Scientific highlights from the annual meeting of
the ACR in Boston 2014: Dr. Dobrota and Dr. Avouac in interview with EUSTAR
The abstracts are available
Rucsandra Dobrota and coworkers on "Prediction of Improvement in
Skin Fibrosis in Diffuse Cutaneous Systemic Sclerosis.", Arthritis Rheum
2014; 66 (11) 1220 abstr. #722
EUSTAR: Dr. Dobrota, why
is it important to understand factors predicting the improvement of skin
fibrosis in diffuse cutaneous SSc?
Dr. Dobrota: The eventual
decrease of the modified Rodnan skin score during the evolution of the
disease is generally accepted as the “natural course” of skin fibrosis in
patients with diffuse cutaneous systemic sclerosis. However, the time to the
peak skin score, as well as the pattern of skin involvement vary widely
across patients. Being able to identify those patients who are most likely
to show skin improvement during an upcoming time-frame (e.g. in our study we
focused on one year of follow-up) could help guide the therapeutic
intervention in clinical practice. For example, this could be an important
factor to consider while pondering on the initiation of immunosuppressive
therapy for skin fibrosis. In addition, it could represent an important
asset for cohort enrichment in clinical trials in skin fibrosis. In this
case, in order to show a therapeutic effect, a minimal number of
“spontaneous improvers” should be included in the cohort.
EUSTAR: How did you discover or investigate those predictors of skin
Dr. Dobrota: For this study, we have analyzed the
EUSTAR cohort, including over 11’000 patients at the time of data export,
704 of whom met the inclusion criteria for the study. Skin improvement was
defined as a decrease in the modified Rodnan skin score (mRSS) at 12 months’
follow-up of >5 points and ≥25% from the baseline value based on the minimal
clinically important difference. First, in a univariate analysis, we looked
for correlations between the standard EUSTAR clinical and investigational
parameters and skin improvement. The potential predictors (p<0.2) were
analyzed for face validity through expert opinion, using the nominal group
technique. Multiple imputation was used to compensate for missing data.
Next, using multivariable logistic regression, we identified a prediction
model for skin improvement at one year of follow-up, which was confirmed
when re-tested in the dataset without missing values. We also performed a
temporal validation using non-previously included cases from the EUSTAR
cohort. For this complex analysis, we worked closely with an experienced
biostatistician (Nicole Graf, graf biostatistics).
Which were the surprising findings of your study?
Dr. Dobrota: Our
results highlight a high baseline skin score and a normal erythrocyte
sedimentation rate as independent predictors of skin improvement. In other
words, patients with an already advanced skin fibrosis (as reflected by a
high mRSS) are actually more likely to experience skin improvement during a
one year follow-up.
EUSTAR: How would you implicate your
findings into clinical practice?
Dr. Dobrota: The high likelihood
of “spontaneous” skin improvement in patients with extensive skin fibrosis
supports the idea that a therapeutic intervention should also be considered
in patients with milder skin fibrosis, who are actually most likely to
progress, as shown in previous work from the EUSTAR group by Maurer et al.1
I would like to underline that our analysis is, nonetheless, a group
analysis and is not readily applicable to individual cases in clinical
practice. It could however directly influence cohort selection for clinical
trials, by choosing the mRSS threshold used as an inclusion criteria in
order to minimize the number of “spontaneous improvers” in the study cohort.
According to our results, an mRSS threshold between 18 and 25 would allow
the inclusion of a high ratio of progressors over regressors into the
EUSTAR: Which are the next steps you will take with this
Dr. Dobrota: We are currently writing the
manuscript, which we plan to complete in the following months. Afterwards we
shall proceed with submission, and hope for the best. We will also work on
risk charts that will allow risk prediction for progression and regression
on the individual patient level. Finally, I would like to underline that
all these analysis would not have been possible without the outstanding
support of all contributing EUSTAR centers.
Ref.: Maurer B, Graf N, Michel BA, Müller-Ladner
U, Czirják L, Denton CP, Tyndall A, Metzig C, Lanius V, Khanna D, Distler O;
EUSTAR co-authors. Prediction of worsening of skin fibrosis in patients with
diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann Rheum
Dis. 2014 Jun 30. pii: annrheumdis-2014-205226. doi:
10.1136/annrheumdis-2014-205226. [Epub ahead of print]
Dr. Dobrota at the 2014 Annual Meeting of the ACR.
Jérôme Avouac and coworkers on "Joint and Tendon Involvement Predict
Severe Disease Progression in Systemic Sclerosis: A Prospective Study.",
Arthritis Rheum 2014; 66 (11) 1220 abstr. #2711
Dr. Avouac, the joint has long been ignored in the field of systemic
sclerosis while much attention has been paid to internal organ
manifestations. Is it time to pay more attention to joint involvement in the
Dr. Avouac: It is definitively the time to pay more
attention to joint involvement in systemic sclerosis (SSc). First, joint
involvement is very frequent in SSc, with a point prevalence of 28% in the
EUSTAR registry. Joint involvement has been shown to strongly contribute to
impaired hand function, characterized by decreased hand mobility, reduced
dexterity and decreased grip force, which has been clearly identified by SSc
patients as a major source of difficulties in their activities of daily
living. In addition, the recent results of our prospective study revealed
that joint and tendon involvement is predictive of disease progression.
EUSTAR: How did you get interested in joint manifestations in
Dr. Avouac: We first get interested in joint and tendon
manifestations since this field was previously neglected and because they
are a frequent complaint of patients with SSc. Moreover, a preliminary
analysis of the EUSTAR registry, performed by our group, showed that
synovitis and tendon friction rubs (TFRs) were associated with disease
activity and systemic inflammation (Avouac et al, J Rheumatol 2010).
However, the impact of this study was limited by its cross-sectional design.
We also know from literature that TFRs are predictive of the further
development of renal, cardiac and gastro-intestinal involvement. However,
these results were obtained for a limited number of patients and were
restricted to patients with early diffuse cutaneous SSc. Thus, one
hypothesis was that joint and tendon involvement might be a marker of
disease progression in patients with early SSc. Therefore, the aim of our
prospective study was to determine for the first time the value of synovitis
as a predictor of disease progression, and extend in a large cohort the data
previously obtained for TFRs in early diffuse SSc patients. This study has
been made possible by the implementation of systematic longitudinal
follow-up of SSc patients included in the EUSTAR registry, updated on an
annual basis, which has been a major step forward, and now allows the
identification of predictors of disease course.
is the key message of your study?
Dr. Avouac: Our study included
1301 patients with a disease duration <3 years and a follow-up of at least 2
years. The key message of our study is that synovitis and tendon friction
rubs, detected by clinical examination, are predictive of disease
progression in patients with early SSc. Indeed, synovitis and tendon
friction rubs were identified as independent predictors of skin progression,
defined by a worsening of the modified Rodnan skin score (mRSS) ≥30% and ≥5
points. In addition, synovitis was also independently predictive of the
occurrence of new digital ulcers and of reduction of left ventricular
ejection fraction. TFRs were also confirmed in our large study sample to be
an independent predictor of scleroderma renal crisis. No impact of synovitis
and TFRS was observed on lung outcomes (pulmonary hypertension and
interstitial lung disease progression).
EUSTAR: How would you
implicate your findings into clinical practice?
Dr. Avouac: Joint
synovitis and TFRs are easily detected clinical markers which may be useful
for the risk stratification of SSc patients. The implication of our results
in clinical practice is important since these indicators SSc may serve to
select high-risk patients with early disease, who may be more closely
followed-up since they are at risk of organ progression. Moreover, joint and
tendon involvement may also be used to guide therapies and as potential
surrogate markers for disease progression.
EUSTAR: Which are
the next steps you will take with this exciting project?
Avouac: The next steps would be to generalize our data in the whole SSc
community since this study focused on patients with early disease, and
because we excluded patients with active digital ulcers, renal involvement
and cardiac failure at inclusion. Moreover, it would be very interesting to
study whether changes in synovitis or TFRs within time influence changes in
disease progression. Moreover, regarding the recent development of
ultrasounds in the field of rheumatology, and based on preliminary promising
results (Elhai et al, Arthritis Care Res 2013), one perspective would be to
assess the predictive value of joint and tendon involvement detected by
EUSTAR thanks both researchers for their kindness and support in
summarizing their excellent pieces of work.