eustar  —  european scleroderma trials and research




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 here.

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 improvement?
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).  

EUSTAR: 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 cohort.

EUSTAR: Which are the next steps you will take with this interesting project?
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

EUSTAR: 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 disease?  
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 SSc?  
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.  

EUSTAR: What 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?  
Dr. 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 ultrasounds.    


EUSTAR thanks both researchers for their kindness and support in summarizing their excellent pieces of work.