The Place of Nailfold Capillaroscopy Among Instrumental Methods for Assessment of Some Peripheral Ischaemic Syndromes in Rheumatology Sevdalina N

DOI: 10.1515/folmed-2016-0011 REVIEW

The Place of Nailfold Capillaroscopy Among Instrumental Methods for Assessment of Some Peripheral Ischaemic Syndromes in Rheumatology Sevdalina N. Lambova Department of Propedeutics of Internal Medicine, Faculty of Medicine, Medical University of Plovdiv, Plovdiv, Bulgaria

Correspondence: Sevdalina Lam- Micro- and macrovascular pathology is a frequent fi nding in a number of common bova, Department of Propedeutics rheumatic diseases. Secondary Raynaud’s phenomenon (RP) is among the most in Internal Medicine, Faculty of common symptoms in systemic sclerosis and several other systemic autoimmune Medicine, Medical University of diseases including a broad diff erential diagnosis. It should be also diff erentiated Plovdiv, Plovdiv, 15A Vassil Aprilov from other peripheral vascular syndromes such as embolism, thrombosis, etc., Blvd., 4002 Plovdiv, Bulgaria E-mail: [email protected] some of which lead to clinical manifestation of the blue toe syndrome. Tel: +359 889 560 104 The current review discusses the instrumental methods for vascular assessments. Received: 9 March 2016 Nailfold capillaroscopy is the only method among the imaging techniques that Accepted: 4 May 2016 can be used for morphological assessment of the nutritive capillaries in the nail- Published: 30 June 2016 fold area. Laser-Doppler fl owmetry and laser-Doppler imaging are methods for Key words: Raynaud’s phenome- functional assessment of microcirculation, while thermography and plethysmog- non, blue toe syndrome, rheu- raphy refl ect both blood fl ow in peripheral arteries and microcirculation. Doppler matic diseases, microcirculation; ultrasound and angiography visualize peripheral arteries. The choice of the appro- nailfold capillaroscopy priate instrumental method is guided by the clinical presentation. The main role of Citation: Lambova SN. The capillaroscopy is to provide diff erential diagnosis between primary and secondary Place of Nailfold Capillaroscopy RP. In rheumatology, capillaroscopic changes in systemic sclerosis have been re- Among Instrumental Methods for cently defi ned as diagnostic. The appearance of abnormal capillaroscopic pattern Assessment of Some Peripheral inherits high positive predictive value for the development of a connective tis- Ischaemic Syndromes in Rheuma- sue disease that is higher than the predictive value of antinuclear antibodies. In tology. cases of abrupt onset of peripheral ischaemia, clinical signs of critical ischaemia, Folia Medica 2016;58(2);77-88, unilateral or lower limb involvement, Doppler ultrasound and angiography are doi: 10.1515/folmed-2016-0011 indicated. The most common causes for such clinical picture that may be referred to rheumatologic consultation are the antiphospholipid syndrome, mimickers of vasculitides such as atherosclerosis with cholesterol emboli, and neoplasms.

INTRODUCTION RESULTS

Micro- and macrovascular pathology is a common RAYNAUD’S PHENOMENON feature in a number of common rheumatic diseases. Raynaud’s phenomenon (RP) is among the most Reliable diagnostic tools should be used in order to common symptom in systemic autoimmune diseases. guide physicians in the differential diagnosis and It manifests as reversible vasospasm of the small administration of well-timed treatment that would peripheral arteries and arterioles at cold exposure or improve prognosis, slow up or prevent future dam- emotional stress. It presents in three or two phases age or provide full recovery in cases of medical e. g., ischaemia, asphyxia and reactive hyperemia emergency. with skin discolouration from pallor to cyanosis and redness with clearly visible demarcation line. It AIM affects acral body parts such as ﬁ ngers, toes, nose, The present review discusses the instrumental ears, lips. RP could be idiopathic or primary, when methods for vascular assessment. Two case reports there is no underlying cause for its development and are presented to illustrate the possibilities of the the clinical course is benign without development of imaging modalities in clinical context. trophic changes because of the lack of endothelial

77 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 S. Lambova damage. Secondary RP is observed in a number of to the higher use of different vascular interventions connective tissue diseases and includes a broad dif- such as vascular surgery or invasive percutaneous ferential diagnosis including drug-induced RP and procedures i.e., angiography and angioplasty. In paraneoplastic conditions. The profound endothelial addition, anticoagulant therapy could also induce damage may lead to appearance of digital ulcers this iatrogenic complications.6 in a proportion of cases with secondary RP.1-4 It A number of instrumental techniques are used should be also differentiated from other peripheral to assess microcirculation in patients with symp- vascular syndromes such as embolism, thrombosis, toms of RP in order to prove the presence of etc., some of which lead to clinical manifestation vascular pathological changes and to differentiate of the blue toe syndrome. A number of laboratory the primary from secondary forms of the disease and instrumental methods are essential for the dif- that is crucial for the therapeutic approach such ferential diagnosis. Interpretation of the fi ndings is as nailfold capillaroscopy, laser Doppler fl owmetry, in the concrete clinical context. laser Doppler imaging, thermography at rest and in RP is diagnosed clinically. The diagnosis is combination with cold provocation. Colour Doppler based on the direct observation of 2 among the 3 and angiography are additional instrumental tech- possible phases of the condition. To be diagnosed niques that visualize larger vessels and facilitate with RP, a patient should have a history of sensi- the differential diagnosis in more complex cases tivity to the cold and episodic pallor, cyanosis or of peripheral vascular ischaemic pathology. redness of the distal portions of the digits after Nailfold capillaroscopy is the only method for exposure to cold. Photographs of the hands may morphological assessment of nutritive capillaries. be obtained during an attack and used to confi rm Laser Doppler and thermography assess cutaneous the history. In routine clinical practice it is not blood vessel function.7 necessary to perform a cold provocation test to RAYNAUD’S PHENOMENON IN RHEUMATIC DISEASES make a defi nitive diagnosis of RP.5 RP is a characteristic feature in a number of rheu- BLUE TOE SYNDROME matic diseases with substantially high frequency in The term ‘blue toe syndrome’ describes the devel- systemic sclerosis (SSc) - approximately 90-95% opment of blue or violaceous discoloration of one (Table 1).8,9 RP in SSc is a clinical manifesta- or more toes in the absence of obvious trauma, tion of vasospasm of the peripheral digital arteries serious cold-induced injury, or disorders producing and arterioles as well as of permanent structural generalized cyanosis. The condition may develop in endothelial damage of the microcirculation that is cases of micro-, macrovascular pathology, impaired associated with the high rate of development of venous outfl ow and hyperviscosity syndromes. Three digital ulcers in these patients in over half of the major categories are recognized: cases.10 In 100 SSc patients, La Montagna et al. 1. disorders with decreased arterial fl ow - arterial (2002) found that symptoms of RP of the feet obstruction due to: are present in 90% of the cases vs 100% fre- • embolism (atheroemboli due to spontaneous plaque quency of RP at the hands. In 43% of the cases haemorrhage or induced by different provoking from this group, RP of the feet was presented at factors, cardiac or aortic tumor, infective endo- initial evaluation, while 47% developed it in the carditis); course of the follow-up. In contrast, RP of the • thrombosis (antiphospholipid syndrome, malig- hands was registered in 100% of patients at the nancy (paraneoplastic acral vascular syndrome, initial evaluation. The onset of clinically evident disseminated intravascular coagulation, warfarin involvement of the feet was found to occur later skin necrosis); in limited SSc than in the diffuse form of the • vasoconstrictive disorders (acrocyanosis, chil- disease. Lower rate of necrotizing RP was found blains, drug induced vasoconstriction, infectious and non-infectious vessel infl ammation; in the feet of patients with SSc as compared with 11 2. impaired venous outfl ow (venous thrombosis); the hands. 3. abnormal circulating blood (paraproteinemia Among other common rheumatic diseases, the with hyperviscosity, myeloproliferative disorders, prevalence of RP in systemic lupus erythematosus cryofi brinogenemia, cryoglobulinemia). varies between 10 and 45% and it usually indicates 8,12 Prevalence of atheroembolism is increased due a more benign course without tissue necrosis.

78 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 Instrumental Methods for Assessment of Peripheral Ischaemic Syndromes in Rheumatology

Table 1. Common differential diagnosis of Raynaud’s phenomenon in rheumatologic practice.

Systemic sclerosis Mixed connective tissue disease Undifferentiated connective tissue disease Systemic lupus erythematosus Dermatomyositis, polymyositis Sjögren syndrome Rheumatoid arthritis Systemic vasculitides - Buerger disease, Takayasu arteritis, polyarteritis nodosa, granulomatosis with poly- angiitis, etc. Other common conditions that are associated with Raynaud’s phenomenon and are included in the differential diagnosis in rheumatologic practice Drug-induced Raynaud’s phenomenon - beta blockers, cytotoxic drugs - vinblastine, bleomycin, interferon, etc. Paraneoplastic Raynaud’s phenomenon - associated with solid tumours and haematological malignancies.

RP occurs in over 75-96% of patients with RP in men with RA (7.5%) than in women (3.2%) mixed connective tissue disease (MCTD) that is was interesting. In comparison, in a cohort of 919 characterized with a specifi c immunologic marker – patients with osteoarthritis, a global tendency of a anti-U1- RNP antibody. Due to its high frequency, female predominance of RP was observed. The higher RP is included in the currently used classifi cation prevalence of RP in men with RA was explained by criteria for MCTD (the criteria of Allargon – Sego- the authors with a stronger association of RA with via and Villareal, Kasukawa et al., Sharp, Kahn). secondary vasculitis in men.18 These results are in Development of trophic changes of the fi ngers is agreement with the fi ndings of Carrol et al. (1981, a frequent complication in these patients.12,13 North Australia), who found a manifestation of RP In undifferentiated connective tissue disease in 2.7% of 141 patients with RA.19 In а French (UCTD) patients, features of systemic rheumatic population of RA patients, Saraux et al. found а disease are present, but there is not a full set of higher prevalence of RP in RA (17.2%, 54/322).20 characteristics of a well-defi ned rheumatic disorder. NAILFOLD CAPILLAROSCOPY RP is a frequent symptom that may be observed in about 80% of the cases. During a longer period The main indication for nailfold capillaroscopic of follow-up, a part of these patients (1/4 to 1/3) examination in rheumatology is presence of RP. develop a distinct rheumatic entity, the most frequent The method is of crucial value for the differential being SSc, SLE, rheumatoid arthritis (RA), Sjögren diagnosis of primary and secondary RP in rheumatic syndrome, but the majority of patients remain in diseases. The capillaroscopic pattern in healthy a clinically and laboratory stable condition in the subjects remains unchanged for prolonged periods scope of the term UCTD. In some of these patients of time. The normal capillaroscopic pattern is (1/4 to 1/3), Nagy et al. found a scleroderma-like characterized with hair-pin shaped capillary loops capillaroscopic pattern in 13.8% of 65 patients with regular distribution and parallel orientation. In with “UCTD”.14 In our own study of 31 UCTD each dermal papilla there are one to three capillary 15,21 patients, we have found a frequency of RP 78%, loops (Fig. 1). and in 38% of cases a scleroderma-like pattern Capillaroscopic examination reveals specific at capillaroscopic examination was observed.15,16 changes in SSc - the so-called scleroderma type The prevalence of RP in RA is not well-defi ned. capillaroscopic pattern, which is a reference pattern Some authors consider that such an association is in rheumatology. It was described for the fi rst time 22 quite rare9, while other authors include RA among by Maricq et al. (1980) and is characterized by the rheumatic diseases associated with RP8,17. Grassi dilated, giant capillaries, haemorrhages, avascular et al. (1994, Italy) found a low incidence of RP areas, and neoangiogenic capillaries. It is observed in RA - 4.6%, (19/411). The higher prevalence of in the majority of SSc patients analogous to the

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Presence of RP is scored with 3 points and positive SSc-related autoantibodies (anti-centromere, anti- Scl-70 and anti-RNA polymerase III) with 3 points (maximum score 3 for the whole section).25,26 The normal capillaroscopic pattern is a diagnostic criterion for primary RP (Le Roy and Medsger, 1992). For the diagnosis of primary RP, the lack of the following criteria (Le Roy and Medsger) is required: а) digital ulcerations and gangrenes; b) elevated erythrocyte sedimentation rate; c) positive test for antinuclear autoantibodies (ANA) with a high titer; d) abnormal capillaroscopic pattern.17 Capillaroscopic pattern in primary RP is not specifi c and the demonstrated capillaries are normal Figure 1. Capillaroscopic pattern in a healthy subject - in number and size. The mean capillary diameter, hair-pin shaped capillary loops with regular distribution capillary density and capillary morphology do not and parallel orientation. differ signifi cantly from those of healthy subjects. The capillary diameter can be slightly enlarged, but high frequency of RP (in more than 90%).15,21 it does not have a diagnostic value.27 In primary Cutolo et al. (2000) recognized three phases of RP patients, Bukhari et al.28 and Anderson et al.29 capillaroscopic changes in SSc: found enlarged capillary loops when compared 1. an “early” phase, which is characterized with with healthy subjects, which suggests minimal few dilated and/or giant capillaries and few haemor- microvascular abnormalities. In an own study, rhages. Avascular areas do not exist and the capillary nonsignifi cant dilation of capillary loops was de- distribution is preserved. tected by the software for quantitative assessment 2. In the “active” phase, numerous giant capillaries in patients with primary RP.15 The appearance of and haemorrhages, a moderate capillary loss and an abnormal nailfold capillary pattern is the best derangement are present. In addition, pericapillary predictor of transition of primary RP into second- oedema could be found. ary RP in connective tissue disease with positive 3. In the “late” phase, there is severe loss of cap- predictive value of 47% vs 30% positive predictive illaries and capillary derangement as well as evi- value of antinuclear antibodies.30 dence of neoangiogenesis with bushy and ramifi ed Maricq et al. found components of the sclero- capillaries.23 derma type capillaroscopic pattern in a group of The capillaroscopic changes develop in the early diseases from the scope of scleroderma-spectrum stages of SSc even before the establishment of the disorders such as mixed-connective tissue disease, defi nite diagnosis. To improve the early diagnosis undifferentiated connective tissue disease, overlap of SSc, Le Roy and Medsger proposed patients syndromes, dermatomyositis - the so-called scleroder- with RP and abnormal nailfold capillaroscopic ma-like capillaroscopic pattern.22,31 Scleroderma-like changes or positive specifi c for SSc autoantibodies capillaroscopic pattern is found in about 50-65% to be diagnosed as pre-scleroderma or limited SSc of MCTD patients, which is signifi cantly lower even in the absence of other manifestations of the compared with the frequency of microvascular disease (Le Roy and Medsger, 2001).24 changes in SSc.32 More recently, the capillaroscopic changes are Scleroderma-like capillaroscopic pattern in SLE defi ned as diagnostic for SSc according to the new was reported to vary between 2 and 9%14,22,33,34 classifi cation criteria of European League Against and slightly higher as reported by Furtado - 15%35. Rheumatism (EULAR) and American College of An association between presence of scleroderma- Rheumatology (ACR) (2013) in order to improve like capillaroscopic pattern and anti-U1-RNP the possibilities for early and very early diagnosis antibodies has been observed. This stimulated of the disease. According to the new EULAR/ACR the hypothesis that it could be manifestation of classifi cation criteria for SSc, defi nitive diagnosis is an overlap syndrome with SSc. In an own study, established if the patient’s total score is ≥ 9, and scleroderma-like pattern was observed in 13.3% of capillaroscopic changes are scored with 2 points. the examined 30 patients with SLE (4/30). In all

80 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 Instrumental Methods for Assessment of Peripheral Ischaemic Syndromes in Rheumatology the patients with scleroderma-like capillaroscopic reactivity is based on the assumption that fi nger fi nding, high immunologic activity was found, but skin temperature depends on the rate of blood fl ow signs for overlap with other connective tissue dis- through the digit that is valid only under standard- ease were not present. In two out of four patients ized laboratory conditions. Limitation of the fi nger with such capillaroscopic fi ndings a vasculitis of skin thermometry is its dependence not only on peripheral vessels was evident. Anti-RNP antibody the digital blood fl ow but also on environmental was positive in all but one patient with secondary factors such as room temperature, air velocity, and RP without vasculitis of peripheral vessels.15,16 In humidity.38 conclusion, scleroderma-like capillaroscopic pat- Contrary to the skin thermometry that mea- tern may be observed in patients with SLE with sures temperature at a single point, the infrared active vasculitis of peripheral vessels as well as in thermography is a method that provides a colour cases with secondary RP, in the presence of high image of the surface temperature using a thermal immunologic activity without evidence of overlap camera. It is suggested that the skin temperature with SSc or other connective tissue disease. is representative of the underlying blood fl ow that Nagy et al. did not fi nd scleroderma-like capil- involves both muscle and skin perfusion.7 laroscopic pattern in 14 patients with RA.14 In a In the diagnostic workup of RP patients, ther- previous study that included 62 RA with and with- mography is mainly used for dynamic testing of out RP, a scleroderma-like pattern was observed in patients’ response to cold challenge. The assessed 14.5% (9/62), (2 males and 7 females). In one of parameters are basal temperature prior to cold these cases, an overlap of RA with SLE, second- provocation, temperature immediate after the cold ary RP and secondary vasculitis was found. In the challenge, the maximum temperature recovery rate, rest, 8/9 patients, no overlap with other connective the time between the end of the cold challenge to tissue disease was evident. In all RA patients with the onset of rewarming, recovery index (the ratio scleroderma-like capillaroscopic pattern (9/9), a between temperature increase and initial temperature secondary RP was present, and in 2/9 - a second- decrease x 100%).39 ary vasculitis. This suggests that scleroderma-like A distal-dorsal difference of >1°C between the capillaroscopic pattern may be observed in RA fi ngertips and the dorsum of the hand, (fi ngers patients with secondary RP and cases associated cooler) in any fi nger evaluated via thermography with vasculitis of peripheral vessels although with was found to inherit a positive predictive value low frequency and its presence is not obligatorily of 70%, and a negative predictive value of 82%, associated with overlap syndromes. Similar fi ndings in identifying the patient with RP secondary to have not been reported by other researchers in the SSc thus aiding the prediction of SSc in patients current rheumatologic literature.15,36 with RP.40 In cases of paraneoplastic scleroderma-like con- THERMOGRAPHY AND COLD PROVOCATION TEST dition with RP associated with pulmonary cancer and 2 patients with paraneoplastic DM and RP in O’Reilly D. et al. (1992) compared the cold chal- the context of pulmonary and thyroid cancer re- lenge responses in 16 patients with primary RP, 20 spectively, we were the fi rst to report the absence patients with SSc and secondary RP and 21 healthy of differences between capillaroscopic changes in subjects via quantitative computed thermography that paraneoplastic rheumatic conditions and the respec- provides temperature recovery curves. The assessed tive idiopathic rheumatic diseases.15,37 parameters were as follows: basal temperature prior The development of pathologic capillaroscopic to cold provocation (Тpre °C), temperature immedi- changes requires time, which should be considered ate after the cold challenge (Т0°C). In addition, the for the intervals of follow-up in these patients, that maximum temperature recovery rate (Gmax - °C/ is about 6 months or shorter if clinical deteriora- minute) and the time at which this occurred (Тlag) tion occurs.15 were measured that represented the lag phase from cold provocation until the rewarming began. At 1, SKIN THERMOMETRY AND THERMOGRAPHY 5, 10, and 15 minutes after cold challenge, an in- Finger skin temperature is considered a useful physi- dex of percentage recovery was calculated and the ological parameter to evaluate the response of the maximum observed recovery index was assessed digital vessels to cold challenge. The use of skin (%) that is the ratio between temperature increase thermometry to assess peripheral vessels and their and initial temperature decrease x 100%. The basal

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temperature (Tpre °C) and the temperature immediate of the deeper lying thermoregulatory component cold challenge (T0ºC) were found to be signifi cantly of blood fl ow and the more superfi cial nutritional lower in both patients with primary RP and second- component of the blood fl ow.7,41-44 A signifi cant ary RP in SSc in comparison with healthy subjects disadvantage of the technique is the large site-to-site without signifi cant difference between the groups of signal variation. Even a minor change in position primary and secondary RP for both parameters. In or orientation of the probe can lead to signifi cant healthy controls, there was a short lag phase fol- variation in the estimation of blood fl ow. Thus, lowed by a rapid to above basal levels, which was two signals from two different adjacent sites vary proved by the signifi cant differences in Tlag, Gmax making the technique poorly reproducible, even and the recovery index with the other two groups. when protocols incorporate dynamic testing. The In patients with primary RP, there was a longer direct contact of the probe with the skin causing lag phase with slower and incomplete recovery. In mild compression might itself infl uence blood fl ow.7 patients with SSc and secondary RP, there was a Laser Doppler imaging is a new instrumental prolonged period without signifi cant temperature technique that measures fl ux over a greater area recovery by 15 minutes after the cold challenge. not in a single point via scanning laser Doppler

Although the dynamic parameters (Gmax, recovery equipment. It offers the advantage of not requir- index) were more powerful discriminants between ing direct contact between a probe and the skin. primary and secondary RP as compared with Tpre Laser Doppler images represent a pictorial fl ux and T0, the difference did not reach statistical map. Laser Doppler imaging equipment is cur- signifi cance. rently mainly a research tool that is available in In conclusion, the quantitative thermography few specialized centres. and the analysis of rewarming curves measures Laser Doppler investigation could be applied the response of RP patients to cold challenge that together with administration of drugs that mediate is characterized with slower temperature recovery evaluation of endothelium-dependent and endothe- after a longer delay.39 lium-independent vasodilation. A lot of research However, thermography is not currently an has focused on the early detection of endothelial established technique for differential diagnosis of dysfunction in humans that is characterized with primary and secondary RP due to lack of signifi cant reduction of the bioavailability of several active discriminative values. vasodilators e.g., nitric oxide with a concurrent increase in bioavailability of endothelium-derived LASER DOPPLER FLOWMETRY AND LASER DOPPLER IMAGING contracting factors such as endothelin-1, causing Laser Doppler fl owmetry is a non-invasive method an overall reduction in endothelium-dependent for assessment of cutaneous microcirculatory fl ow vasodilation. using laser light. The technique depends on the Measurement of the cutaneous perfusion by laser Doppler broadening of laser light scattered by mov- Doppler fl owmetry accompanied by iontophoresis ing particles and gives information about moving of acetylcholine and sodium nitroprusside as a particle density and fl ux. Flux is the parameter used measure of endothelial function is a noninvasive to express blood fl ow and the average velocity is test for assessment of endothelial function. Ionto- calculated by dividing fl ux to density. Helium-neon phoresis is the introduction of ions of soluble salts lasers with small probes are most commonly used into the tissues of the body by means of a direct with a wavelength of 632.8 nm (red light). The depth electrical current. of penetration of skin by the laser beam depends Endothelial-dependent vasodilation is induced on the equipment and is usually about 1 mm with after administration via iontophoresis of acetyl- surface area about 1 mm2, resulting in a theoreti- 3 choline (methacholine, bradykinin, and substance cal total measured tissue volume of 1 mm . The P could also be used). Acetylcholine is a stan- method includes assessment of blood fl ow of both dard substance that mediates vasodilatation via the superfi cial nutritional capillaries and the deeper endothelial-dependent production of NO and/or thermoregulatory vessels. The tissue penetration prostanoids with a possible accessory role played of green light with wavelength 543.5 nm is about by endothelium-derived hyperpolarizing factor. 60% of that of red light with over 20% greater Endothelial-independent vasodilation is induced absorption. Using laser Doppler fl owmetry at the after administration of sodium nitroprusside that is two wavelengths could provide separate evaluation a donor of NO and reacts with tissue sulfhydryl

82 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 Instrumental Methods for Assessment of Peripheral Ischaemic Syndromes in Rheumatology groups under physiologic conditions to produce is blocked, and the degree of the fi nger swelling NO directly and thereby stimulate smooth muscle immediately after occlusion refl ects the blood fl ow cells relaxation acting equally on all arterial and into the fi nger. venous vessels. Compromised vasodilation after Maricq et al. found different values of the stimulation with acetylcholine with preserved re- mean blood fl ow measured by venous occlusion sponse to sodium nitroprusside is an indicator for plethysmography in patients with primary RP, “cold endothelial dysfunction.45 sensitive” subjects, patients with SSc spectrum Impaired microvascular response measured by disorders and controls, but the difference was not laser Doppler iontophoresis has been demonstrated statistically signifi cant.50 in essential hypertension, diabetes, systemic scle- Plethysmography (without occlusion) can be rosis.46-48 used to detect presence or absence of arterial blood fl ow. A strain gauge placed around the distal FINGER SYSTOLIC BLOOD PRESSURE phalanx measures the pulsatile changes in volume The Nielsen test to diagnose RP (introduced by that indicates patent vessels and can be used detect Nielsen, 1977) represents a measurement of fi nger digital systolic opening pressure.7 systolic blood pressure (FSBP) after cold provocation. Local cold provocation test may be performed DOPPLER ULTRASOUND (cooling the hands for 5 minutes at 15, 10 and 6°C) High resolution ultrasound scanners allow detec- as well as combined local plus whole body cooling. tion of arterial pulses, and therefore artery patency FSBP is measured with an infl atable plastic cuff of and is indicated in cases of suspicion of structural the proximal phalanx of the thumb or at the middle digital artery disease. Visualisation and measure- phalanx of the fi ngers from 2nd to 5th. The exami- ment of digital arteries diameter and of arterial nation provides information about digital arteries. blood velocity could facilitate the quantifying of In healthy individuals, at standard temperature, the structural artery disease, and vasospasm. In patients FSBP is identical with the blood pressure measured with RP, dynamic testing is studied in evaluation of at the brachial artery. The diurnal and between-day vasospasm but it remains mainly a research tool.7 variations are between 5 and 10% in healthy people, Naidu et al. also reported that the degree of reduc- which makes the method highly reproducible. Mea- tion in digital artery diameter after a standard cold surement of FSBP after cold provocation leads to challenge could differentiate between patients with drop of FSBP only in RP due to increased blood RP and controls, although the technique did not vessel tone that refl ects the cold-induced vasospasm. discriminate between primary and secondary RP.7,51 In healthy individuals, the strongest decrease of ANGIOGRAPHY FSBP after 5-minutes cold provocation test during the next 15 minutes of evaluation is 68% from the Conventional angiography and magnetic resonance initial values. An RP attack was verifi ed as a zero angiography (MRA) of the peripheral arteries could blood FSBP. However, obtaining a zero FSBP in provide information about vascular anatomy prior to laboratory conditions has been found diffi cult to surgery, for diagnosing of pathology of peripheral 52 achieve. The gap of FSBP% between 68% of the blood vessels e.g., emboli, thrombosis, vasculitides. starting values and zero was accepted to detect an The fi ndings from angiography in patients with abnormal reaction in patients with anamnestic RP primary and secondary RP are not pathognomonic but no provoked RP attack, subjects with exagger- in most of the cases. Angiography is indicated in ated subclinical cold reaction but without anamnestic patients with clinical signs of critical ischemia, RP, and subjects with a false-positive test. False- unilateral limb involvement for diagnosing emboli, negative results have been observed in some cases thrombosis, atheromatous plaque, some forms of of milder forms of RP.49 vasculitides. MRA has been used with and without intrave- PLETHYSMOGRAPH Y nous injection of contrast media - gadolinium as a Most types of plethysmography rely on volume safe, reliable, and accurate technique for evaluation change. It may be performed with venous occlusion of vascular pathology of the hand. MRA allows placing a blood pressure cuff around the proximal accurate evaluation of arterioles and is also well phalanx of the fi nger and infl ated above venous suited for evaluating the extent of venous lesions.53 pressure but below arterial pressure. This leads to The following vascular lesions were found at increased fi nger volume because the venous return MRA in 38 SSc patients by Allanore et al. (2007):

83 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 S. Lambova proper digital artery that did not reach the fi rst of the menstrual cycle in women, patient’s age phalanx, thin arteries, one or more avascular areas, and gender. In addition, the lack of standardization abnormal or missing venous return. Of note, patients of the testing conditions e.g., room temperature, with SSc who had ≥4 proper digital arteries that duration of acclimatization as well as the severity did not reach the fi rst phalanx more frequently had and duration of the dynamic cold challenge does digital ulcers. The study demonstrates the presence not permit comparison of the results from the dif- of substantial vascular involvement in SSc that ferent studies.7 involve both arterial and venous vessels of small Two case reports are presented to better demon- caliber as well as the microcirculation.53 strate the opportunities of some of the instrumental techniques in differential diagnosis of peripheral WHICH INSTRUMENTAL METHOD TO CHOOSE? ischaemic syndromes. The instrumental methods for vascular assessments provide the following information: CASE REPORT 1 • nailfold capillaroscopy - the only method for A 55-year-old woman diagnosed with SLE pre- morphological assessment of nutritive capillaries sented at consultation with severe pain in the right in the nailfold area; lower extremity distal to knee joint that appeared • laser-Doppler flowmetry and laser-Doppler 3 days before examination. The diagnosis was es- imaging are methods for functional assessment of tablished 1 year ago with symmetric polyarthritis, microcirculation; skin, haematologic and immunologic involvement, • measurement of fi nger systolic blood pressure serositis and secondary RP. She had been treated and Doppler ultrasound - methods for assessment with corticosteroids and methotrexate. The physical of peripheral arteries including digital arteries; examination revealed erythematous lesions at the • conventional angiography and magnetic resonance neck, symmetric arthritis of the hands, mild RP of angiography - a method that could be used for hands and feet, preserved symmetric arterial pul- evaluation of peripheral arteries including digital sations. During the dynamic follow-up in 3-week arteries; period she developed vasculitis of peripheral vessels • thermography and plethysmography - refl ect both of hands and feet with the respective skin lesions. blood fl ow in peripheral arteries and microcirculation. The laboratory investigations revealed normal Doppler ultrasound is a standard technique for values of parameters of peripheral blood count assessment of the structural arterial pathology in e.g., red blood cells - 4.48 T/l, haemoglobin - 146 patients with connective tissue disease. The nail- g/l, haematocrit - 43.5, МСV 97.3 fl , white blood fold capillaroscopy is also already available in the cells, 11.8G/l with differential count within normal majority of centres of rheumatology specialized in range, platelets – 295 G/l, erythrocyte sedimenta- diagnosis and differential diagnosis of peripheral tion rate - 30 mm/hour, C-reactive protein - 1.5, ischaemic syndromes. Moreover, the abnormal capil- alkaline phosphatase and transaminases – within laroscopic pattern in SSc is validated as diagnostic normal values. criterion of the disease, while the absence of signs Immunological profi le with examination of auto- of microangiopathy is crucial for the diagnosis antibodies via ELISA method included the following of the idiopathic primary RP. The other imaging positive tests - anti-dsDNA - 125.3 (<25), anti-Sm techniques are available only in a limited number - 21.6 (<7.5), anti-cardiolipin IgG - 56.77 (<48), of centres that possess sophisticated equipment anti-beta2-glycoprotein - negative (<5). Fractions of used mainly in research projects. serum complement were within normal values: C3 It should be considered that some of the instru- - 1.914 (0.61-2.09), C4 - 0.452 (0.122-0.495). The mental techniques provide opportunity for functional disease manifestation was categorized as second- vascular assessment and most involve dynamic ary vasculitis of peripheral vessels and secondary testing. Many of these require further validation antiphospholipid syndrome. The therapy included to assess their sensitivity and specifi city in dif- methylprednisolone – 1 mg/kg, heparin – 1000U/ ferentiation of primary and secondary forms of hour in 24-hour infusion, opioid analgesics for RP in rheumatic diseases. In addition, apart from the severe ischaemic pain. In the next 3-4 days, the exact used protocol and equipment, functional the patient presented with necrosis of toe of the assessment is infl uenced also by patient’s degree right foot, necrotic lesion of the right lower leg of sympathetic tone during examination, the stage that evolved into ulcer (Figs 2, 3).

84 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 Instrumental Methods for Assessment of Peripheral Ischaemic Syndromes in Rheumatology

was performed that showed thrombosis at the level of right popliteal artery. The patient underwent two operations at a 3-day interval due to relapse; thrombectomy was performed. Perioperative treatment included methylprednisolone - 1 mg/kg, im- munovenin - 3×20 ampules intravenously every other day, antibiotic, heparin that was switched on acenocoumarol in 1 month, vasodilators, local antiseptic care for the ulcer. After ulcer healing in a period of 3.5 months a monthly pulse-therapy with cyclophosphamide and methylprednisolone was initiated that lead to good control of disease activity without relapse of the symptoms (Fig. 3).

CASE REPORT 2 A 34-year-old woman presented with 3-year history of tri-phasic RP, which had worsened in the previous year in terms of frequency, duration and the severity of vasospastic attacks. RP was located at the fi ngers and toes, being more severe at the hands without history for digital ulcers. At physical examination, no puffy fi ngers, skin thickening or other abnormal fi ndings suggestive of secondary RP were found. No concomitant diseases were present. At capillaroscopic examination, scleroderma Figure 2. Blue toe syndrome lesion of the 4th toe of right foot is demonstrated in a patient with systemic type capillaroscopic pattern, “early” phase was lupus erythematosus, antiphospholipid syndrome and observed. Numerous dilated and giant capillar- thrombosis of peripheral artery (case 1). ies, without haemorrhages, preserved distribution, normal mean capillary density were present (Fig. Pulsation of the vessels distal to right popliteal 4). The routine laboratory investigations showed artery were absent at physical examination. Dop- normal values of parameters of peripheral blood pler ultrasound demonstrated a lack of signal at count, e.g., red blood cells - 4.24 T/l, haemoglobin peripheral arteries of the right lower extremity - 137 g/l, haematocrit - 39.7, МСV 93.8 fl , white distal to the right popliteal artery. Angiography blood cells - 7.0 G/l, platelets, 246 G/l. Erythrocyte

Figure 3. Necrotic lesion of the lower extremity in the Figure 4. Scleroderma type capillaroscopic pattern, context of peripheral artery thrombosis (case 1). early phase: presence of dilated and single giant capillary loop (arrow) (case 2).

85 Folia Medica I 2016 I Vol. 58 I No. 2 I Article 1 S. Lambova sedimentation rate was slightly elevated, 55 mm/hour, of 47% that is higher than antinuclear antibodies. the major parameters of biochemistry (creatinine, The development of pathologic capillaroscopic transaminases) were within normal values. changes requires time, which should be considered The test for ANA was negative (1:40, direct for the intervals of follow-up in these patients that immunofl uorescence). The ELISA tests for sclero- is about 6 months. Nailfold capillaroscopy is indi- derma-specifi c autoantibodies e.g., anti-centromere cated in all patients with symptoms of RP. If signs and anti-Scl-70 were negative. of microangiopathy are absent, the patients should The diagnosis of “pre-scleroderma” was made. undergo regular clinical, capillaroscopic, laboratory Treatment with a vasodilator and antiplatelet drugs and immunological follow-up at a 6-month interval was initiated and closer follow-up by rheuma- or in case of clinical deterioration. tologist was recommended. In a 3-month period oedema of fi ngers was present and in an 8-month REFERENCES period skin thickening of the entire upper and 1. Cortes S, Cutolo M. Capillaroscopic patterns in lower extremities, chest, abdomen, back and face rheumatic diseases. Acta Reum Port 2007;32:29-36. was evident. Thus, the diagnosis was modifi ed to 2. Ho M, Belch JJ. Raynaud’s Phenomenon: State of SSc with diffuse cutaneous involvement. Therapy the Art 1998. Scand J Rheumatol 1998;27:319-22. with d-penicillamine, vasodilators (calcium channel 3. Carrol GJ, Withers K, Bayliss CE. The prevalence blockers, ACE-inhibitor), antiplatelet agent was of Raynaud’s syndrome in rheumatoid arthritis. Ann Rheum Dis 1981;40:567-70. initiated. In a 1-year period, the skin involvement 4. Müller-Ladner U. Raynaud’s phenomenon and improved signifi cantly and after 3 years it was peripheral ischemic syndromes. 1st ed, Bremen: evident only at the hands, feet and face. ANA test UNI-MED Verlag AG; 2008, pp. 36-41. remained permanently negative during the follow- 5. Wigley FM. Raynaud’s phenomenon. N Engl J Med up. This case report confi rms the role of nailfold 2002;347(13):1001-8. capillaroscopy for very early diagnosis of SSc. It 6. Hirschmann JV, Raugi GJ. Blue (or purple) toe syn- also could lead to possible better disease evolu- drome. J Am Acad Dermatol 2009;60(1):1-20. tion in cases of early treatment administration that 7. Herrick A, Clark S. Quantifying digital vascular disease in patients with primary Raynaud’s phe- remains to be confi rmed. nomenon and systemic sclerosis. Ann Rheum Dis 1998;57(2):70-78. CONCLUSIONS 8. Block JA, Sequeira W. Raynaud’s phenomenon. In cases of abrupt onset of peripheral ischaemia Lancet 2001;357(9273):2042-8. (hours, days, weeks), signs of critical ischemia, in 9. Seibold JR, Steen VD. Systemic sclerosis. In: Klippel cases of unilateral or lower limb involvement - dy- JH, Dieppe PA. Rheumatology. London: Mosby; namic physical examination should be performed, 1994: 6.8.- 6.11. 10. Hachulla E, Clerson P, Launay D, et al. Natural his- Doppler ultrasound of peripheral vessels and an- tory of ischemic digital ulcers in systemic sclerosis: giography are indicated. Most common causes for single-center retrospective longitudinal study. J such clinical picture are as follows: Rheumatol 2007;34:2423-30. • antiphospholipid syndrome; 11. La Montagna G, Baruffo A, Tirri R, Buono G, Val- • hyperviscosity syndrome - myeloproliferative entini G. Foot involvement in systemic sclerosis: a syndromes, cryoglobulinemia, cryofi brinogenemia; longitudinal study of 100 patients. Semin Arthritis • mimickers of vasculitides (peripheral atheroscle- Rheum 2002;31(4):248-55. rosis, atherosclerosis with cholesterol emboli - after 12. Kirou KA, Crow MK. Raynaud’s phenomenon. In: Paget SA, et al. Manual of rheumatology and out- coronarography, during anticoagulation therapy), patient orthopedic disorders: diagnosis and therapy. emboli from cardiac or aortic origin (for example 4th ed., Philadelphia, Lippincot Williams & Willkins in infective endocarditis), neoplasms. 2000, 82-7. Nailfold capillaroscopy is the only method for 13. Smolen JS, Steiner G. Mixed connective tis- morphological assessment of nutritive capillaries in sue disease: to be or not to be? Arthritis Rheum the nailfold area. Its main role is to provide dif- 1998;41(5):768-77. ferential diagnosis between primary and secondary 14. Nagy Z, Czirjac L. Nailfold digital capillaroscopy RP. In rheumatology, capillaroscopic changes are in 447 patients with connective tissue disease and Raynaud’s disease. J Europ Acad Dermatol Venerol diagnostic for SSc. The appearance of abnormal 2004;18:62-8. capillaroscopic pattern for development of connec- 15. Lambova S. The role of capillaroscopy in rheumatol- tive tissue disease possesses high predictive value ogy. [Dissertation] Justus Liebig University, Gies-

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Место капилляроскопии ногтевого ложа среди инструментальных методов оценки некоторых периферических ишемических синдро- мов в ревматологии Севдалина Н. Ламбова Кафедра пропедевтики внутренней медицины, Факультет медицины, Медицинский университет, Пловдив, Болгария

Для корреспонденции: Микро- и макроваскулярная патология представляет собой часто встречающе- Севдалина Ламбова, Кафедра еся явление в ряде обычных ревматических заболеваний. Вторичный феномен пропедевтики внутренней Рейно (RP) входит в число наиболее распространенных симптомов при наличии медицины, Факультет медици- систематического склероза и некоторых других систематических аутоиммунных ны, Медицинский университет, заболеваний, включая широкий дифференциальный диагноз. Необходимо его Пловдив, бул. Васила Априлова разграничение и от других васкулярных синдромов, таких как эмболия, тромбоз № 15А, 4002 Пловдив, Болгария и др., некоторые из которых приводят к клиническому проявлению синдрома го- E-mail: [email protected] лубых пальцев. Тел.: +359 889 560 104 В данной разработке рассматриваются инструментальные методы васкулярной Дата получения: 09 марта 2016 г. диагностики. Дата приемки: 04 мая 2016 г. Капилляроскопия ногтевого ложа представляет собой единственный метод в Дата публикации: 30 июнья числе техник визуальной диагностики, который можно использовать для морфо- 2016 г. логической оценки питающих капилляров в области ногтевого ложа. Лазерная допплеровская флоуметрия и лазерное допплеровское исследование являются Ключевые слова: Феномен методами для функциональной диагностики микроциркуляции, в то время как та- Рейно, синдром голубых кие методы, как термография и плетизмография отображают как состояние пото- пальцев, ревматические ка крови в периферических артериях, так и микроциркуляцию крови. С помощью заболевания, микроциркуляция; метода допплеровской ультрасонографии и ангиографии визуализируются пери- капилляроскопия ногтевого ферические артерии. Выбор подходящего инструментального метода основан на ложа клиническом представлении. Основная роль капилляроскопии заключается в предоставлении дифференциального диагноза между первичным и вторичным Цитаты: Ламбова СН. Место RP. В ревматологии капилляроскопические изменения при наличии системати- капилляроскопии ногтевого ческого склероза с недавних пор используются в качестве средства диагностики. ложа среди инструментальных Появление анормальных капилляроскопических признаков унаследует высокий методов оценки некоторых предиктивный показатель развития заболеваний соединительной ткани, являю- периферических ишемических щийся выше предиктивного показателя антиядерных антител. В случаях внезап- синдромов в ревматологии. ного проявления периферической ишемии, клинических признаков критической Folia Medica 2016;58(2);77-88, ишемии, с односторонним вовлечением конечностей или с участием нижних ко- doi: 10.1515/folmed-2016-0011 нечностей, рекомендуется использование допплеровской ультрасонографии и ангиографии. Самой распространенной причиной подобной клинической кар- тины, которую можно соотнести с ревматологической консультацией, являются антифосфолипидный синдром, имитирующие васкулит состояния, такие как ате- росклероз с холестериновой эмболией и неоплазма.

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