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The Different Photoplethysmographic Patterns Can Help to Distinguish Patients With Primary and Sclerodermic Raynaud Phenomenon
CLINICAL INVESTIGATION
The Different Photoplethysmographic Patterns Can Help to Distinguish Patients With Primary and Sclerodermic Raynaud Phenomenon Edoardo Rosato, MD, PhD, Carmelina Rossi, MD, Federica Borghese, MD, Ilenia Molinaro, Simonetta Pisarri, MD and Felice Salsano, MD
Abstract: Introduction: The aim of this study is to investigate pulsatility of digital arteries of hands by means of photoplethysmography (PPG) in patients with primary Raynaud phenomenon (PRP) and systemic sclerosis (SSc) and to compare the results with those obtained in healthy controls. Methods: One hundred five patients with SSc, 96 patients with PRP and 85 healthy controls were recruited in this study. Nailfold videocapillaroscopy and PPG were performed in healthy controls and patients. In patients with SSc, the capillaroscopic pattern was classified as early, active and late group pattern. A baseline PPG was recorded simultaneously in all 10 fingers of the hands. The photoplethysmographic curves were evaluated for morphology and amplitude of sphygmic wave. Results: In healthy controls group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc and 2 subsets of disease. Conclusion: PPG represents a technique noninvasive to evaluate simultaneously in all 10 fingers of hands digital arteries pulsatility. PPG improves the evaluation of vascular damage in patients with primary and sclerodermic RP. Key Indexing Terms: Photoplethysmography; Raynaud phenomenon; Systemic sclerosis. [Am J Med Sci 2010;340(6):457–461.]
T
he term Raynaud phenomenon (RP) is used to describe the episodic events that represent vasoconstriction of the digital arteries, precapillary arterioles and cutaneous arteriovenous shunts. It typically starts in 1 or several digits after exposure to the cold or a stressful situation and then spreads symmetrically to all fingers of both hands. Primary Raynaud phenomenon (PRP) is characterized by symmetric attacks, absence of tissue necrosis, ulceration or gangrene, absence of a secondary cause, normal nailfold capillaries, a negative test for antinuclear antibodies, normal erythrocyte sedimentation rate and normal value of the C-reactive protein.1,2 Systemic sclerosis (SSc) is a disorder characterized by alterations of the microvasculature, dysfunction of the immune system and deposition of collagen in connective tissue. Vascular impairment, a main feature of the pathogenesis of SSc, involves both the macro- and the microvasculature. Vascular symptoms are the major prognostic factors for SSc, with a following general outcome depending on the extent and severity of vascular lesions.3 Irrespective of the
From the Department of Clinical Medicine, Clinical Immunology UnitScleroderma Center, Sapienza University of Rome, Rome, Italy. Submitted January 23, 2010; accepted in revised form June 23, 2010. Correspondence: Felice Salsano, MD, Department of Clinical Medicine, Sapienza University of Rome, Viale dell’Universita` 37, Rome 00185, Italy (E-mail: [email protected]).
classification of the disease, SSc is typically associated with RP.4 RP secondary to SSc is characterized by microvascular damage and high plasma adrenomedullin and endothelin-l levels.5–7 Capillaroscopy is crucial to differentiate between PRP and secondary RP.8,9 Actually nailfold videocapillaroscopy (NVC) represents the best method to analyze microvascular damage in rheumatic diseases. In healthy subjects, the microvascular pattern is characterized by a regular array of microvessels with large intra- and interindividual variability. The presence of megacapillaries and a decreased capillary density are the hallmarks of the SSc capillary pattern, which can be detected by nailfold capillaromicroscopy. Recently, 3 defined major NVC patterns have been considered useful for assessing the appearance and the progression of sclerodermic microangiopathy (“early,” “active” and “late” patterns).10,11 Today, noninvasive and invasive examination techniques have become a common method of assessing peripheral vascular perfusion: color-coded duplex Doppler ultrasonography, angiography, computed tomography, magnetic resonance angiography and laser Doppler perfusion image.12–15 Actually, photoplethysmography (PPG) occupy a indefinite position among these methods in the RP assessment. The first photoelectric plethysmography was described in the 1930s. Today, PPG systems operate in near infrared light and allow the transcutaneous registration of venous and/or arterial blood volume changes in the skin vessels. In this wavelength range, hemoglobin in the blood absorbs much more strongly than the remaining tissue. Wavelengths around 900 nm are most suitable because they combine good penetration with good contrast between the dark vessels and the light tissue. The simplest PPG sensor consists of an IR-LED and a photodetector. In quantitative PPG, the optical illumination is automatically adjusted for each different type of skin until a predetermined level of reflected light is reached. With this technology, PPG measurements are independent of skin color, thickness and individual blood volume, so that interindividual registrations and registrations with different devices can be compared. Arterial PPG detects the pulse-related changes in skin blood volume and has a limited penetration depth, reflecting pulsatile blood volume changes of the skin including the plexus.16 The main applications of PPG include the muscle pump test (assessment of calf pump failure in chronic venous insufficiency), vein occlusion test (thrombotic obstruction), venous resting pressure test, arterial perfusion test, peripheral arteriosclerosis quantification, vascular responses to drugs, macro- and microcirculatory assessment of cold sensitivity after traumatic finger amputation and microsurgical replantation.17–19 PPG was also used to quantify the vascular damage in hand-arm vibration syndrome. Therefore, its application in RP is limited to evaluate response of digital arteries to cold test and drugs.20,21 This study was designed to assess whether PPG can help to distinguish likely patients with idiopathic and sclerodermic RP.
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TABLE 1. Epidemiological and clinical features of the patients with SSc (n ⫽ 105) Sex (female/male) Age (mean ⫾ SD) (yr) SSc duration since diagnosis (yr), mean ⫾ SD Raynaud phenomenon duration (yr), mean ⫾ SD Subseta (n) dcSSc/lcSSc ANA pattern, n (%) Speckled Speckled and nucleolar Nucleolar Centromere SSc-specific autoantibody, n (%) Antitopoisomerase I Anticentromere antibody None DAIb DSIc
94/11 55.6 ⫾ 12.6 7.2 ⫾ 17.5 13 ⫾ 110.5 41/64 20 (19) 12 (11) 20 (19) 53 (50) 33 (31) 53 (51) 19 (18) 2.1 ⫾ 11.8 4.5 ⫾ 12.6
a
Subset according to LeRoy et al.23 Disease Activity Index (DAI) according to Valentini et al.24 c Disease Severity Index (DSI) according to Medsger et al.25 dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; ANA, antinuclear antibodies. b
METHODS Subjects One hundred five patients with SSc (94 women and 11 men; mean age, 55.6 ⫾ 12.6 years), who were admitted to the Clinical Immunology Unit of Sapienza University of Rome from January 2000 to December 2007, were recruited for this study. All patients fulfilled the American College of Rheumatology criteria for the diagnosis of SSc,22 and the patients were grouped according to whether they had limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc).23 Table 1 lists the main baseline epidemiological and clinical features of the patients. Disease activity and disease severity in SSc were measured by means the Scleroderma Disease Activity Score by Valentini et al24 and the Disease Severity Scale by Medsger et al25, respectively. Ninety-six patients (81 women and 15 men; mean age, 36 ⫾ 18 years) who fulfilled the PRP criteria2,26 were also studied. In patients with PRP, the RP duration (mean ⫾ SD) is 13 ⫾ 14 years. Eighty-five healthy controls with negative test for antinuclear antibodies (73 women and 12 men; mean age 47 ⫾ 11 years) were enrolled in this study. All patients with SSc had been previously treated with iloprost and nifedipine, but iloprost had been discontinued at least 6 months before recruitment and nifedipine at least 2 weeks before recruitment. The majority of patients with RP had been previously treated with nifedipine, but nifedipine was discontinued at least 2 weeks before recruitment. The subjects’ written consent was obtained according to the Declaration of Helsinki, and the design of the work conforms to standards currently applied in the country of origin. Exclusion criteria included those who were unable to give informed consent, actual therapy with prostacyclin analogues and/or endothelin receptor antagonists and/or phosphodiesterase 5 inhibitors subjects with a history of uncontrolled systemic hypertension, hyperlipidemia, cardiac failure, hepatic
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failure, diabetics, peripheral vascular disease, coagulopathy, smokers and pregnant or breastfeeding women. Digital Photoplethysmography PPG was performed out using a Termoflow machine (Microlab Elettronica Sas, Pordenone, Italy). Termoflow, a computerized system, allows the simultaneous photoplethysmographic detection out of 10 fingers. Transducers fixed on the distal phalanx of each finger and insensitive to ambient light are optically calibrated to ensure uniformity of the response of the system “finger-transducer.” The person who analyzed the PPG results was blinded to patient diagnosis and NVC. Baseline tracings of all digits of both hands were acquired in a quiet, air-conditioned room (24°C ⫾ 0.4°C) when the subjects were accustomed to the room temperature after around 20 minutes. Patients and healthy controls were not allowed to drink coffee and alcoholic beverages for 2 days before the examination. The acquired photoplethysmographic curves are evaluated for morphology and amplitude of sphygmic wave. For the evaluation of pattern, the authors have used morphology and amplitude of sphygmic wave. A homogeneous pattern was defined as a pattern showing uniformity of morphology and amplitude of sphygmic wave in all 10 fingers. A dyshomogeneous pattern was characterized by different morphology in 2 or more fingers of each hand with mean variation of sphygmic wave amplitude ⱖ15% in 2 or more fingers of each hand. The magnitude of sphygmic wave was expressed as percentage of maximum value of sphygmic wave amplitude. This maximum value is done by constructor of Termoflow machine and is equivalent to pulsatility of brachial artery. The magnitude of sphygmic wave was calculated as mean value of magnitude of sphygmic wave of all 10 fingers of both hands. In patients with SSc with sclerodactyly, PPG was performed only when the maximal maximum flexion of the fingers, evaluated as the point of maximum distance from the surface, was ⬍5 mm. In fact, in our experience, the sclerodactyly with a flexion of the fingers ⬍15 mm does not cause significant changes in the digital PPG parameters. Nailfold Videocapillaroscopy NVC was performed in a quiet, air-conditioned room (24 ⫾ 0.4°C) when the subjects were accustomed to the room temperature after approximately 20 minutes. Another operator performed the NVC in each patient by using an optical probe videocapillaroscopy equipped with magnification 100⫻ contact lens and connected to image analysis software (Pinnacle Studio, Version 8; Pinnacle Systems, Mountain View, CA). Each subject was inside the building for a minimum of 15 minutes before the nailfold was examined at a room temperature of 20°C to 22°C. The nailfold (distal row) of the second, third, fourth and fifth finger was examined in each patient. The following capillaroscopic parameters were considered according to previous observations: presence of enlarged and giant capillaries, hemorrhages, loss of capillaries, disorganization of the microvascular array and capillary ramifications. According to Cutolo et al,10,11 the patterns identified within the “SSc pattern” include: “early” NVC pattern: few enlarged/giant capillaries, few capillary hemorrhages, relatively well-preserved capillary distribution and no evident loss of capillaries; “active” NVC pattern: frequent giant capillaries, frequent capillary hemorrhages, moderate loss of capillaries, mild disorganization of the capillary architecture, absent or mild ramified capillaries; and “late” NVC pattern: irregular enlargement of the capillaries, few or absent giant capillaries and hemorrhages, severe loss of capillaries with extensive avascular areas, disorVolume 340, Number 6, December 2010
Photoplethysmography and Raynaud Phenomenon
FIGURE 1. (A) In healthy controls, photoplethysmographic pattern is homogeneous, and sphygmic wave amplitude is high. (B) In patients with systemic sclerosis, photoplethysmographic pattern is dyshomogeneous, and sphygmic wave amplitude is reduced. (C) in patients with Raynaud phenomenon, photoplethysmographic pattern is homogeneous, and sphygmic wave amplitude is markedly reduced.
ganization of the normal capillary array and ramified/bushy capillaries. Statistical Analysis All the results were expressed as mean ⫾ standard deviation. Commercially available software (SPSS version 12.0; SPSS, Chicago, IL) was used for the statistical analysis. The 2 test was used for categorical variables. Impaired Student t test was used for numeric variables. Correlation coefficient (r) was used to evaluate correlation negative or positive between numerical variables. All calculated P values were 2 -tailed, and P values ⬍0.05 were considered significant.
RESULTS In the healthy controls and patients with RP, the pattern of PPG was homogeneous. Conversely, in the patients with SSc, the photoplethysmographic pattern was dyshomogeneous. Digital PPG showed a homogeneous pattern in the 96% of healthy controls (82 of 85), 96% of PRP (92 of 96) and 26% of patients with SSc (27 of 105) (Figure 1). The presence of homogeneous pattern was significantly (P ⬍ 0.001) lower in patients with SSc than in healthy controls and patients with RP. We did not find any significant difference in the homogeneous pattern presence between patients with PRP and healthy controls (Table 2). In the 3 groups of the study population, the mean value of sphygmic wave amplitude is significantly different. The mean value of sphygmic wave amplitude is lower (⬍0.0001) in the PRP group than in SSc group (11 ⫾ 10 versus 24 ⫾ 24). The mean value of sphygmic wave amplitude is lower (⬍0.0001) in the SSc group than in healthy controls (24 ⫾ 24 versus 56 ⫾ 19; Table 2). To distinguish between patients with SSc and PRP, the photoplethysmographic pattern have demonstrated an good sensitivity (74% confidence interval, 66%– 82%) and high specificity (96% confidence interval, 92%–99%). Significant differences have not been observed between disease subset (limited cutaneous SSc and diffuse cutaneous SSc) and photoplethysmographic pattern and mean value of sphygmic wave amplitude. The study of correlations between mean value of sphygmic wave amplitude and Raynaud duration not showed a © 2010 Lippincott Williams & Wilkins
relation that is statistically significant (r ⫽ 0.01 and P value ⬎ 0.05). In addition, between mean value of sphygmic wave amplitude and disease duration, no relative statistically significant value was observed (r ⫽ 0.03 and P value ⬎ 0.05). Dyshomogeneous pattern is significantly (P ⬍ 0.001) different in 3 capillaroscopic pattern. In early capillaroscopic group, a dyshomogeneous pattern is present in 91% of patients; in active capillaroscopic group, a dyshomogeneous pattern is present in 94% of patients; and in late capillaroscopic group, a dyshomogeneous pattern is present in only 19% of patients (Table 2). In addition, mean value of sphygmic wave amplitude is significantly different in 3 capillaroscopic groups of patients. In late capillaroscopic group, mean value of sphygmic wave amplitude is lower than in active capillaroscopic groups (4 ⫾ 8 versus 20 ⫾ 15), and in early capillaroscopic group, this value is significantly higher than in active and late groups (Table 2). In the late capillaroscopic group, mean value of sphygmic wave is statistically (P ⫽ 0.002) lower than PRP group (4 ⫾ 8 versus 11 ⫾ 10). In Table 3, we synthesized the findings of PPG.
TABLE 2. Findings of photoplethysmography in study population
Healthy controls (85) Patients with PRP (96) Patients with systemic sclerosis (105) Capillaroscopic pattern Early (43) Active (36) Late (26)
Homogeneous pattern, N (%)
Sphygmic wave amplitude (%) (mean ⴞ SD)
81 (95.3) 92 (96) 27 (26)
56 ⫾ 19 11 ⫾ 10 24 ⫾ 24
4 (9) 2 (6) 21 (81)
40 ⫾ 28 20 ⫾ 15 4⫾8
PRP, primary Raynaud phenomenon.
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TABLE 3. Photoplethysmography findings in study population
Healthy controls Patients with RP Patients with systemic sclerosis Capillaroscopic pattern Early Active Late
Homogeneous pattern
Sphygmic wave amplitude (%) (mean ⴞ SD)
Present Present Absent
56 ⫾ 19 11 ⫾ 10 24 ⫾ 24
Absent Absent Present
40 ⫾ 28 20 ⫾ 15 4⫾8
RP, Raynaud phenomenon.
DISCUSSION Vascular dysfunction is one of the hallmarks of SSc and involves both the macro- and microvasculature.27 Several techniques have been developed to study the function of the microcirculation: transcutaneous oxygen tension, NCV, orthogonal polarization spectral imaging, thermal infrared imaging and LDPI.28 Color-coded duplex Doppler ultrasonography, computed tomography, arteriography and magnetic resonance angiography are used to evaluate peripheral arteries.12–14 Actually, arteriography represents the best method to analyze damage of peripheral arteries in the SSc. The arteriographic changes of the vessels in SSc are smooth and tend to show tapering segmental lesions in the distal vessels. Vascular involvement in SSc has been believed to be limited to digital arteries. It is extremely rare that patients with SSc without vascular risk factors have macrovascular lesions above the elbow or knee. However, a relatively high incidence of vascular involvement between the digits and the elbow or knee has been described.29 Previous studies have shown that PPG is able to quantify the vascular damage in hand-arm vibration syndrome and to evaluate response of digital arteries to cold test and drugs.20,21 For the first time, our study shows that in a representative group of patients, PPG is a useful noninvasive diagnostic technique for evaluating function of digital arteries of hands in patients with PRP and SSc. In the study population, we can demonstrate that photoplethysmographic pattern, simultaneously recorded in all 10 fingers of hands, is different in the 3 groups of subjects and 3 capillaroscopic groups. In healthy control group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The vascular system of acral parts of the body has major thermoregulatory functions and, as such, is influenced by environmental temperature. Therefore, RP affects primarily digits or toes. Primary and secondary RP seem to have in common an unphysiologically increased contractile response to sudden cooling and to ␣2-adrenergic agonists.5 We can suppose that PPG dyshomogeneity is related to variable degree of vasospasm in digits of patients with SSc. Therefore, it needs more PPG studies to evaluate blood flow
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directly at baseline and after cold challenge in all the digits to show difference in cold-induced vasospasm in SSc digits. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc. The capillaroscopic early group is easily distinguishable for the absence of homogeneous photoplethysmographic pattern and high mean value of sphygmic wave amplitude. The capillaroscopic active group is characterized by dyshomogeneous photoplethysmographic pattern, and the mean value of sphygmic wave amplitude comprised between the two other capillaroscopic groups. In the late capillaroscopic group, mean value of sphygmic wave amplitude is low, and the photoplethysmographic pattern is homogeneous for absence or extreme reduction of sphygmic wave. In patients with PRP, the digital arteries does not have structural alteration have been demonstrated with ultrasonographic studies. The diameter and flow volume of the digital and ulnar arteries of the patients with RP, evaluated by dynamic Doppler, were lower at rest, but resistive index was significantly high in all arteries. After cold provocation, the diameters of the radial and ulnar arteries and the flow volume of the digital arteries of the patients were significantly lower than those of the controls.30 Instead, in patients with secondary RP, color Doppler ultrasonography shows structural arterial damage in 63% of patients: narrowing, chronic occlusion and acute occlusions.31 These ultrasonographic changes correspond to histological damage characterized by endothelial cell injury, platelet activation and thrombosis, increased synthesis of extracellular matrix molecules and a hypertrophic and fibrotic remodeling of the blood vessels with progressive lowering of the inner vascular diameters. In addition to increased contractile responses, secondary RP in SSc is also characteristically associated with structural alterations of the involved vessels. Structural vascular abnormalities of both the microvasculature and digital artery are well recognized in SSc. In secondary RP, structural vascular changes in small- and medium-sized arteries lead to fixed narrowing of the lumen. These structural vascular changes (intimal proliferation and fibrosis) are more evident in the final stages of illness. Fibrotic intimal hyperplasia is a main characteristic in this context, and it usually precedes the loss of vascular elasticity and the increasing luminal narrowing. As a result of this fibrotic intimal hyperplasia, these vessels cannot compensate for a major impairment of blood flow during severe attacks of secondary RP. This then leads to critical impairment of blood flow and to so-called ischemia-reperfusion reactions. They may include activation of endothelial adhesion molecules, higher release of vasoconstrictors or reduced release of vasodilators, increase of oxygen radicals and of other toxic products that could modify antigens to induce autoimmunity, activation of platelets with release of the vasoconstrictors serotonin and thromboxane and possibly a procoagulant endothelial surface. These factors increase the propensity for new attacks of RP and, thus, induce further structural alterations of the vessels, a vicious circle.5 Future prospective studies will need to see whether patients with SSc develop digital ulcers in the fingers with reduced or absent pulsatility. It would also be important to assess if patients with RP and those with positive test for antinuclear antibodies present different PPG patterns and if any pattern is associated with an increased risk of developing the disease. In conclusion, we can suppose that in late stage of disease endothelial damage, fibrosis and autonomic dysfunction of peripheral arteries reduce pulsatility of digital arteries. PPG represents a noninvasive technique to evaluate digital arteries pulsatility of hands in patients with primary and secondary RP. Volume 340, Number 6, December 2010
Photoplethysmography and Raynaud Phenomenon
REFERENCES 1. Wigley FM. Clinical practice. Raynaud’s Phenomenon. N Engl J Med 2002;347:1001– 8. 2. Allen EV, Brown GE. Raynaud’s disease: a critical review of minimal requisites for diagnosis. Am J Med Sci 1932;183:187–200. 3. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000;43:2437– 44. 4. Kahaleh MB. Vascular involvement in systemic sclerosis (SSc). Clin Exp Rheumatol 2004;22(suppl 33):19 –23. 5. Herrick AL. Pathogenesis of Raynaud’s phenomenon. Rheumatology 2005;44:587–96. 6. Flavahan NA, Flavahan S, Mitra S, et al. The vasculopathy of Raynaud’s phenomenon and scleroderma. Rheum Dis Clin North Am 2003;29:275–91. 7. Salsano F, Letizia C, Proietti M, et al. Significant changes of peripheral perfusion and plasma adrenomedullin levels in acetylcysteine long term treatment of patients with sclerodermic Raynauds phenomenon. Int J Immunopathol Pharmacol 2005;18:761–70. 8. Gayraud M. Raynaud’s phenomenon. Joint Bone Spine 2007;74:1– 8. 9. Maricq HR, LeRoy EC. Patterns of finger capillary abnormalities in connective tissue disease by ‘wide-field’ microscopy. Arthritis Rheum 1973;16:619 –28. 10. Cutolo M, Sulli A, Pizzorni C, et al. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol 2000;27:155– 60.
patients with secondary Raynaud’s phenomenon. Microvasc Res 1999; 57:187–98. 17. Kelechi TJ, Bonham PA. Measuring venous insufficiency objectively in the clinical setting. J Vasc Nurs 2008;26:67–73. 18. Allen J. Photoplethysmography and its application in clinical physiological measurement. Physiol Meas 2007;28:1–39. 19. Klein-Weigel P, Pavelka M, Dabernig J, et al. Macro- and microcirculatory assessment of cold sensitivity after traumatic finger amputation and microsurgical replantation. Arch Orthop Trauma Surg 2007;127: 355– 60. 20. Thompson A, House R, Manno M. The sensitivity and specificity of thermometry and plethysmography in the assessment of hand-arm vibration syndrome. Occup Med (Lond) 2008;58:181– 6. 21. Cardillo C, Schinzari F, Melina D, et al. Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis. Arthritis Rheum 2009;60:1840 – 4. 22. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581–90. 23. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1998; 15:202–5. 24. Valentini G, Silman AJ, Veale D. Assessment of disease activity. Clin Exp Rehumatol 2003;21(suppl 29):39 – 41.
11. Cutolo M, Sulli A, Secchi ME, et al. Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement? Rheumatology 2006;45(suppl 4):43– 6.
25. Medsger TA Jr, Bombardieri S, Czirjak L, et al. Assessment of severity and prognosis. Clin Exp Rehumatol 2003;21(suppl 29):42– 6.
12. Schmidt WA, Krause A, Schicke B, et al. Color Doppler ultrasonography of hand and finger arteries to differentiate primary from secondary forms of Raynaud’s phenomenon. J Rheumatol 2008;35:1591– 8.
27. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol 2000;12:527–33.
13. Dabich L, Bookstein JJ, Zweifler A, et al. Digital arteries in patients with scleroderma. Arteriographic and plethysmographic study. Arch Intern Med 1972;130:708 –14. 14. Allanore Y, Seror R, Chevrot A, et al. Hand vascular involvement assessed by magnetic resonance angiography in systemic sclerosis. Arthritis Rheum 2007;56:2747–54. 15. Rosato E, Borghese F, Pisarri S, et al. Laser Doppler perfusion imaging is useful in the study of Raynaud’s phenomenon and improves the capillaroscopic diagnosis. J Rheumatol 2009;36:2257– 63. 16. Hahn M, Hahn C, Junger M, et al. Local cold exposure test with a new arterial photoplethysmographic sensor in healthy controls and
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26. LeRoy EC, Medsger TA Jr. Raynaud’s phenomenon: a proposal for classification. Clin Exp Rheumatol 1992;10:485– 8.
28. Kellogg DL Jr. In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J Appl Physiol 2006;100:1709 –18. 29. Hasegawa M, Nagai Y, Tamura A, et al. Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis. Br J Dermatol 2006;155:1159 – 64. 30. Toprak U, Selvi NA, Ates¸ A, et al. Dynamic Doppler evaluation of the hand arteries of the patients with Raynaud’s disease. Clin Rheumatol 2009;28:679 – 83. 31. Schmidt WA, Krause A, Schicke B, et al. Color Doppler ultrasonography of hand and finger arteries to differentiate primary from secondary forms of Raynaud’s phenomenon. J Rheumatol 2008;35:1591– 8.
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The Different Photoplethysmographic Patterns Can Help to Distinguish Patients With Primary and Sclerodermic Raynaud Phenomenon Edoardo Rosato, MD, PhD, Carmelina Rossi, MD, Federica Borghese, MD, Ilenia Molinaro, Simonetta Pisarri, MD and Felice Salsano, MD
Abstract: Introduction: The aim of this study is to investigate pulsatility of digital arteries of hands by means of photoplethysmography (PPG) in patients with primary Raynaud phenomenon (PRP) and systemic sclerosis (SSc) and to compare the results with those obtained in healthy controls. Methods: One hundred five patients with SSc, 96 patients with PRP and 85 healthy controls were recruited in this study. Nailfold videocapillaroscopy and PPG were performed in healthy controls and patients. In patients with SSc, the capillaroscopic pattern was classified as early, active and late group pattern. A baseline PPG was recorded simultaneously in all 10 fingers of the hands. The photoplethysmographic curves were evaluated for morphology and amplitude of sphygmic wave. Results: In healthy controls group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc and 2 subsets of disease. Conclusion: PPG represents a technique noninvasive to evaluate simultaneously in all 10 fingers of hands digital arteries pulsatility. PPG improves the evaluation of vascular damage in patients with primary and sclerodermic RP. Key Indexing Terms: Photoplethysmography; Raynaud phenomenon; Systemic sclerosis. [Am J Med Sci 2010;340(6):457–461.]
T
he term Raynaud phenomenon (RP) is used to describe the episodic events that represent vasoconstriction of the digital arteries, precapillary arterioles and cutaneous arteriovenous shunts. It typically starts in 1 or several digits after exposure to the cold or a stressful situation and then spreads symmetrically to all fingers of both hands. Primary Raynaud phenomenon (PRP) is characterized by symmetric attacks, absence of tissue necrosis, ulceration or gangrene, absence of a secondary cause, normal nailfold capillaries, a negative test for antinuclear antibodies, normal erythrocyte sedimentation rate and normal value of the C-reactive protein.1,2 Systemic sclerosis (SSc) is a disorder characterized by alterations of the microvasculature, dysfunction of the immune system and deposition of collagen in connective tissue. Vascular impairment, a main feature of the pathogenesis of SSc, involves both the macro- and the microvasculature. Vascular symptoms are the major prognostic factors for SSc, with a following general outcome depending on the extent and severity of vascular lesions.3 Irrespective of the
From the Department of Clinical Medicine, Clinical Immunology UnitScleroderma Center, Sapienza University of Rome, Rome, Italy. Submitted January 23, 2010; accepted in revised form June 23, 2010. Correspondence: Felice Salsano, MD, Department of Clinical Medicine, Sapienza University of Rome, Viale dell’Universita` 37, Rome 00185, Italy (E-mail: [email protected]).
classification of the disease, SSc is typically associated with RP.4 RP secondary to SSc is characterized by microvascular damage and high plasma adrenomedullin and endothelin-l levels.5–7 Capillaroscopy is crucial to differentiate between PRP and secondary RP.8,9 Actually nailfold videocapillaroscopy (NVC) represents the best method to analyze microvascular damage in rheumatic diseases. In healthy subjects, the microvascular pattern is characterized by a regular array of microvessels with large intra- and interindividual variability. The presence of megacapillaries and a decreased capillary density are the hallmarks of the SSc capillary pattern, which can be detected by nailfold capillaromicroscopy. Recently, 3 defined major NVC patterns have been considered useful for assessing the appearance and the progression of sclerodermic microangiopathy (“early,” “active” and “late” patterns).10,11 Today, noninvasive and invasive examination techniques have become a common method of assessing peripheral vascular perfusion: color-coded duplex Doppler ultrasonography, angiography, computed tomography, magnetic resonance angiography and laser Doppler perfusion image.12–15 Actually, photoplethysmography (PPG) occupy a indefinite position among these methods in the RP assessment. The first photoelectric plethysmography was described in the 1930s. Today, PPG systems operate in near infrared light and allow the transcutaneous registration of venous and/or arterial blood volume changes in the skin vessels. In this wavelength range, hemoglobin in the blood absorbs much more strongly than the remaining tissue. Wavelengths around 900 nm are most suitable because they combine good penetration with good contrast between the dark vessels and the light tissue. The simplest PPG sensor consists of an IR-LED and a photodetector. In quantitative PPG, the optical illumination is automatically adjusted for each different type of skin until a predetermined level of reflected light is reached. With this technology, PPG measurements are independent of skin color, thickness and individual blood volume, so that interindividual registrations and registrations with different devices can be compared. Arterial PPG detects the pulse-related changes in skin blood volume and has a limited penetration depth, reflecting pulsatile blood volume changes of the skin including the plexus.16 The main applications of PPG include the muscle pump test (assessment of calf pump failure in chronic venous insufficiency), vein occlusion test (thrombotic obstruction), venous resting pressure test, arterial perfusion test, peripheral arteriosclerosis quantification, vascular responses to drugs, macro- and microcirculatory assessment of cold sensitivity after traumatic finger amputation and microsurgical replantation.17–19 PPG was also used to quantify the vascular damage in hand-arm vibration syndrome. Therefore, its application in RP is limited to evaluate response of digital arteries to cold test and drugs.20,21 This study was designed to assess whether PPG can help to distinguish likely patients with idiopathic and sclerodermic RP.
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TABLE 1. Epidemiological and clinical features of the patients with SSc (n ⫽ 105) Sex (female/male) Age (mean ⫾ SD) (yr) SSc duration since diagnosis (yr), mean ⫾ SD Raynaud phenomenon duration (yr), mean ⫾ SD Subseta (n) dcSSc/lcSSc ANA pattern, n (%) Speckled Speckled and nucleolar Nucleolar Centromere SSc-specific autoantibody, n (%) Antitopoisomerase I Anticentromere antibody None DAIb DSIc
94/11 55.6 ⫾ 12.6 7.2 ⫾ 17.5 13 ⫾ 110.5 41/64 20 (19) 12 (11) 20 (19) 53 (50) 33 (31) 53 (51) 19 (18) 2.1 ⫾ 11.8 4.5 ⫾ 12.6
a
Subset according to LeRoy et al.23 Disease Activity Index (DAI) according to Valentini et al.24 c Disease Severity Index (DSI) according to Medsger et al.25 dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; ANA, antinuclear antibodies. b
METHODS Subjects One hundred five patients with SSc (94 women and 11 men; mean age, 55.6 ⫾ 12.6 years), who were admitted to the Clinical Immunology Unit of Sapienza University of Rome from January 2000 to December 2007, were recruited for this study. All patients fulfilled the American College of Rheumatology criteria for the diagnosis of SSc,22 and the patients were grouped according to whether they had limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc).23 Table 1 lists the main baseline epidemiological and clinical features of the patients. Disease activity and disease severity in SSc were measured by means the Scleroderma Disease Activity Score by Valentini et al24 and the Disease Severity Scale by Medsger et al25, respectively. Ninety-six patients (81 women and 15 men; mean age, 36 ⫾ 18 years) who fulfilled the PRP criteria2,26 were also studied. In patients with PRP, the RP duration (mean ⫾ SD) is 13 ⫾ 14 years. Eighty-five healthy controls with negative test for antinuclear antibodies (73 women and 12 men; mean age 47 ⫾ 11 years) were enrolled in this study. All patients with SSc had been previously treated with iloprost and nifedipine, but iloprost had been discontinued at least 6 months before recruitment and nifedipine at least 2 weeks before recruitment. The majority of patients with RP had been previously treated with nifedipine, but nifedipine was discontinued at least 2 weeks before recruitment. The subjects’ written consent was obtained according to the Declaration of Helsinki, and the design of the work conforms to standards currently applied in the country of origin. Exclusion criteria included those who were unable to give informed consent, actual therapy with prostacyclin analogues and/or endothelin receptor antagonists and/or phosphodiesterase 5 inhibitors subjects with a history of uncontrolled systemic hypertension, hyperlipidemia, cardiac failure, hepatic
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failure, diabetics, peripheral vascular disease, coagulopathy, smokers and pregnant or breastfeeding women. Digital Photoplethysmography PPG was performed out using a Termoflow machine (Microlab Elettronica Sas, Pordenone, Italy). Termoflow, a computerized system, allows the simultaneous photoplethysmographic detection out of 10 fingers. Transducers fixed on the distal phalanx of each finger and insensitive to ambient light are optically calibrated to ensure uniformity of the response of the system “finger-transducer.” The person who analyzed the PPG results was blinded to patient diagnosis and NVC. Baseline tracings of all digits of both hands were acquired in a quiet, air-conditioned room (24°C ⫾ 0.4°C) when the subjects were accustomed to the room temperature after around 20 minutes. Patients and healthy controls were not allowed to drink coffee and alcoholic beverages for 2 days before the examination. The acquired photoplethysmographic curves are evaluated for morphology and amplitude of sphygmic wave. For the evaluation of pattern, the authors have used morphology and amplitude of sphygmic wave. A homogeneous pattern was defined as a pattern showing uniformity of morphology and amplitude of sphygmic wave in all 10 fingers. A dyshomogeneous pattern was characterized by different morphology in 2 or more fingers of each hand with mean variation of sphygmic wave amplitude ⱖ15% in 2 or more fingers of each hand. The magnitude of sphygmic wave was expressed as percentage of maximum value of sphygmic wave amplitude. This maximum value is done by constructor of Termoflow machine and is equivalent to pulsatility of brachial artery. The magnitude of sphygmic wave was calculated as mean value of magnitude of sphygmic wave of all 10 fingers of both hands. In patients with SSc with sclerodactyly, PPG was performed only when the maximal maximum flexion of the fingers, evaluated as the point of maximum distance from the surface, was ⬍5 mm. In fact, in our experience, the sclerodactyly with a flexion of the fingers ⬍15 mm does not cause significant changes in the digital PPG parameters. Nailfold Videocapillaroscopy NVC was performed in a quiet, air-conditioned room (24 ⫾ 0.4°C) when the subjects were accustomed to the room temperature after approximately 20 minutes. Another operator performed the NVC in each patient by using an optical probe videocapillaroscopy equipped with magnification 100⫻ contact lens and connected to image analysis software (Pinnacle Studio, Version 8; Pinnacle Systems, Mountain View, CA). Each subject was inside the building for a minimum of 15 minutes before the nailfold was examined at a room temperature of 20°C to 22°C. The nailfold (distal row) of the second, third, fourth and fifth finger was examined in each patient. The following capillaroscopic parameters were considered according to previous observations: presence of enlarged and giant capillaries, hemorrhages, loss of capillaries, disorganization of the microvascular array and capillary ramifications. According to Cutolo et al,10,11 the patterns identified within the “SSc pattern” include: “early” NVC pattern: few enlarged/giant capillaries, few capillary hemorrhages, relatively well-preserved capillary distribution and no evident loss of capillaries; “active” NVC pattern: frequent giant capillaries, frequent capillary hemorrhages, moderate loss of capillaries, mild disorganization of the capillary architecture, absent or mild ramified capillaries; and “late” NVC pattern: irregular enlargement of the capillaries, few or absent giant capillaries and hemorrhages, severe loss of capillaries with extensive avascular areas, disorVolume 340, Number 6, December 2010
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FIGURE 1. (A) In healthy controls, photoplethysmographic pattern is homogeneous, and sphygmic wave amplitude is high. (B) In patients with systemic sclerosis, photoplethysmographic pattern is dyshomogeneous, and sphygmic wave amplitude is reduced. (C) in patients with Raynaud phenomenon, photoplethysmographic pattern is homogeneous, and sphygmic wave amplitude is markedly reduced.
ganization of the normal capillary array and ramified/bushy capillaries. Statistical Analysis All the results were expressed as mean ⫾ standard deviation. Commercially available software (SPSS version 12.0; SPSS, Chicago, IL) was used for the statistical analysis. The 2 test was used for categorical variables. Impaired Student t test was used for numeric variables. Correlation coefficient (r) was used to evaluate correlation negative or positive between numerical variables. All calculated P values were 2 -tailed, and P values ⬍0.05 were considered significant.
RESULTS In the healthy controls and patients with RP, the pattern of PPG was homogeneous. Conversely, in the patients with SSc, the photoplethysmographic pattern was dyshomogeneous. Digital PPG showed a homogeneous pattern in the 96% of healthy controls (82 of 85), 96% of PRP (92 of 96) and 26% of patients with SSc (27 of 105) (Figure 1). The presence of homogeneous pattern was significantly (P ⬍ 0.001) lower in patients with SSc than in healthy controls and patients with RP. We did not find any significant difference in the homogeneous pattern presence between patients with PRP and healthy controls (Table 2). In the 3 groups of the study population, the mean value of sphygmic wave amplitude is significantly different. The mean value of sphygmic wave amplitude is lower (⬍0.0001) in the PRP group than in SSc group (11 ⫾ 10 versus 24 ⫾ 24). The mean value of sphygmic wave amplitude is lower (⬍0.0001) in the SSc group than in healthy controls (24 ⫾ 24 versus 56 ⫾ 19; Table 2). To distinguish between patients with SSc and PRP, the photoplethysmographic pattern have demonstrated an good sensitivity (74% confidence interval, 66%– 82%) and high specificity (96% confidence interval, 92%–99%). Significant differences have not been observed between disease subset (limited cutaneous SSc and diffuse cutaneous SSc) and photoplethysmographic pattern and mean value of sphygmic wave amplitude. The study of correlations between mean value of sphygmic wave amplitude and Raynaud duration not showed a © 2010 Lippincott Williams & Wilkins
relation that is statistically significant (r ⫽ 0.01 and P value ⬎ 0.05). In addition, between mean value of sphygmic wave amplitude and disease duration, no relative statistically significant value was observed (r ⫽ 0.03 and P value ⬎ 0.05). Dyshomogeneous pattern is significantly (P ⬍ 0.001) different in 3 capillaroscopic pattern. In early capillaroscopic group, a dyshomogeneous pattern is present in 91% of patients; in active capillaroscopic group, a dyshomogeneous pattern is present in 94% of patients; and in late capillaroscopic group, a dyshomogeneous pattern is present in only 19% of patients (Table 2). In addition, mean value of sphygmic wave amplitude is significantly different in 3 capillaroscopic groups of patients. In late capillaroscopic group, mean value of sphygmic wave amplitude is lower than in active capillaroscopic groups (4 ⫾ 8 versus 20 ⫾ 15), and in early capillaroscopic group, this value is significantly higher than in active and late groups (Table 2). In the late capillaroscopic group, mean value of sphygmic wave is statistically (P ⫽ 0.002) lower than PRP group (4 ⫾ 8 versus 11 ⫾ 10). In Table 3, we synthesized the findings of PPG.
TABLE 2. Findings of photoplethysmography in study population
Healthy controls (85) Patients with PRP (96) Patients with systemic sclerosis (105) Capillaroscopic pattern Early (43) Active (36) Late (26)
Homogeneous pattern, N (%)
Sphygmic wave amplitude (%) (mean ⴞ SD)
81 (95.3) 92 (96) 27 (26)
56 ⫾ 19 11 ⫾ 10 24 ⫾ 24
4 (9) 2 (6) 21 (81)
40 ⫾ 28 20 ⫾ 15 4⫾8
PRP, primary Raynaud phenomenon.
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TABLE 3. Photoplethysmography findings in study population
Healthy controls Patients with RP Patients with systemic sclerosis Capillaroscopic pattern Early Active Late
Homogeneous pattern
Sphygmic wave amplitude (%) (mean ⴞ SD)
Present Present Absent
56 ⫾ 19 11 ⫾ 10 24 ⫾ 24
Absent Absent Present
40 ⫾ 28 20 ⫾ 15 4⫾8
RP, Raynaud phenomenon.
DISCUSSION Vascular dysfunction is one of the hallmarks of SSc and involves both the macro- and microvasculature.27 Several techniques have been developed to study the function of the microcirculation: transcutaneous oxygen tension, NCV, orthogonal polarization spectral imaging, thermal infrared imaging and LDPI.28 Color-coded duplex Doppler ultrasonography, computed tomography, arteriography and magnetic resonance angiography are used to evaluate peripheral arteries.12–14 Actually, arteriography represents the best method to analyze damage of peripheral arteries in the SSc. The arteriographic changes of the vessels in SSc are smooth and tend to show tapering segmental lesions in the distal vessels. Vascular involvement in SSc has been believed to be limited to digital arteries. It is extremely rare that patients with SSc without vascular risk factors have macrovascular lesions above the elbow or knee. However, a relatively high incidence of vascular involvement between the digits and the elbow or knee has been described.29 Previous studies have shown that PPG is able to quantify the vascular damage in hand-arm vibration syndrome and to evaluate response of digital arteries to cold test and drugs.20,21 For the first time, our study shows that in a representative group of patients, PPG is a useful noninvasive diagnostic technique for evaluating function of digital arteries of hands in patients with PRP and SSc. In the study population, we can demonstrate that photoplethysmographic pattern, simultaneously recorded in all 10 fingers of hands, is different in the 3 groups of subjects and 3 capillaroscopic groups. In healthy control group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The vascular system of acral parts of the body has major thermoregulatory functions and, as such, is influenced by environmental temperature. Therefore, RP affects primarily digits or toes. Primary and secondary RP seem to have in common an unphysiologically increased contractile response to sudden cooling and to ␣2-adrenergic agonists.5 We can suppose that PPG dyshomogeneity is related to variable degree of vasospasm in digits of patients with SSc. Therefore, it needs more PPG studies to evaluate blood flow
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directly at baseline and after cold challenge in all the digits to show difference in cold-induced vasospasm in SSc digits. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc. The capillaroscopic early group is easily distinguishable for the absence of homogeneous photoplethysmographic pattern and high mean value of sphygmic wave amplitude. The capillaroscopic active group is characterized by dyshomogeneous photoplethysmographic pattern, and the mean value of sphygmic wave amplitude comprised between the two other capillaroscopic groups. In the late capillaroscopic group, mean value of sphygmic wave amplitude is low, and the photoplethysmographic pattern is homogeneous for absence or extreme reduction of sphygmic wave. In patients with PRP, the digital arteries does not have structural alteration have been demonstrated with ultrasonographic studies. The diameter and flow volume of the digital and ulnar arteries of the patients with RP, evaluated by dynamic Doppler, were lower at rest, but resistive index was significantly high in all arteries. After cold provocation, the diameters of the radial and ulnar arteries and the flow volume of the digital arteries of the patients were significantly lower than those of the controls.30 Instead, in patients with secondary RP, color Doppler ultrasonography shows structural arterial damage in 63% of patients: narrowing, chronic occlusion and acute occlusions.31 These ultrasonographic changes correspond to histological damage characterized by endothelial cell injury, platelet activation and thrombosis, increased synthesis of extracellular matrix molecules and a hypertrophic and fibrotic remodeling of the blood vessels with progressive lowering of the inner vascular diameters. In addition to increased contractile responses, secondary RP in SSc is also characteristically associated with structural alterations of the involved vessels. Structural vascular abnormalities of both the microvasculature and digital artery are well recognized in SSc. In secondary RP, structural vascular changes in small- and medium-sized arteries lead to fixed narrowing of the lumen. These structural vascular changes (intimal proliferation and fibrosis) are more evident in the final stages of illness. Fibrotic intimal hyperplasia is a main characteristic in this context, and it usually precedes the loss of vascular elasticity and the increasing luminal narrowing. As a result of this fibrotic intimal hyperplasia, these vessels cannot compensate for a major impairment of blood flow during severe attacks of secondary RP. This then leads to critical impairment of blood flow and to so-called ischemia-reperfusion reactions. They may include activation of endothelial adhesion molecules, higher release of vasoconstrictors or reduced release of vasodilators, increase of oxygen radicals and of other toxic products that could modify antigens to induce autoimmunity, activation of platelets with release of the vasoconstrictors serotonin and thromboxane and possibly a procoagulant endothelial surface. These factors increase the propensity for new attacks of RP and, thus, induce further structural alterations of the vessels, a vicious circle.5 Future prospective studies will need to see whether patients with SSc develop digital ulcers in the fingers with reduced or absent pulsatility. It would also be important to assess if patients with RP and those with positive test for antinuclear antibodies present different PPG patterns and if any pattern is associated with an increased risk of developing the disease. In conclusion, we can suppose that in late stage of disease endothelial damage, fibrosis and autonomic dysfunction of peripheral arteries reduce pulsatility of digital arteries. PPG represents a noninvasive technique to evaluate digital arteries pulsatility of hands in patients with primary and secondary RP. Volume 340, Number 6, December 2010
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