Fasenmyer Center for Clinical Immunology
in the Department of Rheumatic and
Immunologic Diseases. He can be reached
at 216.444.5258 or calabrl@ccf.org.
Figure 4. Temporal lobe biopsy findings
two months after presentation showing
a noncaseating granuloma characterized
by lymphocytes, epithelioid histiocytes
and a multinucleated giant cell in the
leptomeninges adjacent to a small
artery. Multiple veins in the meninges
show perivascular and intramural
lymphocytes. These histologic findings
are compatible with a primary vasculitis
of the central nervous system.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 15

New Clinic Brings Unsurpassed Collaborative Care
to Adults with Primary Immunodeficiency
“Without a clinic of this type, these complex
patients usually lack a point person to
understand the big picture and coordinate
all their care.” — James Fernandez, MD, PhD
Advancing the Field
with USIDNET
Cleveland Clinic is proud to be one of 36 enrolling sites in
the United States Immunodeficiency Network (USIDNET),
a research consortium founded a few years ago to advance
scientific research in primary immunodeficiency diseases.
Drs. Calabrese (left) and Fernandez
Over his three decades of treating adults with immunodeficiency,
Leonard Calabrese, DO, has seen the clinical importance of
primary immunodeficiency diseases grow substantially.
“These diseases are being recognized with increasing frequency,
and many of them are treatable with intravenous immunoglobulin,
yet there are relatively few practitioners specializing in this,” says
Dr. Calabrese, Director of the R.J. Fasenmyer Center for Clinical
Immunology in Cleveland Clinic’s Department of Rheumatic and
Immunologic Diseases.
To help meet this expanding need, last year Cleveland Clinic
recruited James Fernandez, MD, PhD, an immunology specialist
fresh from a fellowship in allergy and immunology at Brigham
and Women’s Hospital, to assist Dr. Calabrese in establishing the
Adult Immunodeficiency Clinic within the R.J. Fasenmyer Center.
Since last summer, this rheumatologist and allergist/immunologist
team has worked together closely to manage patients with the full
spectrum of primary immunodeficiencies (excluding HIV) who are
referred to the clinic.
A Singular Level of Specialized Care
“Rheumatologists often encounter patients who have features of
allergic diseases — such as chronic urticaria, allergic reactions
to drugs or infusion reactions to biologics — that are challenging
to manage,” says Dr. Calabrese. “To have dedicated expertise in
allergy within a rheumatology clinic provides an extra level of care
and attention to these problems — a level that is offered by very
few other medical centers.”
“We are actively enrolling patients in the USIDNET registry,”
says Dr. Fernandez, who serves as a member of the
USIDNET working group on CVID. “One of the main goals of
USIDNET was to assemble a registry of patients with primary
immunodeficiencies to try to advance the understanding of
these rare diseases.”
One of the consortium’s other goals is to start a mentoring
program to stimulate interest in research in primary
immunodeficiency. To that end, USIDNET runs a visiting
scholar program where fellows can apply to do rotations at
centers highly involved in primary immunodeficiency.
“Working with USIDNET, we plan to involve our Adult
Immunodeficiency Clinic in multicenter clinical trials as well
as scientific research in this field,” Dr. Fernandez says.
Common variable immunodeficiency (CVID) is the condition
most often managed in the Adult Immunodeficiency Clinic,
representing nearly half of all cases (see case study on page 14).
Other diseases frequently managed in the clinic include specific
antibody deficiency, natural killer cell deficiencies, idiopathic CD4
lymphocytopenia and complement deficiencies.
“Patients with these conditions have a diversity of complications,
including pulmonary and gastrointestinal complications and a high
incidence of lymphoma,” says Dr. Fernandez. “Without a clinic of
this type, these complex patients usually lack a point person to
understand the big picture and coordinate all their care. That’s
what we are able to offer through our Adult Immunodeficiency
Clinic.”
Page 16 | Rheumatology Connections | Spring 2013
For referrals, call 800.223.2273, ext. 50096

The clinic is staffed by Drs. Calabrese and Fernandez as well as a
specialized nurse practitioner. They typically see three or four new
patients a week for evaluation of primary immunodeficiency, and
they are closely following about 150 patients a year.
An important part of the clinic’s offerings is its infusion services,
which mostly involve infusion of intravenous immunoglobulin. “The
mainstay of the infusion center is immunoglobulin replacement,”
says Dr. Fernandez, “but we do offer infusions of multiple biologics
for patients who require them.”
Research and Education Missions Too
In addition to furthering its clinical mission to see more patients
and manage them in a more multidisciplinary fashion, the Adult
Immunodeficiency Clinic was established to advance research
and education in primary immunodeficiency disease. “Our plan
is to reach out with patient advocacy groups to help educate and
develop research protocols in this field, as well as to train fellows
in rheumatology/immunology and allergy/immunology about these
diseases,” says Dr. Calabrese.
Dr. Fernandez is taking a lead role in those efforts on a
national level through his activities with the United States
Immunodeficiency Network (see sidebar on page 16). “There’s not
much known about the pathogenesis of these diseases, and not
many biomarkers have been identified,” he says. “We are working
to get involved with biobanking of blood and tissue to help identify
some biomarkers that may yield new therapeutic measures and
better prognostic capabilities.”
To refer a patient to the Adult Immunodeficiency Clinic, call
216.445.0096. Drs. Calabrese and Fernandez can be reached
at calabrl@ccf.org and fernanj2@ccf.org.
Give Us 15 Minutes and We’ll Give
You the World of Rheumatology
T Cell Biology in Health and Disease:
From Bench to Bedside
This program’s Bench Series uses a collection of webcasts to
review basic and clinical immunology with an emphasis on T cell
biology. Its companion Bedside Series employs case-based lessons
to challenge providers to apply T cell biology to clinical care.
Rheumatology Highlights Report
Access 15-minute reports by experts on key scientific presentations
and abstracts from the most recent ACR and EULAR meetings.
Having trouble keeping up with recent
advances in rheumatology and immunology?
Cleveland Clinic can help with that.
The R.J. Fasenmyer Center for Clinical Immunology in the
Department of Rheumatic and Immunologic Diseases offers more
than 100 free online CME activities at ccfcme.org/RheumCME.
Our online CME offerings are broad and deep. They span formats
ranging from webcasts to interactive case-based lessons, from
podcasts to online journal articles, and from slide sets to our
RheumBuzz blog with leading content experts. They also span
a wealth of topics (see examples at right) and feature renowned
faculty from Cleveland Clinic and around the world.
Here’s a sampling of some of our most recent CME series, all of
which include multiple short, focused activities that can be fit into
the busiest of schedules. For a full slate of free activities, as well
as upcoming live CME events, visit ccfcme.org/RheumCME.
Shaping the Future of Psoriatic Disease Care
This collection of eight 15- or 30-minute webcasts presents a
thorough guide to managing psoriatic arthritis and curbing its
impact on quality of life.
Advances in B Cell Biology:
RA, SLE, and Vasculitis Online Series
This series of more than a dozen webcasts — mostly 15 or 30
minutes long — addresses a wide range of focused issues in the
use of B cell-targeted therapies.
New Directions in Small Vessel Vasculitis:
ANCA, Target Organs, Treatment, and Beyond
Choose from individual articles in an online journal supplement
and/or installments in a webcast series to get up to speed on the
features, impact and treatment of small vessel vasculitis.
These activities have been approved for AMA PRA Category 1 Credit.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 17

NOD2-Associated Autoinflammatory Disease (NAID):
Progress in Defining a Newly Recognized Disease Entity
By Qingping Yao, MD, PhD
Autoinflammatory diseases were initially
defined as seemingly unprovoked episodes
of inflammation, without high-titer
autoantibodies or antigen-specific T cells. 1
It has been recently proposed that these
diseases are clinical disorders marked
by abnormally increased inflammation,
mediated predominantly by the cells and
molecules of the innate immune system,
with a significant host predisposition. 2 They represent a wide
disease spectrum, ranging from Mendelian disorders to genetically
complex diseases.
I and my Cleveland Clinic colleagues recently reported a new
autoinflammatory disease associated with nucleotide-binding
oligomerization domain 2 (NOD2) gene mutations. 3 This new
entity is designated NOD2-associated autoinflammatory disease
(NAID).
NAID at a Glance
We prospectively studied a cohort of 22 patients seen in our clinic
between January 2009 and February 2012. 4 We have found that
NAID is a systemic disease involving multiple organs. All patients
with NAID to date have been white, and while both sexes are
affected, there is a slight female predominance. The mean age at
diagnosis is 40.1 years (range, 17-72), and mean disease duration
is 4.7 years (range, 1-13). Most patients do not have a family
history of periodic fever syndromes.
Common constitutional manifestations include flu-like symptoms,
weight loss and fatigue. NAID is primarily characterized by
episodic self-limiting fever (observed in 59 percent of cases),
dermatitis (86 percent) and inflammatory polyarthritis/
polyarthralgia (91 percent). Patients with dermatitis usually
present with intermittent erythematous plaques, patches and
macules (see figure), and dermatopathology reveals mostly
spongiotic dermatitis and, occasionally, granulomatous changes.
About one-third of patients with NAID have distal lower extremity
swelling. 5 Patients with NAID also can experience gastrointestinal
symptoms (observed in 59 percent), sicca-like symptoms (41
percent) and recurrent chest pain (22 percent).
NAID may represent a polygenic
autoinflammatory disease, given
the rarity of family history and the
evidence suggesting that NAID
does not appear to be rare.
Forty percent of patients have elevated acute-phase reactants. All
patients test negative for autoantibodies for systemic autoimmune
diseases. All patients carry the NOD2 gene mutations, with
the intervening sequence variant IVS8 +158 in 95 percent, the
R702W variant in 36 percent and R703C in rare cases. 6 These
NOD2 mutations are located in between the leucine-rich repeat
region and the nucleotide binding domain. 7 NAID is distinct from
pediatric Blau syndrome and other periodic fever syndromes.
Ongoing and Future Research: Pathogenesis, Treatment
While there have been extensive studies about the NOD2
mutations and diseases, 7 the pathogenetic role of the NOD2
gene mutations in NAID is unclear. We believe that the NOD2
gene mutations are presently considered to serve as a diagnostic
molecular tool. We assume that gene dosage effects of NOD2
may play a role in the disease; NAID may represent a polygenic
autoinflammatory disease, given the rarity of family history and
the evidence suggesting that NAID does not appear to be rare. A
further study of NAID pathogenesis is underway.
Pharmacologic therapy for patients with NAID remains empiric,
depending on clinical manifestations. Generally, patients with
fever or skin disease respond well to small doses of prednisone
(< 20 mg daily). Some patients with inflammatory arthritis
respond to sulfasalazine treatment. Hydroxychloroquine and
methotrexate have not proven effective for treating this disease.
The therapeutic role of biologics, such as TNF-α inhibitors and
IL-1 antagonists, needs to be determined. Future studies will
also focus on the innate immune response and cytokine profile in
patients with NAID.
Page 18 | Rheumatology Connections | Spring 2013
For referrals, call 800.223.2273, ext. 50096

Figure. Dermatitis in patients with autoinflammatory disease and NOD2 gene mutations.
(A and B) Erythematous plaques on the face and forehead (A) and the lower leg (B). (C) Patchy erythema on
the upper chest. (D) Erythematous macules on the calf. (E) Pink macules on the arm and back.
Reprinted from reference 4 (Yao et al), ©2012, with permission from the American Academy of Dermatology.
A B C
D
E
References
1. Yao Q, Furst DE. Autoinflammatory diseases: an update
of clinical and genetic aspects. Rheumatology (Oxford).
2008;47:946-951.
2. Kastner DL, Aksentijevich I, Goldbach-Mansky R.
Autoinflammatory disease reloaded: a clinical perspective. Cell.
2010;140:784-790.
3. Yao Q, Zhou L, Cusumano P, et al. A new category of
autoinflammatory disease associated with NOD2 gene mutations.
Arthritis Res Ther. 2011;13(5):R148.
4. Yao Q, Su LC, Tomecki KJ, Zhou L, Jayakar B, Shen
B. Dermatitis as a characteristic phenotype of a new
autoinflammatory disease associated with NOD2 mutations. J Am
Acad Dermatol. 2013;68(4):624-631.
5. Yao Q, Schils J. Distal lower extremity swelling as a prominent
phenotype of NOD2-associated autoinflammatory disease [Epub
ahead of print April 12, 2013]. Rheumatology. doi:10.1093/
rheumatology/ket143.
6. Yao Q, Piliang M, Nicolacakis K, Arrossi A. Granulomatous
pneumonitis associated with adult-onset Blau-like syndrome. Am J
Respir Crit Care Med. 2012;186:465-466.
7. Yao Q. Nucleotide-binding oligomerization domain containing
2: structure, function, and diseases [Epub ahead of print
Jan. 24, 2013]. Semin Arthritis Rheum. doi:10.1016/j.
semarthrit.2012.12.005.
Dr. Yao is a staff physician in the Department of Rheumatic
and Immunologic Diseases. He can be reached at
216.444.5625 or yaoq@ccf.org.
Visit clevelandclinic.org/rheum Rheumatology Connections | Spring 2013 | Page 19