Michael Junger and 2Anja Schlez

1Department of Dermatology of the Ernst-Moritz-Arndt-University, Greifswald, Germany 2Department of Dermatology of the Eberhard-Karls-University, Tübingen, Germany

Circulatory disorders of the extremities in the form of Raynaud's phenomenon belong to the earliest clinical manifestations of systemic scleroderma. The patients complain of cold hands and feet, stiffjoints, and loss of mobility in the extremities. Later cutaneous manifestations of the disease include edematous swelling in the extremities and, in more extreme cases, often very painful, refractory acral necroses.

Nutritive Nailfold Capillaries

Characteristic changes in microcirculation can affect function or morphology. Morphological changes of the nailfold capillaries in systemic sclerosis (SSc) have been studied extensively. The illness is characterized from the very onset by cutaneous microangiopathy in the form of aneurysms, capillary rarefaction and microthromboses, and the development of megacapillaries [1]. Morphological changes of nailfold capillaries are detected in more than 90 percent of patients [2].

For quantitative evaluation of human TV nailfold capillary microscopy a new semiautomated image-analyzing system called "CapiShape" was presented. The outer limits or boundaries are recognized by a special image processing algorithm to describe the shape of capillaries [3].

Enhanced Transcapillary and Interstitial Diffusion

By means of video microscopy after intravenous injection of sodium fluorescein (NaF) and indocyanin green as tracers, a more accurate morphological description became possible, providing measurements of the diameters of the capillary lumen, red blood cell column, plasma layer, and pericapillary halo. Halo diameter was significantly increased at the apex only and not at the two capillary limbs. This finding confirms the visual impression of "apical capping" after NaF injection as a important sign for micro-angiopathy due to collagen vascular disease [4].

Other morphological changes observed with the disease include vascular obliteration and excessive collagen production in the pericapillary area [5]. In many patients, these changes preceded detection of autoantibodies [6].

Reduced Capillary Flow and Pressure

The capillaries of the skin not only undergo morphological changes, but also display functional deficits. Both blood flow velocity and capillary pressure in the nailfold capillaries of SSc patients were significantly lower than in healthy volunteers [7]. Cold exposure leads to a marked slowing of blood flow velocity in the capillaries of the patients, in extreme cases to the point of stasis [8].

These pathological dysfunctions are documented by means of intravital capillaroscopy combined with a cold provocation challenge. In contrast to healthy persons, patients with SSc usually react to cold with prolonged stasis. Vasodilators or the application of heat increases blood cell velocity. Capillaroscopy in combination with a special video image analysis method allowed us to quantify changes in blood cell velocity.

In Vivo Proof of Endothelial Dysfunction

Recently endothelial function, a factor in the regulation of perfusion, was examined in detail in SSc patients and healthy volunteers by administering intracapillary microinjections of vasoactive substances and monitoring the resulting endothelium-dependent (acetylcholine) or endothelium-independent (sodium nitroprusside) vasodilatation, increase in vascular diameter, and decrease in blood flow velocity. The microinjection method used for the first time in this study made it possible to establish that endothelium-independent vasomotion is substantially disturbed in patients with scleroderma [9].

Intimal damage to the blood vessels of SSc patients was already demonstrated serologically in studies showing elevated levels of anti-bleeding factor, endothelin-1 and ACE [10-12]. The trigger for the endothelial damage is still unknown. One potential cause presently under discussion is a vasculopathy caused by cytomegalovirus or parvovirus B19 [13]. Recently, it was possible to show that autoanti-bodies to human cytomegalovirus cause the apoptosis of endothelial cells in systemic scleroderma patients [14].

Therapeutical Effects to the Microcirculation of the Skin

The treatment of cutaneous circulatory problems can range from general measures such as protecting the hands from cold, exercise therapy, and lymph drainage to the use of vasoactive medication such as the prostanoids.

Numerous studies have demonstrated the efficacy of prostaglandin E1 in the treatment of vasospastic and obliter-ative vascular diseases [15, 16]. In almost all studies to date on the use of prostaglandin E1 to treat collagen diseases, medication was given intravenously. The first clinical studies on iloprost for secondary Raynaud's phenomenon were carried out in Europe. They included open [17], crossover, placebo-controlled [18], controlled single-blind [19], and iloprost/nifedipine comparison studies [20]. Watson summarized the European studies in a meta-analysis. Overall, iloprost led to a 20 to 30 percent reduction in the number of Raynaud's episodes. Iloprost was also more effective than placebo in the treatment of ischemic ulcerations. In an American double-blind study on iloprost, of 35 patients with secondary Raynaud's phenomenon, seven patients in the ilo-prost group and four patients in the placebo group had ischemic lesions. After a treatment period of 10 weeks, six of the seven patients in the iloprost group experienced complete healing of the lesions on their fingers, whereas the ulcerations failed to heal in any of the patients of the placebo group [16]. The transdermal application of prostaglandin Ej ethyl ester was also shown to have a favorable effect on nutritive blood flow in the capillaries of the skin in systemic scleroderma patients. The patients experienced clinical benefits: The number of Raynaud's episodes dropped and the trophic skin lesions began to heal [21, 22].

Clinical improvement, that is, abating Raynaud's attacks, is accompanied by an improvement of nutritive cutaneous blood flow shown in decreased blood flow stasis times. Thus the assessment of capillary blood flow in response to cold challenge has prognostic value.

Glossary

Halo: The bright yellow fluorescence of the pericapillary interstitial space after intravenous injection of sodium fluorescein.

Stasis: Blood flow stops in the nailfold capillaries, particularly after cold exposure. It can be observed by means of capillaroscopy.

Systemic scleroderma: A rare, chronic autoimmune disease. The systemic forms can affect any part of the body (skin, blood vessels, and internal organs). The systemic forms of scleroderma cause fibrosis (scar tissue) to be formed in the skin and/or internal organs. The function of the diseased organs is impaired.

References

1. Maricq, H. R., LeRoy, E. C., D'Angelo, W. A., Medsger, T. A. Jr, Rodnan, G. P., Sharp, G. C., and Wolfe, J. F. (1980). Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders. Arthritis. Rheum. 23, 183-189.

2. Grassi, W., Medico, P. D., Izzo, F., and Cervini, C. (2001). Microvascular involvement in systemic sclerosis: capillaroscopic findings. Semin. Arthritis. Rheum. 30, 397-402.

3. Hu, Q., and Mahler, F. (1999). New system for image analysis in nail-fold capillaroscopy. Microcirculation 6, 227-235.

4. Brulisauer, M., and Bollinger, A. (1991). Measurement of different human microvascular dimensions by combination of videomicroscopy with Na-fluorescein (NaF) and indocyanin green (ICG) in normals and patients with systemic sclerosis. Int. J. Microcirc. Clin. Exp. 10, 21-31.

5. LeRoy, E. C. (1996). Systemic Sclerosis. A vascular perspective. Rheum. Dis. Clin. North. Am. 22, 675-694.

6. Jünger, M., Klyscz, T., and Hahn, M. (1998). Clinical relevance of cutaneous microangiopathy in systemic sclerosis (SSc). JEADV 1 (Suppl. 2), 202. Morphological changes of capillaries in scleroderma patients preceded detection of autoantibodies.

7. Hahn, M., Heubach, T., Steins, A., and Jünger, M. (1998). Hemody-namics in nailfold capillaries of patients with systemic scleroderma: Synchronous measurements of capillary blood pressure and red blood cell velocity. J. Invest. Dermatol. 110, 982-985. This study show that blood flow velocity and capillary pressure in nailfold capillaries of SSc patients were significantly lower than in healthy volunteers.

8. Hahn, M., Klyscz , T., Jünger, M., and Rassner, G. (1995). Local cold exposure test as therapy control in patients with Raynaud's phenomenon: Comparison between laser Doppler fluxmetry and simultaneous red blood cell velocity measurements in nailfold capillaries. Br. J. Dermatol. 133, 704-709.

9. Schlez, A., Kittelm, M., Braun, S., Häfner, H. M., and Jünger, M. (2003). Endothelium-dependent regulation of cutaneous microcirculation in patients with systemic scleroderma. J. Invest. Dermatol. 120, 332-334.

10. Maeda, M., Kachi, H., Takagi, H., and Kitajima, Y. (1997). Is there cir-cadian variation of plasma endothelin (ET-1) in patients with systemic scleroderma (SSc)? J. Dermatol. Sci. 16, 38-44.

11. Gordon, M. M., and Madhok, R. (1996). Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J. Rheumatol. 23, 788-789.

12. Herrick, A. L., Illingworth, K., Blann, A., Hay, C. R., Hollis, S., and Jayson, M. I. (1996). Von Willebrand factor, thrombomodulin, throm-boxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Ann. Rheum. Dis. 55, 122-127.

13. Ferri, C., Zakrzewska, K., Longombardo, G., Giuggiols, D., Storino, F., Pasero, G., and Azzi, A. (1999). Parovirus B19 infection of bone marrow in systemic sclerosis patients. Clin. Exp. Rheumatol. 17, 718-720.

14. Lunardi, C., Bason, C., Navone, R., Millo, E., Damonte, G., Corrocher, R., and Puccetti, A. (2000). Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat. Med. 6, 1183-1186.

This study shows that autoantibodies to human cytomegalovirus cause the apoptosis of endothelial cells in systemic scleroderma patients.

16. Fagrell, B., Lundberg, G., Ollson, A., and Östergen, J. (1986). PgE1 treatment of severe skin ischaemia in patients with peripheral arterial insufficiency—the effect of skin microcirculation. Vasa 15, 56-60.

17. Rademaker, M., Thomas, R. H., Provost, G., Beacham, J. A., Cooke, E. D., and Kirby, J. D. (1987). Prolonged increase in digital blood flow following iloprost infusion in patients with systemic sclerosis. Postgraduate Medical Journal 63, 617-620.

18. McHugh, N. J., Csuka, M., Watson, H., Belcher, G., Amadi, A., Ring, E. F., Black, C. M., and Maddison, P. J. (1988). Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic Sclerosis. Ann. Rheum. Dis. 47, 43-47.

19. Kyle, V., Parr, G., Salisbury, R., Thomas, P. P., and Hazleman, B. (1985). Prostaglandin-E1 vasospastic disease and thermography. Ann. Rheum. Dis. 44, 73-78.

20. Rademaker, M., Cooke, E. D., Almond, N. E., Beacham, J. A., Smith, R. E., Mant, T. G., and Kirby, J. D. (1989). Comparision of intravenous infusion of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis. BMJ 298, 561-564.

21. Schlez, A., Kittel, M., Scheuerle, B., Diehm, C., and Jünger, M. (2003). Transdermal application of prostaglandin E1 ethyl ester for treatment of trophic acral skin lesions in a patient with systemic scleroderma. JEADV16, 526-528. 22. Schlez, A., Häfner, H. M., Kittel, M., Braun, S., Diehm, C., and Jünger, M. (2003). Systemic scleroderma patients have improved skin perfusion after the transdermal application of PGE1 ethyl ester. Vasa 32, 83-86.

Capsule Biography

Dr. Jünger was responsible for angiology and phlebology in the Department of Dermatology in Greifswald. He has headed the Department of Dermatology at the University of Greifswald since 2001. Systematically he and his coworkers examined the microangiopathy of the skin in patients with chronic venous disease. His work was supported by grants from the Deutsche Forschungsgemeinschaft and the German Society of Phlebology.

Dr. Schlez has worked in the Department of Dermatology of the University in Tübingen, Germany, since 1997. Systematically she and her coworkers examined the microangiopathy of the skin in patients with scleroderma and chronic venous disease. Her work was supported by a grant of the German Scleroderma Foundation.

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