LUPUS
Activation of T-Follicular Helper Cells and B Cells in Ultraviolet Light-Induced
Murine Model of Systemic Lupus Erythematosus
Misha Zarbafian1, Mehran Ghoreishi2 and Jan Dutz2, 1Medicine, University of British
Columbia Vancouver Fraser Medical Program, Vancouver, BC, Canada, 2University of
British Columbia Department of Dermatology and Skin Science, Vancouver, BC,
Canada
Background/Purpose: Non-obese diabetic (NOD) mice repeatedly exposed to
ultraviolet (UV) light and Toll-like receptor-7 (TLR7) agonist cream (imiquimod)
develop lupus-like disease, modeling a possible cutaneous trigger for systemic lupus
erythematosus (SLE) in genetically predisposed individuals. Previous research has
supported that T-follicular helper (TFH) cells support B cell maturation in germinal
centers, leading to auto-antibody production in the context of SLE. Increased
frequency of circulating TFH cells in the peripheral blood of human SLE patients has
been associated with more severe disease, characterized by more lupus-associated
auto-antibodies and end-organ manifestations. High-mobility group protein B1
(HMGB1) is a pro-inflammatory cytokine which facilitates auto-antibody production
in SLE, both locally and systemically. HMGB1 release from the cell nucleus in skin
occurs early in sun-induced lesions, and has been found to correlate with the
progression of SLE disease. We sought to characterize TFH cells and B cells in skindraining lymph nodes of NOD mice treated with UV and topical imiquimod cream
(TLR7 agonist).
Methods: NOD and Balb/C mice received weekly UVB radiation (5000 J/m2) and 25
μg of topical imiquimod cream. Skin-draining lymph nodes were analyzed by flow
cytometry after four treatments to determine the activation status and number of
TFH cells and B cells. Serum was collected to measure inflammatory cytokines such
as TNFa, IL-6, and IFNg. Extra-nuclear expression of HMGB1 was evaluated in skin
samples from both strains after four treatments.
Results: There was expansion of both TFH and B cells, as well as increased
expression of the B cell activation marker CD40 in skin-draining lymph nodes of
NOD mice following combined UV and imiquimod therapy, in contrast to Balb/C
mice. Extra-nuclear expression of HMGB1 was greater in NOD mice, whereas
expression in Balb/C mice was largely limited to the nucleus.
Conclusion: Skin-draining lymph node TFH cell expansion is an early event after UV
and TLR7 agonist therapy and is correlated with auto-antibody production. HMGB1
redistribution in the skin also correlates with auto-antibody production.
Quantification of circulating TFH cells and local HMGB1 expression may serve as
markers for predicting SLE onset in genetically predisposed individuals.
Immunohistochemical characterization of acute and chronic discoid lupus
erythematosus skin lesions
Jack C. O’Brien, BS1, Gregory A. Hosler, MD1,2, Benjamin F. Chong, MD, MSCS1
1University
2ProPath,
of Southwestern Medical Center, Department of Dermatology, Dallas, TX
Dallas, TX
Background: Cells of both the innate and adaptive immune system have been
implicated in the pathogenesis of discoid lupus erythematosus (DLE). The
inflammatory cell infiltrate in DLE has been described as containing CD4+ and CD8+
T cells, B cells, macrophages, and plasmacytoid dendritic cells. Histologically, DLE
skin lesions can be thought of as having two phases, “acute” and “chronic,” which
can be distinguished based on the absence or presence of dermal sclerosis.
Characterizing the changes in the composition of the inflammatory cell infiltrate of
acute and chronic DLE lesions would elucidate the disease course of DLE.
Objective: To characterize the inflammatory infiltrate in acute and chronic DLE skin
lesions using immunohistochemistry.
Methods: We identified 25 skin biopsies from untreated DLE skin lesions from DLE
patients seen at UT Southwestern Medical Center and Parkland Memorial Hospital
between 2006 and 2015. Patients were classified as having acute (N=7) or chronic
(N=18) DLE based on the presence or absence of deep dermal fibrosis, respectively.
Immunostains for T cells (CD3, CD4, CD8), B cells (CD20), plasmacytoid dendritic
cells (CD123), macrophages (CD163), neutrophils (MPO), and plasma cells (CD138)
were performed. Two independent observers graded the overall intensity of the
infiltrate in three areas, interfollicular interface, perifollicular, and perivascular, on a
0 to 3 scale (0 = none, 1 = mild, 2 = moderate, 3 = marked). Each immunostain was
graded on a 0 to 3 scale based on percentage of positive-staining cells (0 = <1%, 1 =
<10%, 2 = 10-50%, 3 = >50%). Median staining intensities for each group were
calculated and compared using nonparametric tests.
Results: Chronic DLE skin had increased CD20 staining in perifollicular (p=0.002)
and perivascular regions (p=0.009) compared to acute DLE skin. CD8+ cells trended
towards being more frequent in the interfollicular interface (p=0.07) and
perifollicular regions (p=0.05) in acute DLE skin. The CD4:CD8 T cell ratio was
higher in perifollicular (p=0.005) and in perivascular (p=0.02) regions in chronic
DLE.
Conclusions: The inflammatory infiltrate in DLE patients changes as the histology
progresses to dermal fibrosis, as evidenced by fewer CD8+ lymphocytes and
increased CD20+ B cells in different regions of chronic DLE skin. These changes
could reflect an initial inflammatory process driven by a cytotoxic T cell response
that is later mediated by a B cell response in DLE.
Belimumab for the treatment of recalcitrant cutaneous lupus – A pilot project
Priyanka Vashisht MD, Manpreet Sethi MD, Melanie Rohr MD, Debbie Lim MD,
Michelene Hearth-Holmes MD
Background/Purpose: Belimumab (Benlysta) is a monoclonal antibody that
prevents the survival of B lymphocytes by blocking the binding of soluble human B
lymphocyte stimulator (BLyS) to its B cell receptors. Approved by the U.S. Food &
Drug Administration in 2011 for the treatment of adult patients with active,
autoantibody-positive systemic lupus erythematosus (SLE) who are receiving
standard therapy, belimumab reduces B-cell mediated immunity and autoimmune
responses. The utility of benlysta for management of resistant SLE skin
manifestations has not been reported. We present our experience of using this novel
molecule for the successful management of cutaneous lupus at our center.
Methods: We studied 4 patients with severe SLE skin manifestations. All patients
met 1997 ACR SLE criteria and were ANA positive. Two patients had low
complements and 1 patient had positive double-stranded (dS) DNA antibodies. All
patients had failed multiple medications, including anti-malarial therapy and highdose glucocorticoids, to control their skin disease. SLE disease activity indexes
(SLEDAI) and patient’s global assessment (PGA) were recorded before and after
benlysta treatment. Benlysta was added to concomitant standard therapy, as a
loading dose of 10 mg/kg intravenously (IV) every 2 weeks for 3 doses followed by
maintenance of 10 mg/kg every 4 weeks. All patients were pre-medicated with 40
mg prednisone. Patients were followed closely for clinical improvement every 4
weeks. Baseline patient characteristics and clinical images are outlined in the Table
and Figure 1.
Results: All the 4 patients demonstrated marked clinical improvement after
benlysta treatment (Figure 2). The average time to clinical improvement after
treatment initiation was 8-12 weeks. There were no changes in complement levels
or dsDNA antibodies with treatment. All patients had a decrease in prednisone dose
and improvement in both SLEDAI and PGA scores with therapy (Table).
Conclusion: In this case series, the addition of benlysta to standard therapy
improved the signs and symptoms of refractory cutaneous lupus in our patients.
This is one of the first reports highlighting the potential utility of this medication for
treatment of severe skin involvement in SLE. Additional studies need to be
performed to assess use of benlysta in skin lupus.
DERMATOMYOSITIS
The Cutaneous Dermatomyositis Disease Area and Severity Index as a primary
efficacy endpoint in a Phase 2 clinical trial of IMO-8400 in patients with
dermatomyositis
David Fiorentino1, Mark Hurtt2, Julie Brevard2, Victoria Werth3
Department of Dermatology, Stanford University School of Medicine, Redwood City,
California, 2 Idera Pharmaceuticals, Inc., Cambridge, Massachusetts, 3 Division of
Dermatology, Philadelphia Veteran's Affairs Medical Center, Philadelphia,
Pennsylvania
1
Introduction: The Cutaneous Dermatomyositis Disease Area and Severity Index
(CDASI) was developed to evaluate skin manifestations of dermatomyositis (DM),
which can be the most active and severe components of DM in patients. Multiple
studies have demonstrated the validity and reliability of the CDASI in patients with
DM. In addition, it has been established that a difference of about 5 points on the
CDASI activity score is clinically meaningful. IMO-8400 is an investigational
oligonucleotide-based antagonist of Toll-like receptors (TLRs) 7, 8 and 9 that
previously demonstrated activity on the Psoriasis Area and Severity Index in
patients with moderate to severe plaque psoriasis. To evaluate the CDASI as a
potential primary efficacy endpoint in a Phase 2 clinical trial of IMO-8400 in
patients with DM, analyses were conducted on available longitudinal CDASI
outcome data.
Methods: Retrospective analyses were conducted on de-identified CDASI
assessments for 115 unique DM patients with a total of 345 clinic visits. Patients
with multiple assessments approximately 12 or 24 weeks apart were grouped by
the first visit CDASI activity score (<15, 15-19, 20-24 and ≥25), and the change in
CDASI activity score between the visits was assessed. In addition, a simulationbased analysis was conducted to estimate the number of subjects needed for a trial
using the CDASI as an outcome measure.
Results: Over 24 weeks, a 5 point or greater decrease in CDASI activity score was
observed at 31.8% of patient visits, with the change in CDASI activity score ranging
from -23 to +27 points across all patients. Patients with a high first visit CDASI
activity scores demonstrated larger decreases over 24 weeks compared to patients
with low first visit CDASI activity scores. Because some patients experienced
clinically meaningful changes of 4 to 5 points on the CDASI following treatment with
standard of care therapies, a 7 point treatment effect was targeted for the IMO-8400
trial. Sample size calculations resulted in 10 patients per treatment group, assuming
a standard deviation of 8.5 points over 24 weeks using a Repeated Measures Mixed
Model analysis of change from baseline on monthly CDASI assessments (>80%
power on a 1-sided test; alpha=0.05).
Conclusion: Analyses of longitudinal CDASI outcome data demonstrated the
feasibility of the CDASI as a primary efficacy endpoint for use in the Phase 2 clinical
trial of IMO-8400 in patients with DM.
The Janus kinase inhibitor tofacitinib is an alternative treatment option for
refractory cutaneous dermatomyositis
Drew Kurtzman, MD; Natalie Wright, MD; Janice Lin, MD; Alisa Femia, MD; Henry
Townsend, MD; Mital Patel, MD; Ruth Ann Vleugels, MD, MPH
Department of Dermatology, Brigham and Women’s Hospital, Boston, MA
Background: Dermatomyositis is an idiopathic inflammatory myopathy with
characteristic cutaneous findings. As a rare disorder, few validated therapies exist
for disease management, and when traditional agents fail, effective alternatives have
been scarcely reported. Recently, ruxolitinib, a selective inhibitor of the Janus
kinases JAK1 and JAK2, was demonstrated to be effective for inducing remission of
refractory dermatomyositis in a single case report. A related Janus kinase inhibitor,
tofacitinib, is commercially labeled for use in select inflammatory conditions,
however, its use in patients with dermatomyositis has not yet been reported.
Objective: We sought to assess the efficacy of the Janus kinase inhibitor tofacitinib
for treating refractory cutaneous dermatomyositis.
Methods: We identified patients with cutaneous dermatomyositis refractory to
traditional agents. The clinical response to tofacitinib was evaluated. The primary
endpoint was improvement of skin disease as measured by the validated Cutaneous
Dermatomyositis Disease Area and Severity Index (CDASI). Secondary endpoints
included necessity for concurrent therapies, improvement of muscle disease when
applicable, tolerability, and incidence of adverse events.
Results: Three patients with refractory cutaneous dermatomyositis were evaluated
including one with amyopathic dermatomyositis. All patients were female. The
mean prescribed dose of tofacitinib was 6.67 mg (range 5-10 mg, n=3) administered
orally twice daily for a mean period of 8.6 months (range 5-14 months). The mean
age at treatment initiation was 40 years (range 30-50 years, n=3). Prior failed
therapies included topical and systemic corticosteroids, hydroxychloroquine,
methotrexate, azathioprine, mycophenolate mofetil, dapsone, thalidomide,
lenalidomide, isotretinoin, intravenous and subcutaneous immunoglobulin (IVIG
and SCIG), and rituximab. Tofacitinib as a monotherapy produced skin improvement
in all three patients. Mean CDASI scores before and after treatment were 28.3 (range
23-32, n=3) and 17.6 (range 10-27, n=3), respectively. Muscle disease in the two
patients with classic dermatomyositis remained in remission while on therapy; one
patient noted subjective improvement of strength. Tofacitinib was uniformly
tolerated without side effects. No laboratory abnormalities were encountered
throughout the duration of treatment.
Limitations: Small sample size, heterogeneous past treatment regimens.
Conclusions: Tofacitinib is a well-tolerated, easily administered oral medication
capable of improving recalcitrant cutaneous dermatomyositis in select patients.
Additional large-scale and comparative studies are warranted to further support its
use in this setting.
Evaluation of the Reliability and Validity of the Cutaneous Dermatomyositis
Disease Area and Severity Index (CDASI) and the Cutaneous Assessment ToolBinary Method (CAT-BM) Among Pediatric Dermatologists, Rheumatologists,
and Neurologists in Juvenile Dermatomyositis
Janice Tiao, BA,*1, 2 Neelam Khan, MS,*1, 2 Rui Feng, PhD,3 Emily M. Berger, MD,4 John
Brandsema, MD,5 Carrie C. Coughlin, MD,6 Elizabeth A. Kichula, MD, PhD,5 Melissa A.
Lerman, MD, PhD,7 Svetlana Lvovich, DO,8 Patrick J. McMahon, MD,10 Lisa G. Rider,
MD,11 Adam I. Rubin, MD,1,10 Lisabeth V. Scalzi, MD,12 Douglas M. Smith, MD,5 Alysha
J. Taxter, MD, MSCE,9 James R. Treat, MD,10 Sabrina W. Yum, MD,5 Joyce Okawa, MBE,
RN,1 Victoria P. Werth, MD1, 2
*co-first authors
1Department
of Dermatology, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA
2Philadelphia
VA Medical Center, Philadelphia, PA
3Center
for Clinical Epidemiology and Biostatistics, University of Pennsylvania,
Philadelphia, PA
4Hackensack
University Medical Center, Hackensack, NJ
5Division
of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA
6Division
of Dermatology, Washington University School of Medicine, St. Louis, MO
7Division
of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA
8St.
Christopher’s Hospital for Children, Philadelphia, PA
9Wake
Forest Baptist Brenner Children’s Hospital, Winston-Salem, NC
10Division
11National
of Dermatology, Children’s Hospital of Philadelphia, Philadelphia, PA
Institute of Environmental Health Sciences, National Institutes of Health,
Bethesda, MD
12Penn
State Hershey Rheumatology, Penn State Milton S. Hershey Medical Center,
Hershey, PA
Background/Purpose: The Cutaneous Dermatomyositis Disease Area and Severity
Index (CDASI) has been shown to be a reliable and valid outcome measure to assess
cutaneous disease in the adult dermatomyositis (DM) population. Better
instruments are needed to assess cutaneous disease in the juvenile DM (JDM)
population. The purpose of this study is to compare two outcome measures, the
CDASI and the Cutaneous Assessment Tool-Binary Method (CAT-BM), for use by
pediatric dermatologists, rheumatologists, and neurologists in JDM patients.
Methods: Five pediatric dermatologists, 5 pediatric rheumatologists, and 5
pediatric neurologists evaluated 14 JDM patients using the CDASI, CAT-BM, and
Physician Global Assessment (PGA) scales. Patients were scored independently by
each physician. Inter-rater reliability, intra-rater reliability, and construct validity
were compared.
Results: Inter-rater reliability for CDASI activity and damage scores was good to
moderate for dermatologists and rheumatologists, but poor for neurologists. The
inter-rater reliability for CAT-BM activity and damage scores was moderate for
dermatologists and rheumatologists, but poor for neurologists (Table 1). Notably,
the inter-rater reliability for neurologists for CDASI activity and damage improved
to moderate (0.66 and 0.61, respectively) when an outlier neurologist and patient
were removed. Intra-rater reliability for CDASI activity and damage scores was
excellent for dermatologists, moderate for neurologists, and moderate to excellent
for rheumatologists. Intra-rater reliability for CAT-BM activity and damage scores
was excellent for dermatologists and neurologists and moderate to excellent for
rheumatologists (Table 2). Strong positive associations were found between the
change in PGA activity and damage scores and the respective CDASI activity and
damage scores (0.224 with p<0.0001 and 0.343 with p<0.0001), as well as between
the change in PGA activity and damage scores and the respective CAT-BM activity
and damage scores (0.484 with p<0.0001 and 0.256 with p=0.0019).
Conclusion: Our data confirm the reliability and validity of the CDASI activity and
damage scores and the CAT-BM activity scores when used by pediatric
dermatologists and rheumatologists. Significant variation in the pediatric
neurologists’ scores suggests that outliers affect results considerably.
Table 1. Inter-observer correlation coefficient
Within pediatric
dermatologists (n=5)
Within pediatric
neurologists (n=5)
Within pediatric
rheumatologists
(n=5)
Activity
0.52 (0.44-0.61)
0.47 (0.39-0.56)
0.81 (0.76-0.85)
Damage
0.59 (0.51-0.67)
0.46 (0.37-0.54)
0.59 (0.51-0.66)
Activity
0.58 (0.50-0.66)
0.42 (0.33-0.51)
0.67 (0.60-0.74)
Damage
0.49 (0.41-0.58)
0.29 (0.20-0.38)
0.48 (0.39-0.57)
Activity
0.64 (0.50-0.78)
0.38 (0.29-0.47)
0.47 (0.39-0.56)
Damage
0.71 (0.65-0.83)
0.73 (0.67-0.79)
0.31 (0.22-0.40)
CDASI
CAT-BM
PGA
Table 2. Intra-rater reliability ICC (95% C.I.)
Within pediatric
dermatologists (n=5)
Within pediatric
neurologists (n=5)
Within pediatric
rheumatologists (n=5)
Activity
0.90 (0.78-1.00)
0.65 (0.29-1.00)
0.91 (0.79-1.00)
Damage
0.97 (0.94-1.00)
0.78 (0.53-1.00)
0.64 (0.27-1.00)
Activity
0.86 (0.70-1.00)
0.91 (0.80-1.00)
0.88 (0.74-1.00)
Damage
0.93 (0.85-1.00)
0.89 (0.76-1.00)
0.73 (0.44-1.00)
Activity
0.95 (0.90-1.00)
0.83 (0.64-1.00)
0.50 (0.03-0.96)
Damage
0.84 (0.66-1.00)
0.96 (0.91-1.00)
0.55 (0.12-0.98)
CDASI
CAT-BM
PGA
*ICC scores between 0.50 and 0.70 are considered moderate and minimally
acceptable, 0.70 to 0.81 good, and >0.81 excellent. Scores <0.5 are considered poor.
Activity of Type I and Type II Interferons in Dermatomyositis Skin is
Correlated with Characteristic Pathologic Features
Hayley Leatham1, Kerri Rieger2, Lorinda Chung3, Shufeng Li1, Brandon Higgs4,
Yihong Yao4, Kavita Sarin1, David Fiorentino1
Departments of Dermatology1 and Dermatopathology2, Stanford University
Division of Immunology and Rheumatology3, Stanford University
Translational Sciences, MedImmune4, Gaithersburg, MD
Background/Purpose: Interferon (IFN) signaling is upregulated in
dermatomyositis (DM) skin, but the relationship to classic histopathologic features
is unknown.
Methods: Thirty-nine skin biopsies from patients with dermatomyositis underwent
gene expression analysis using Affymetrix arrays, as well as histologic analysis by a
blinded dermatopathologist. Biopsies were scored for severity of several cardinal
histopathologic features, including basal vacuolar change (BV), dermal mucin
deposition, and perivascular inflammation. Type I and type II IFN scores were
generated based on the average relative expression of selected genes previously
demonstrated to be specifically upregulated by IFN-alpha and IFN-gamma,
respectively. Expression levels of IFN transcripts were measured by quantitative
PCR. Univariate analysis was performed to evaluate the association between IFN
scores and IFN transcripts with key histopathologic features, with subsequent
multivariate models constructed to include potentially confounding variables such
as biopsy site, medication use, age, and length of disease.
Results: Skin biopsies were heterogeneous with regard to both histopathologic
features as well as type I and II IFN scores. The type I IFN gene set was comprised of
three genes (OAS1, OAS2, IFIT1) and the type II IFN gene set consisted of six genes
(GBP1, GBP2, HLA-DMB, HLA-DRA, IL18BP, WARS); these scores were significantly
correlated (r=0.6636, p<0.0001). Type I IFN scores correlated strongly with IFN
beta expression (r=0.70956, p<0.0001) but not other type I (alpha, kappa, omega)
transcript levels; type I IFN scores also correlated with IFN gamma transcripts
(r=0.4539, p=0.008). Type II IFN scores correlated strongly with IFN gamma
(r=0.839, p<0.0001), as well as IFN beta (r=0.481, p=0.0046). In univariate analysis,
keratinocyte injury (reflected by BV score) was found to be associated with both
type I and type II IFN scores (p=0.0046 and p=0.004, respectively); these
associations remained significant in multivariate analysis. Similar analysis of
additional histopathologic features showed an association between mucin
deposition and higher type I IFN scores (OR 1.13, p=0.0001) but not type II IFN
scores (OR 1.32, p=0.071); additionally, lymphocytic dermal inflammation was
associated with type II IFN scores (OR 1.36, p=0.0413) but not type I IFN scores (OR
1.03, p=0.3275). Other analyzed histologic features, including epidermal atrophy,
basement membrane thickening, and vessel damage were not statistically
associated with either IFN score.
Conclusion: Our results highlight that IFN signaling in DM skin likely represents a
combination of at least type I and II activity. Furthermore, our data suggest that
both type I and II IFN signaling may be associated with shared as well as distinct
pathologic processes in DM skin, although there is a clearly a high correlation and
degree of overlap in gene expression between our two scores. Keratinocyte injury,
the sine qua non finding in DM skin, is associated with both type I and II IFN activity.
Finally, our results imply that IFN beta is the relevant IFN driving type I IFN
signaling in DM skin and point to both IFN beta and IFN gamma as potential targets
of pharmacologic inhibition in cutaneous DM.
MORPHEA
Changes of disease activity and damage over time in morphea patients
Jack C. O’Brien, BS1 and Heidi T. Jacobe MD, MSCS1
1University of Southwestern Medical Center, Department of Dermatology, Dallas, TX
Background: Morphea, also known as localized scleroderma, is characterized by
inflammation followed by sclerosis, producing devastating functional and cosmetic
impairment in those affected. Very little is known about the natural history of
morphea. It was previously thought to “burn out” within 5 years. Newer studies,
including our own, imply some patients have a remitting relapsing course. However,
no studies have prospectively examined morphea disease activity over time.
Understanding the course of morphea is important, not only in determining how to
counsel and evaluate patients, but also for appropriately planning outcome and
interventional studies.
Objective: To define the disease course of morphea with respect to activity and
damage based on validated clinical outcome measures in a prospective, longitudinal
cohort of patients.
Methods: This is prospective cohort study including 118 study patients from the
Morphea in Adults and Children (MAC) cohort. Patients were included if they had at
least three study visits with localized scleroderma activity index (LoSAI) scores
recorded. Patients were divided into two groups based on disease activity at
baseline visit, with those with LoSAI scores <10 being considered to have mild
disease and those ≥ 10 were classified as having moderate to severe disease activity.
Mean disease activity over time was measured by plotting time on the x-axis and
LoSAI on the y-axis for each patient. Area under the curve per year (AUC/yr),
reflecting disease activity over time, was determined for each patient using the
trapezoidal rule. Linear regression analysis was used to determine the slope of each
line, reflecting the overall disease course for each patient. Similar analyses were
conducted using the Modified Rodnan Skin Score (MRSS), localized scleroderma
damage index (LoSDI), and physician’s global assessment of activity (PGA-A), and
damage (PGA-D). Longitudinal regression analyses are currently underway to
model the relationship between baseline demographic and clinical features and
activity and damage over time. We compared mean AUC/yr and mean slopes in
patients with mild disease activity and in those with moderate to severe disease
activity with the Mann-Whitney U Test using GraphPad Prism 6.0.
Results: 118 patients with a total of 535 study visits were included in this study. 71
patients had four visits, 49 had five visits, and 36 had six or more study visits. 39%
were children and 61% adults at baseline visit. The majority of patients were
Caucasian (75%) and female (79%). 61% of patients had mild disease activity at
baseline and 39% of patients had moderate-severe disease activity. Mean disease
activity and damage measurements for patients at baseline visit were LoSAI 13.2 ±
20.1, LoSDI 16.8 ± 17.3, PGA-A 31.4 ± 29.6, PGA-D 34.0 ± 23.7, and MRSS 6.6 ± 5.7.
Mean AUC/yr for LoSAI scores in patients with moderate-severe activity was higher
than those with mild activity (27.7 vs. 4.1; p<0.0001). Patients with moderatesevere disease activity also had higher disease damage scores as measured by LoSDI
and MRSS (p=0.001 and p=0.005, respectively). The mean slope for patients with
mild disease activity was -0.76 while the mean slope for patients with moderatesevere disease activity was -9.20 (p<0.0001).
Conclusions: Disease activity improves in the majority of morphea patients over
time. As expected, morphea patients with higher disease activity at baseline
progress to having higher damage scores than those with mild disease activity as
activity resolves with damage. An unexpected finding was that damage scores in
patients, after initially worsening as activity subsided, improved in many patients.
We hypothesize that this may occur more frequently in the subgroup with dermal
involvement, as compared to those with deep involvement.
Acknowledgements: We are grateful to Jeannette Olazagasti and Victoria P. Werth,
MD, for sharing their data analysis plan for this project.
Epidemiology and treatment of post-irradiation morphea: a retrospective
analysis from three large tertiary care centers
*Renee
Fruchter BA1, *Drew Kurtzman MD2, Daniel R. Mazori BA1, Natalie A. Wright
MD2, Mital Patel MD2, ϮRuth Ann Vleugels MD MPH2, ϮAlisa N. Femia MD1
1. The Ronald O. Perelman Department of Dermatology, New York University
Langone Medical Center
2. Brigham and Women’s Hospital Department of Dermatology, Harvard Medical
School
*represent co-first authors
Ϯrepresent co-last authors
Background: Post-irradiation morphea (PIM) is a rare and potentially disabling
cutaneous complication of radiotherapy, affecting approximately 2 in every 1000
patients treated with radiation. Only 67 cases are reported in the literature to date,
and treatment data is reported in only half of cases.
Objective: The objective of this retrospective cohort study was to characterize the
nature and treatment of patients with PIM.
Methods: Using medical record databases at New York University (2005-2015) and
Partners Healthcare (Brigham and Women’s and Massachusetts General Hospitals;
2000-2015), we reviewed all charts with ICD-9 code 701.0 to identify all patients
with PIM at three large tertiary care centers.
Results: Twenty-four patients with PIM were identified. All were female. Twentythree of the 24 were treated with radiotherapy for breast cancer, while one patient
had a history of an acinic cell carcinoma of the parotid gland treated with radiation.
The mean age of onset was 57.9 years. Where data was available, 24% (n=5)
developed PIM within 1 year of first radiation exposure, 52% (n=11) within 1-5
years, and 24% (n=5) after 5 years. All had PIM within the irradiated site, and 46%
(n=11) had PIM extending beyond the irradiation field to sites including the
contralateral breast, abdomen, back, groin, extremities, and face. Fifty-four percent
(n=13) were asymptomatic, 29% (n=7) complained of pruritus, 17% (n=4)
endorsed pain, and 8% (n=2) reported a sensation of tightening. One patient had a
documented history of radiation dermatitis, and only one had a prior history of a
connective tissue disease. All but one patient were referred to a dermatologist.
Where treatment data was available (n=22), 91% (n=20) were treated with topical
agents including corticosteroids, vitamin D analogues, tacrolimus, dapsone, and
azelaic acid; of these, 40% (n=8) had improvement with topical therapy alone.
Thirty-six percent (n=8) of patients received systemic agents (methotrexate,
prednisone, etanercept, doxycycline, colchicine, calcitriol, and pentoxifylline)
and/or phototherapy. Although only utilized in four patients, methotrexate led to
disease stabilization or improvement in all of those treated with this medication.
Post-irradiation morphea was treatment-refractory in 36% (n=8) of patients,
requiring trials of three or more therapies.
Conclusion: In conclusion, this study represents the largest PIM cohort to date as
well as the largest study to describe treatment outcomes. This study highlights the
varied nature of PIM in terms of associated symptoms, latency period from
treatment with radiotherapy, and sites of disease involvement. In addition, this
study underscores the potentially refractory nature of PIM, as well as the need to
better define a treatment algorithm for this condition. Additional investigations are
warranted to further characterize this disorder.
MISCELLANEOUS
Myelodysplastic Syndrome Presenting as Generalized Granulomatous
Dermatitis
Oral Presentation: David A. Wetter, M.D.
Abstract was previously published in the following article:
Samuel J. Balin, *David A. Wetter, Paul J. Kurtin, Louis Letendre, Mark R. Pittelkow
Arch Derm 2011;147(3):331-335.
Background: Granulomatous dermatitis rarely has been reported as a
manifestation of leukemia or myelodysplastic syndromes. We describe a case of
widespread granulomatous dermatitis that preceded the diagnosis of
myelodysplastic syndrome by 2 years.
Observations: A 71-year-old man had development of a generalized, mildly pruritic
eruption that slowly progressed over a 2-year period. Punch biopsy specimens
demonstrated interstitial dermal granulomatous inflammation. Complete blood
count with differential showed marked monocytosis, and subsequent biopsy of the
bone marrow confirmed myelodysplastic syndrome. The patient started treatment
with lenalidomide and his skin condition improved after 6 weeks of treatment;
however, the myelodysplastic syndrome progressed to acute leukemia, and he died
shortly thereafter.
Conclusions: A paucity of literature exists documenting the occurrence of
granulomatous dermatitis as a manifestation of an underlying hematologic disorder.
This case illustrates a striking example of widespread granulomatous dermatitis
heralding the onset of myelodysplastic syndrome. It is imperative that the
dermatologic community recognize the rare association of granulomatous
dermatitis with myelodysplasia, because the cutaneous manifestations may be the
presenting finding and can precede the development of leukemia by several years.