Scleroderma Highlights

Laura K. Hummers, MD

Abstract #608: A Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma (DSSc)

Authors:

Janet Pope, Donna L. McBain, Lisa Petrlich, Sharon Watson, Louise Bender, Faye Deleon and Kelly Summers

Background:

This is a small double blind RCT using imatinib (Gleevec) for the treatment of active diffuse skin disease.

Methods:

Subjects with active diffuse skin disease were enrolled and randomized 4:1 of study drug (up to 600 mg) vs. placebo. Outcomes included modified Rodnan skin score, skin biopsy and possible plasma biomarkers. Patients were stratified by background methotrexate use.

Results:

Only 10 patients were enrolled in this study as the study investigators halted enrollment due to high number of adverse events. The characteristics of the patients were characteristic for what you would expect for early diffuse scleroderma (mean age 51 years, disease duration 3 years, skin score 33. The main AE that was seen was peripheral edema, nausea, vomiting and chest pain. Only 4/10 completed study at the target dose. The one SAE was someone who developed marked edema. In this limited experience the authors did not find any significant change in skin score, plasma cytokines, and patient and physician global scores.

Editorial Comment:

This study suggests high intolerance rates of imatinib in scleroderma patients with early diffuse skin disease. This study was terminated prior to goal enrollment due to high rates of edema/fluid retention.

Abstract # 606: Imatinib Mesylate (Gleevec) in the Treatment of Systemic Sclerosis: Interim Results of a Phase IIa, One Year, Open Label Clinical Trial

Authors:

Jessica Gordon, Jamie Mersten, S. Lyman, S.A. Kloiber, H. F. Wildman, M. K. Crow, K. A. Kirou and R.F. Spiera

Background:

To determine the effect of imatinib (Gleevec) in a single-center, open-label study of patients with diffuse scleroderma treated for 12 months.  

Methods:

Patients with diffuse scleroderma were enrolled without limitation on disease duration or prior therapy. Assessments were performed at 1 month intervals and outcomes included safety, change in modified Rodnan skin score and changes in lung function (FVC and DLCO). The investigators also reported results of histological changes seen on skin biopsy in a separate abstract (#1727) in a subset of patients.

Results:

Thirty patients were enrolled. 20/30 had disease duration of <4 years, but 10/30 had disease duration of >4 years. The mean skin score at enrollment was 30 in the 17 patients with 12 month data (6 patients dropped out the remainder had not reached the 12 month assessment point). Patients were treated with imatinib 400 mg per day, although because of adverse reactions leading to dose reduction (83%), the median dose was 350 mg. The investigators reported 340 AEs and 24 SAEs during the study period and included edema in 80% of patients, nausea in 73%, and myalgia in 63%. There were 36 infections including 7 who required hospitalization. The skin score difference in the 17 patients who completed 12 months was -0.4 at 3 months, -4.9 at 6 months, -6.5 at 9 months and -7.3 at 12 months. There were also some benefit seen in lung function with FVC change from 84 to 90% and DLCO change from 80 to 88%.

Conclusion:

This study suggested improvements in skin scores in patients treated with imatinib for 12 months, but a very high adverse event rate was noted in this study with high rates of edema and several severe adverse events at a dose of 400 mg/day.

Editorial Comment for abstract #606 and 608:

These are 2 clinical trials examining the use of imatinib for early diffuse scleroderma. There was a substantial amount of preclinical data published on the role of tyrosine kinase pathway and inhibitors in animal and in vitro models of fibrosis in the past1-2 years. These are the first clinical trials examining the use of a tyrosine kinase inhibitor in scleroderma patients.

It is clear from these 2 studies that there are significant side effects from these medications. The drug in both studies was associated with a significant problem with fluid retention, and it is not clear if scleroderma patients have more edema than has been reported in patients with CML or stromal tumors (FDA-labeled indications). It is conceivable, however, that scleroderma patients may have comorbid factors or be using concomitant medications that could exacerbate edema.

The Canadian RCT study (#608 Pope at al.) data is likely too small to make and conclusions about efficacy. The second study (#606 Gordon et al.) did show some improvement in skin scores beginning at the 6 month time point. But this was an open label, non-controlled study, which makes this degree of change difficult to discern from the natural history of diffuse scleroderma. In a recently published study examining the data from prior negative placebo controlled RCT in scleroderma  skin disease, Amjadi et al demonstrate a mean change of -4.83 in the Relaxin trial at 6 months and this change was as high as -6.3 at 6 months in the group with disease duration >4 years. This study also noted that in the oral collagen study there was a mean decrease in skin score of -3.4 at 12 months but the degree of improvement also seemed to increase in those with longer disease duration in that there was a -5.6 change in skin score in the subgroup with disease duration > 4 years. So it is not entirely clear that the changes noted in this study are that different than other negative trials or the natural history of disease.

There likely is, however, sufficient suggestion from this data of possible efficacy and that combined with the substantial preclinical data is enough to pursue further RCT. There are several other Phase II studies ongoing currently that will hopefully further delineate the possible use and safety of this medication in the scleroderma population.

Abstract #1262: Genome-Wide Association Scan in Systemic Sclerosis Identifies MHC Region and Two Additional Susceptibility Loci On 2q32 and 7q32

Authors:

Timothy RDJ Radstake, Behrooz Z. Alizadeh, Rogelio Palomino-Morales, Jasper C. A. Broen, Jose-Ezequiel Martin, Ruben 'T slot, Carmen Simeon, Lorenzo Beretta, Norberto Ortego-Centeno, P. Airo, Gabriela Riemekasten, Miguel A. Gonzalez-Gay, N. Hunzelmann, Anna Pros, MC Vonk, Marieke Coenen, J.M. van Laar, Ariane L. Herrick, R. Hesselstrand, Vanessa Smith, Filip de Keyser, F. Houssiau, Mayte Camps, Patricia E. Carreira, Bernardino Diaz, Paloma de la Peña, Esther F. Vicente, L. Rodriguez-Rodriguez, Jose Román-Ivorra, Antonio Fernández-Nebro, Vicent Fonollosa, Francisca Gonzalez-Escribano, Meng May Chee, Rajan Madhok, Paul Shiels, Rene Westhovens, Wilfride de Baere, Torsten Witte, L. Padyukov, L. Klareskog, J. Worthington, Blanca Rueda, Bobby PC Koeleman and Javier Martin

Background:

This is a genome wide association study in a large number of Caucasian European scleroderma patients compared to healthy controls to identify genes that may associate with susceptibility to scleroderma.  
Methods: This study compared DNA from 842 scleroderma patients to 1711 control subjects using the Illumina human BeadChip covering 370,000 markers. Controls were matched for country of origin. There were 3 populations, 222 Dutch, 223 German and 411 Spanish patients. After quality control ~296,000 SNPs were analyzed. Principal components analysis confirmed differences between the 3 sub-populations, but no differences with controls.

Results:

This study demonstrated associations with several MHC and 5 non-MHC SNPs. These included: STAT4, POLS/TRF4 (a DNA polymerase), EXOC2/IRF4 (regulates TH2 cytokines and B and T cell activation), AMRC9/PSMD1 (involved in ubiquination pathway) and PSD3 (ADP-ribosylation factor of unknown function). The STAT4 gene is of unknown function has been previously reported to be associated with scleroderma and when combined with the US dataset, continued to show significant association with scleroderma.

Conclusion:

This study suggests that there are several candidate genes that may confer susceptibility to scleroderma including some genes already implicated in other autoimmune rheumatic diseases (i.e. STAT4) and perhaps several novel susceptibility candidates as well.

Editorial Comment:

This is one of two large scale genome-wide association studies in scleroderma presented at the ACR meeting this year. The other (#548 below) was carried out in a US population. There were associations seen in both studies with MHC and non-MHC loci showing associations with susceptibility to scleroderma. Some of these loci have been noted in other single-gene studies (STAT4) in several populations (US, European and Japanese) and interestingly also associate with susceptibility to other autoimmune diseases including SLE, Sjogren’s syndrome, rheumatoid arthritis and inflammatory bowel disease. STAT4 is involved in interferon signaling. This European group plans to replicate the top genes in larger cohort combined with other datasets and to stratify by clinical phenotype and auto-antibody status.  

Abstract #548: Genome-Wide Association Study of Systemic Sclerosis in a Large US Cohort of Over 1,500 Cases

Authors:

Olga Gorlova, Shih-Feng Weng, Jun Ying, Fredrick M. Wigley, Laura K. Hummers, Peter K. Gregersen, AnnetteT Lee, Christopher Amos, Frank C. Arnett, Shervin Assassi, Pravitt R. Gourh, Filemon K. Tan, John D. Reveille, J. Lee Nelson, Terry A. McNearney, Michael Fischbach and M. Mayes

Background:

This is a genome wide association study in a large number of European-American Caucasian scleroderma patients compared to healthy controls to identify genes that may associate with susceptibility to scleroderma. 

Methods:

This study was composed of initially 1678 US scleroderma patients from University of Texas Houston, Johns Hopkins University and Fred Hutchinson Cancer Center which was reduced to 1486 after quality control measures. They were compared to 3477 controls from 3 publically available databases selected to reflect the female: male composition of the scleroderma cases of 7:1. This study used the Illumina 550K SNP chip examining >488,000 SNPs. The principal components analysis showed comparability between cases and controls but some genetic variability in the group. Results: The results revealed statistical association with several MHC and non-MHC SNPs with the scleroderma subgroup. There were from 3 non-MHC genes that associated with scleroderma: TSSC1 (tumor suppressing sub-transferable fragment candidate gene 1), TNPO3 (transportin 4, a nuclear import receptor which is in linkage dissociation with IRF5). Since IRF5 (Interferon regulatory factor 5) has been seen in association in several candidate gene studies, that this is the gene that likely explains the association. The group also presented some preliminary data regarding association with phenotype where they examined possible SNP associations with antibody status, but was insufficiently powered to show any clear associations with centromere or topoisomerase antibodies, but there were signals in the MHC region.

Conclusion:

This study suggests that there are several candidate genes that may confer susceptibility to scleroderma in a large genome wide study in a Caucasian US population.

Editorial Comment:

This second genome-wide association study in scleroderma again confirms the presence of MHC gene associations along with the European study. The non-MHC associations were different than the European GWAS group, but when the data were combined, STAT4 and IRF5 remain interesting candidate genes (the European group noted in their presentation an association with IRF5 in the limited subgroup of their analysis). The investigators note further work which will replicate the top gene candidates in a validation cohort as well as additional work to examine gene/phenotype associations.

Abstract #1263: Tyrosine Kinase Inhibitors (TKI) Are Promising Therapeutic Agents for the Proliferative Vasculopathy in SSc

Authors:

Britta Maurer, Nicole Busch, Astrid Jüngel, Renate E. Gay, Georg Schett, Beat A. Michel, Steffen Gay, Jörg HW Distler and Oliver Distler

Background:

This study examined the role of tyrosine kinase inhibition in the Fra-2 transgenic mouse model of scleroderma.

Methods:

This study utilized the Fra-2 transgenic mouse model which shares multiple common features with human scleroderma including endothelial cell apoptosis, decreased capillary density, fibrosis of skin and lung and an obliterative vasculopathy of the lung. The natural history of this mouse includes pulmonary fibrosis, skin fibrosis and pulmonary hypertension.

Results:

These mice were treated with a tyrosine kinase inhibitor (nilotinib) at 8 weeks which significantly reduced evidence of the proliferative vasculopathy in the lung without impacting the lung fibrosis or perivascular inflammation. When staining of alpha smooth muscle actin and von Willebrand factor were employed, the treatment showed evidence of significantly reducing the number of vascular smooth muscle cells without impacting endothelial cells. Untreated Fra-2 mice show increased staining of PDGF receptor beta and c-abl, both of which diminished with nilotinib therapy. They noted decrease in pulmonary vascular wall thickness and obliteration. There was no change in skin fibrosis by histology with treatment. The authors report significant differences in this model compared to the bleomycin mouse model and tight skin mouse model for PDGF2β and c-ABL staining, noting that in the Fra-2 model the staining is in blood vessels. They also note that Fra-2 is expressed the lungs in scleroderma-PAH, the skin of scleroderma patients and in myofibroblasts in blood vessels.
Conclusion: The target for tyrosine kinase inhibitors is variable between different mouse models of scleroderma. In this model, the expression is specific to vascular smooth muscle and tyrosine kinase inhibition reduces the proliferative vasculopathy in the lung.

Editorial Comment:

This is a very interesting mouse model and although does not recapitulate all of the features of scleroderma, may be useful to study particular aspects such as the proliferative vasculopathy (seen both in periphery and lung tissue). This study yields some important insight into possible mechanisms of benefit of tyrosine kinase inhibition in scleroderma. Early reports of clinical trial data in scleroderma patients is conflicting, but doesn’t appear dramatic. This is in contradiction to prior pre-clinical/animal data which made this class of medications quite appealing. This mouse model may yield some insight into mechanisms of this class of drugs in scleroderma patients and possibly lead to new avenues of intervention for scleroderma vascular disease. See further information about this model in recent publication in Circulation (Circulation. 2009: 120:2367-76).

Abstract #604: Improving Survival Despite Greater Disease Burden in Systemic Sclerosis

Authors:

Svetlana I. Nihtyanova, Edward C. Tang, Carol M. Black and Christopher P. Denton

Background:

This study examines trends in outcomes in 2 cohorts of patients out of a single large specialty center.

Methods:  

Two groups of patients were compared, one from a “historical cohort” of 234 patients with disease onset from 1990-1993 and a “contemporary cohort” of 286 patients with disease onset from 2000-2003. These groups were compared in terms of disease severity and survival by Kaplan-Meier survival estimates based disease subset. Organ manifestations were defined by objective criteria. Lung disease by FVC or DLCO <55% or drop of >=15% of these measures during follow up in the presence of fibrosis by CT scan. Renal disease defined by accepted criteria (new onset significant hypertension with >30% drop in GFR) and pulmonary hypertension by right heart catheterization (mean PAP >25 with normal PCWP) and cardiac disease by the presence of arrhythmia, pericardial effusion or heart failure requiring therapy. Survival measured from disease onset of first non-Raynaud symptoms.

Results:

The contemporary cohort had significantly improved survival compared to the historical cohort. The five year survival was 85% in the contemporary cohort of diffuse patients compared with 69% in the historical controls (p=0.018). There was no significant change in survival comparing the two limited cohorts (91 vs. 93 % in the historical and contemporary cohorts, p=0.53).  Among the diffuse subgroups, there were significantly more diagnosed pulmonary complications (both pulmonary fibrosis and pulmonary hypertension) among the contemporary cohort compared to the historical cohort. In the contemporary cohort, 38% developed pulmonary fibrosis compared to 8% of the historical cohort and similarly 7% vs. 1% developed PAH comparing the two groups (p=0.148). In the limited subtype, there was also more pulmonary fibrosis (16% vs. 3%, p<0.001) and pulmonary hypertension (8% vs. 1%, p=0.002) in the contemporary vs. historical cohorts. There was no difference seen in development of renal crisis or clinically significant cardiac disease between the two groups, but had low incidence overall.

Conclusion:

Despite more apparent disease burden in the later cohort with more pulmonary fibrosis and pulmonary hypertension detected in this group, survival in the past 10 years seems to have significantly improved in the patients with diffuse scleroderma.

Comment:

It is very likely that our detection of pulmonary disease has been greatly improved over the 10 years of this study period. Our ability to detect pulmonary disease at an earlier stage may contribute to the improvement in survival seen in this study. For the pulmonary hypertension in particular, it is probably much more likely that a patient has a right heart catheterization than in the past prior to the development of any good therapeutic options. As well, in the past 10 years, there are clearer guidelines for screening and monitoring of pulmonary complications, so there is likely some detection bias in the reported incidence of pulmonary disease. There was no difference seen in the limited group, but may require longer follow up period to ascertain more cases of pulmonary hypertension. There was no data collection on treatment in this group, so determining whether earlier detection led to more therapy was unable to be determined.

Abstract #1717: Predicting Lung Function Decline in Systemic Sclerosis

Authors:

Shikha Mittoo, Keng Wong, David Robinson, Marie Hudson, Murray Barron. Canadian Scleroderma Research Group

Background:

To determine correlation between baseline levels of surfactant protein D and changes in lung function among patients with scleroderma.

Methods:  

Patients from a multi-center observational cohort were included if they had 2 or more PFTs separated by at least 1 year. Annual change in FVC and DLCO was calculated by total change/years of follow up. Changes in these values were correlated with levels of surfactant protein D measured at baseline. Rapid progression was defined as a >2 times the expected rate of decline of the general population (2%/year) for both FVC and DLCO.

Results:

Sixty seven patients were included with mean disease duration of 8.6 years and 60% were categorized as having diffuse cutaneous involvement. Baseline PFTs showed a mean FVC of 94% and DLCO of 72%. The annualized rate of decline for the group was -2.9% predicted/year and -3.3% predicted for FVC and DLCO respectively. 63% were rapid progressors. Rapid progressors had a significantly higher baseline surfactant protein D level. An inverse correlation was seen between surfactant protein D level and FVC (r=-0.27, p=0.03), but not with DLCO. In a multivariate analysis examining potential confounders of age, gender, subtype, disease duration and smoking, surfactant protein D levels remain significantly associated with rapid progression.

Conclusion:

Serum surfactant protein D levels at baseline correlate with decline in lung function over a mean period of 2-3 years. surfactant protein D levels are higher in those patients with more lung function decline.

Editorial Comment:

We still do not have a good way to predict a group of patients that will have progressive decline in lung function. Prior retrospective studies have suggested that BAL neutrophilia and eosinophilia associated with decline in PFT measures in the absence of treatment, but this finding did not hold true in the SLS study (although underpowered to show this). Therefore, easily measurable biomarkers that may predict continued decline in lung function are clearly needed. This study adds to available literature possibly supporting the utility of this marker for this purpose. The retrospective nature of this study may limit its findings somewhat and this marker should be included as a potential biomarker in future studies of patients with lung disease and prospective cohort studies.

Abstract # 450: Close Temporal Relationship Between Onset of Cancer and Scleroderma in Patients with RNA Polymerase I/III Antibodies

Authors:

Ami A. Shah, Antony Rosen, Laura K. Hummers, Fredrick M. Wigley, Livia Casciola-Rosen

Background:

This study examines the relationship between onset of scleroderma and onset of cancer and whether the time between the two diagnoses is different based on clinical or serologic profile and examined auto-antigen expression in tumor histology.

Methods:

Patients were included if they met criteria for diagnosis of scleroderma, had a history of malignancy and had an available serum and tissue specimen sample from their cancer. Sera were tested for anti-centromere, anti-topoisomerase and anti-RNA polymerase I/III antibodies. Paraffin tissue samples from tumors were stained for RNAP polymerase II antibodies.

Results:

Twenty four subjects met entry criteria. Of the 24, 7 had antibodies to RNA polymerase I/III, 5 to topoisomerase I and 8 for centromere (4 with none of those 3 antibodies). The mean duration of scleroderma at time of diagnosis of cancer differed significantly between the groups (centromere and no recognized antibody groups analyzed together). Patients in the RNA Polymerase III group had a mean scleroderma duration of -1 year compared to topoisomerase group (+13 years) and centromere/no antibody group (+5.1 years). Pathology was examined for 3 patients who produce RNA polymerase III antibodies and robust nuclear staining of RNA polymerase III was noted in tumor tissue specimens of all 3 patients. Tissue specimens for matched, non-cancer, non-scleroderma organs showed minimal staining.

Conclusion:

In patients who produce antibodies to RNA polymerase I/III with cancer, the onset of scleroderma and cancer is nearly coincident. In a subset of these patients, tumor sections demonstrate nuclear staining of RNA polymerase.

Editorial Comment:

This study is the first to examine possible mechanistic connection between scleroderma and cancer. Epidemiological studies have suggested an increase in cancer risk among patients with scleroderma compared with the general population, but the reason for this increase in risk is not clear. This study shows a strikingly close disease onset to cancer onset in the subgroup that produces RNA polymerase antibodies. The fact that the tumor expresses RNA polymerase much more highly than control tissue suggests it is conceivable that cancerous tissue may be the source of antigen for the scleroderma-associated immune response. This study is preliminary and needs more control specimens and larger numbers for confirmation of this finding, however.

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