Correspondence

Scleroderma

N Engl J Med 2009; 361:826-827August 20, 2009

Article

To the Editor:

In their review article on scleroderma, Gabrielli et al. (May 7 issue)1 incorporate their earlier observations that all patients with this disease have activating antibodies to platelet-derived growth factor (PDGF) receptors (PDGFRs).2 These antibodies were described as being specific for scleroderma and for chronic extensive graft-versus-host disease, two conditions that share some clinical features. The review does not reflect the current debate on the existence of such antibodies. Researchers from several centers, including ours, have challenged the results of Gabrielli et al.3,4 We did not find evidence of these antibodies in serum samples obtained from two independent cohorts of patients.3 Using different methods, Loizos et al. detected antibodies against PDGFRs in some patients, but these antibodies were also detected in healthy people and did not have agonist activity.4 We believe it is incorrect to conclude that the mechanism of this disease is linked to stimulating autoantibodies directed against PDGFRs.

Jean-Baptiste Demoulin, Ph.D.
Université Catholique de Louvain, Brussels, Belgium
jb.demoulin@uclouvain.be

Olle Kämpe, M.D., Ph.D.
Fredrik Rorsman, M.D., Ph.D.
Uppsala University Hospital, Uppsala, Sweden

4 References

1. 1

   Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009;360:1989-2003
   Full Text | Web of Science | Medline

2. 2

   Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-2676
   Full Text | Web of Science | Medline

3. 3

   Classen JF, Henrohn D, Rorsman F, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 2009;60:1137-1144
   CrossRef | Web of Science | Medline

4. 4

   Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145-1151
   CrossRef | Web of Science | Medline

To the Editor:

Gabrielli et al. state that transforming growth factor β (TGF-β) “is a potent profibrotic cytokine,” but this is not accurate. Only the TGF-β1 isoform plays a critical role in fibrosis, whereas the TGF-β2 and TGF-β3 isoforms may have antifibrotic effects.1 One study showed a reduction in expression of a profibrotic procollagen α2 type I messenger RNA variant in embryonic University of California at Davis (UCD) line (UCD-200) chicken fibroblasts by TGF-β2,1 whereas another showed no significant difference in levels of TGF-β3 in patients with scleroderma and controls.2 Concentrations of TGF-β1 are increased in the bronchoalveolar-lavage fluid of patients with scleroderma, whereas TGF-β2 levels are reduced, as compared with controls.3 TGF-β1 has also been shown to induce fibrosis in the distal colon in patients with scleroderma.4 These studies underscore the role of TGF-β1 as an important cytokine in scleroderma.

Roger Kapoor, M.D., M.B.A.
Massachusetts General Hospital, Boston, MA

John R. Kapoor, M.D., Ph.D.
Stanford University, Palo Alto, CA

4 References

1. 1

   Prelog M, Scheidegger P, Peter S, Gershwin ME, Wick G, Sgonc R. Diminished transforming growth factor beta2 production leads to increased expression of a profibrotic procollagen alpha2 type I messenger RNA variant in embryonic fibroblasts of UCD-200 chickens, a model for systemic sclerosis. Arthritis Rheum 2005;52:1804-1811
   CrossRef | Web of Science | Medline

2. 2

   Coker RK, Laurent GJ, Jeffery PK, du Bois RM, Black CM, McAnulty RJ. Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung. Thorax 2001;56:549-556
   CrossRef | Web of Science | Medline

3. 3

   Meloni F, Caporali R, Marone Bianco A, et al. BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21:111-118
   Web of Science | Medline

4. 4

   Vallance BA, Gunawan MI, Hewlett B, et al. TGF-beta1 gene transfer to the mouse colon leads to intestinal fibrosis. Am J Physiol Gastrointest Liver Physiol 2005;289:G116-G128
   CrossRef | Web of Science | Medline

Author/Editor Response

We emphasize, in response to Demoulin et al., that our review article on scleroderma focused on a critical survey of available clinical and biologic data in scleroderma to reduce ambiguity and advance a testable model of a common mechanism underlying the disease. The anti-PDGFR and anti–topoisomerase I autoantibodies were not the main focus of the review, and the sentence “the specificity of these stimulatory antibodies remains to be established” reflects the current knowledge on this issue. We have not discussed the controversy regarding their presence in scleroderma, because the two articles challenging our findings1,2 were published after the submission of our review.

The experiments described in the two articles show contradictory results: one finds the antibodies in normal controls and patients2; the other does not find any antibodies.1 In one case, the IgG preparations were contaminated by PDGF.1 The assays performed by the two groups were carried out in conditions that were different from those described in our original article in 2006.3

In response to Kapoor and Kapoor: because of space constraints, we did not discuss the function or functions of the three TGF-β isoforms. TGF-β1 is a potent stimulator of collagen, whereas the functions of the other TGF-β isoforms in scleroderma are still elusive.4 In our article, we refer to TGF-β1 as TGF-β.

Armando Gabrielli, M.D.
Università Politecnica delle Marche, Ancona, Italy
a.gabrielli@univpm.it

Enrico V. Avvedimento, M.D.
University of Naples Federico II, Naples, Italy

Thomas Krieg, M.D.
University of Cologne, Cologne, Germany

4 References

1. 1

   Classen JF, Henrohn D, Rorsman F, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 2009;60:1137-1144
   CrossRef | Web of Science | Medline

2. 2

   Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145-1151
   CrossRef | Web of Science | Medline

3. 3

   Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-2676
   Full Text | Web of Science | Medline

4. 4

   Sgonc R, Wick G. Pro- and anti-fibrotic effects of TGF-beta in scleroderma. Rheumatology (Oxford) 2008;47:Suppl 5:v5-v7
   CrossRef | Web of Science | Medline