HERALD of North-Western State Medical University named after I.I. MechnikovHERALD of North-Western State Medical University named after I.I. Mechnikov2618-71162618-9704Eco-Vector4399610.17816/mechnikov43996Research ArticlePossibilities of nailfold capillaroscopy in the differential diagnosis of immuno-inflammatory and rheumatological diseasesPeninIlya N.<p>Rheumatologist</p>md_pin@mail.ruMaslyanskiyA. L.<p>Senior Researcher of Rheumatology Department, Almazov National Medical Research Centre</p>esc_4@mail.ruhttps://orcid.org/0000-0003-2427-4148KonradiA. O.<p>MD, Professor, Corresponding Member Russian Academy of Sciences, Deputy General Director for Science, Head of the Research Department of Hypertension</p>konradi@almazovcentre.ruhttps://orcid.org/0000-0001-8169-7812MazurovVadim I.<p>D. Sci. (Med.), Prof., RAS academician, Head of the research institute of Rheumatology, head of Department of Therapy, Rheumatology, Examination of Temporary Disability and Quality of Medical Care named after E.E.Eichwald </p>maz.nwgmu@yandex.ruhttps://orcid.org/0000-0002-0797-2051Almazov National Medical Research CentreLeningrad Regional Clinical HospitalITMO UniversityNorth-Western State Medical University named after I.I. Mechnikov2012202012321261209202022092020Copyright © 2020, Penin I.N., Maslyanskiy A.L., Konradi A.O., Mazurov V.I.2020<p>This article considers capillaroscopic changes in the patients with systemic sclerosis compared to the patients with a group of rheumatological diseases (rheumatoid arthritis, polymyositis, osteoarthritis) and the patients with idiopathic pulmonary hypertension. All the patients diagnosed with systemic sclerosis according to nailfold capillaroscopy had a characteristic combination of capillary disorders (Raynauds syndrome): the expansion of all three segments of the capillary loop, the loss of capillaries, and the destruction of the nail fold. In the comparison groups, the capillaroscopic picture was represented by single pathological changes that did not add up to the pathognomonic scleroderma patterns, with the exception of the groups with dermato/polymyositis, where 2 patients had significant Raynauds syndrome. There were also significant differences in the density of the capillaries in the patients with systemic sclerosis in comparison with the other groups.</p>capillaroscopysystemic sclerosisrheumatoid arthritispolymyositisosteoarthritispulmonary arterial hypertensionкапилляроскопиясистемная склеродермияревматоидный артритполимиозитостеоартритлегочная артериальная гипертензия<h2>Introduction</h2>
<p>Capillaroscopic analysis of the microvasculature was established in 1939 when Muller published various color capillaroscopic images. In the following decades, capillaroscopy method gained importance in the diagnosis of Raynauds syndrome and associated pathological conditions since Maricq and LeRoy published in 1973 the first study to describe specific capillaroscopic patterns in systemic sclerosis (SS) [1].</p>
<p>In 1976, the same authors noted a continuous change in the nature of the capillary blood flow during cold exposure in both primary and secondary Raynauds syndrome. Detailed studies by Bollinger, Grassi, Carpentier, and Herrick (19801990) contributed to the further use of nailfold capillaroscopy (NFC) in the diagnosis of rheumatological diseases [24].</p>
<p>In 2000, Cutolo et al. identified three main NFC patterns, namely, early, active, and late, to identify and assess the progression of microangiopathy in SS and created a qualitative and semi-quantitative assessment system of the recorded alterations [5, 6]. Since 2004, the European League Against Rheumatism (EULAR) has held annual training courses on NFC, which indicates an increased interest and the need to master this technique. In addition, capillaroscopy was included in the 2013 American College of Rheumatology (ACR)/EULAR criteria for diagnosis of SS.</p>
<p><strong>This study aimed</strong> to compare capillaroscopic changes in the nail bed in SS and in rheumatological diseases (such as rheumatoid arthritis, polymyositis, and osteoarthritis) and idiopathic pulmonary hypertension.</p>
<h2>Materials and methods</h2>
<p>The SS group included 68 patients. The 1980 APA classification criteria were used to verify the diagnosis. Of the 68 patients, 32 had a diffuse form and 36 had a limited form. The median age was 50.2 [42.060.0] years, and the median disease duration was 7 [3.09.0] years. Most of the patients were women (98%).</p>
<p>The comparison groups were as follows:</p>
<ol>
<li>Thirteen patients (11 women and 2 men) with idiopathic pulmonary hypertension, with median age of 51 [33.060.0] years and median disease duration of 12.6 [6.418.5] months.</li>
<li>Twenty patients (18 women and 2 men) with rheumatoid arthritis diagnosed based on the 2010 EULAR criteria, with median age of 62.5 [44.078.0] years and median disease duration of 18.2 [8.024.5] months.</li>
<li>Twenty patients with primary generalized osteoarthritis (16 women and 4 men), with median age of 59.5 [44.082.0] years and median disease duration of 15.4 [12.218.4] months.</li>
<li>Twelve patients (all women) with primary dermatomyositis/polymyositis (diagnosed based on the criteria developed by Bohan and Peter in 1975). The median age was 55.3 [29.071.0] years, and the median disease duration was 20.4 [16.325.7] months.</li>
</ol>
<p>NFC was performed using a DigiMicro Lab 5.0 digital microscope. Lesions of the microvasculature were assessed according to the proportions of the parameters of sclerodermic patterns (such as giant capillaries, loss of capillaries, microhemorrhages, and capillary branching). Three main patterns are generally accepted in the standards of capillaroscopic research technique, namely, early, active, and late (Figs. 14).</p>
<p></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 1. Normal structure of capillaroscopic pattern. Homogeneous structure of the capillaries, their parallelism. Capillary density is more than 7 capillaries per 1 mm2" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77603-2-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77603-2-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 1. Normal structure of capillaroscopic pattern. Homogeneous structure of the capillaries, their parallelism. Capillary density is more than 7 capillaries per 1 mm2</strong></p>
<p><strong>Рис. 1. </strong><strong>Нормальная структура капилляроскопического паттерна. Однородная структура капилляров, их параллельность. Плотность</strong> <strong>на</strong><strong> 1 </strong><strong>мм</strong><strong><sup>2</sup></strong> <strong>более</strong><strong> 7 </strong><strong>капилляров</strong></p>
<p><strong></strong></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 2. Early pattern. The capillaries with dilated ascending and descending loops, marked loss of parallelism. Capillary density is normal: more than 7 capillaries per 1 mm2" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77604-2-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77604-2-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 2. Early pattern. The capillaries with dilated ascending and descending loops, marked loss of parallelism. Capillary density is normal: more than 7 capillaries per 1 mm2</strong></p>
<p><strong>Рис</strong><strong>. 2. </strong><strong>Ранний паттерн. Капилляры с расширенными восходящими и нисходящими петлями, отмечается потеря параллельности. Плотность</strong> <strong>нормальная</strong><strong>, </strong><strong>более</strong><strong> 7 </strong><strong>капилляров</strong> <strong>на</strong><strong> 1 </strong><strong>мм</strong><strong><sup>2</sup></strong></p>
<p><strong></strong></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 3. Active pattern. The dilated capillaries with a more than three-fold increase in the diameter (giant capillaries). Non-parallelism is more expressed than in the early pattern. Capillary density is less than 7 capillaries per 1 mm2" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77605-2-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77605-2-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 3. Active pattern. The dilated capillaries with a more than three-fold increase in the diameter (giant capillaries). Non-parallelism is more expressed than in the early pattern. Capillary density is less than 7 capillaries per 1 mm2</strong></p>
<p><strong>Рис</strong><strong>. 3. </strong><strong></strong><strong>Активный</strong><strong> </strong><strong>паттерн</strong><strong>. </strong><strong>Расширенные капилляры с увеличением диаметра более чем в 3 раза от нормы (гигантские капилляры). Непараллельность выражена больше, чем при раннем паттерне. Плотность капилляров менее 7 на 1 мм</strong><strong><sup>2</sup></strong></p>
<p><strong></strong></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 4. Late pattern. A rapid decrease in density of the capillaries, complete destruction of the capillary structure, the signs of neoangiogenesis" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77606-2-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-77606-2-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 4. Late pattern. A rapid decrease in density of the capillaries, complete destruction of the capillary structure, the signs of neoangiogenesis</strong></p>
<p><strong>Рис. 4. </strong><strong>Поздний паттерн. Резкое снижение плотности капилляров, полное разрушение структуры капилляров, признаки неоангиогенеза</strong></p>
<p></p>
<p>The experiment was performed using immersion oil applied to the base of the nail bed of the phalanges of fingers IIV of both hands. Parameters such as morphology, architecture, and capillary density were evaluated. When the number of pathologically altered capillaries correlated with the number of capillaries along 1 mm in the distal row of the nail bed, a semi-quantitative assessment of morphological changes was also performed. The average value for each capillaroscopic parameter was calculated by analyzing at least two fields in the middle area of the nail bed of each finger. The average values of each of these eight fingers were added and then divided by eight. The resulting index for each capillaroscopic parameter was analyzed according to the system presented in Fig. 5 (03 points).</p>
<p></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 5. Semi-quantitative assessment of capillaroscopic changes" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96407-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96407-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 5. Semi-quantitative assessment of capillaroscopic changes</strong></p>
<p><strong>Рис</strong><strong>. 5. </strong><strong>Полуколичественная</strong> <strong>оценка</strong> <strong>капилляроскопических</strong> <strong>изменений</strong></p>
<p></p>
<h2>Results</h2>
<p>In all patients with SS, the NFC revealed a characteristic pathognomonic combination of capillary disorders in the nail bed, namely, dilatation of all three segments of the capillary loop, loss of capillaries, and destruction of the nail capillary bed. Many branched capillaries were also recorded. According to the proportions of the parameters of the scleroderma pattern (i.e., giant capillaries, loss of capillaries, microhemorrhages, and branching of the capillaries), one of three main patterns (i.e., early, active, and late) was identified in all subjects. The ratios of these patterns were 10%, 45%, and 45%, respectively.</p>
<p>The distribution of patterns depending on the disease duration was established. Table presents the sensitivity and specificity of various elements of the capillaroscopic patterns in patients with varying disease durations.</p>
<p></p>
<p>Sensitivity and specificity of various elements of the capillaroscopic pattern in the patients with systemic scleroderma of different duration</p>
<p>Чувствительность и специфичность различных элементов капилляроскопического паттерна у больных системной склеродермией с различной длительностью заболевания</p>
<table>
<tbody>
<tr>
<td rowspan="2">
<p>Systemic sclerosis</p>
</td>
<td colspan="2">
<p>Early pattern</p>
</td>
<td colspan="2">
<p>Active pattern</p>
</td>
<td colspan="2">
<p>Late pattern</p>
</td>
</tr>
<tr>
<td>
<p>Sensitivity, %</p>
</td>
<td>
<p>Specificity, %</p>
</td>
<td>
<p>Sensitivity, %</p>
</td>
<td>
<p>Specificity, %</p>
</td>
<td>
<p>Sensitivity, %</p>
</td>
<td>
<p>Specificity, %</p>
</td>
</tr>
<tr>
<td>
<p>Early form</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>66,67</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p></p>
</td>
<td>
<p></p>
</td>
</tr>
<tr>
<td>
<p>Active form</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>94,4</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
</tr>
<tr>
<td>
<p>Late form</p>
</td>
<td>
<p>50</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
<td>
<p>100</p>
</td>
</tr>
</tbody>
</table>
<p></p>
<p>In the comparison groups, the capillaroscopic pattern was represented by single pathological changes in the capillaries that did not indicate pathognomonic sclerodermic patterns, except for the group with dermatomyositis/polymyositis where significant Raynauds syndrome was diagnosed in two patients (Figs. 69).</p>
<p></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 6. Pathological changes of the capillary bed in the group of patients with idiopathic pulmonary hypertension" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96408-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96408-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 6. Pathological changes of the capillary bed in the group of patients with idiopathic pulmonary hypertension</strong></p>
<p><strong>Рис. 6. </strong><strong>Патологические изменения капиллярного русла в группе пациентов с идиопатической легочной гипертензией</strong></p>
<p></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 7. Pathological changes of the capillary bed in the group of patients with osteoarthritis" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96409-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96409-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 7. Pathological changes of the capillary bed in the group of patients with osteoarthritis</strong></p>
<p><strong>Рис. 7. </strong><strong>Патологические изменения капиллярного русла в группе пациентов с остеоартритом</strong></p>
<p><strong></strong></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 8. Pathological changes of the capillary bed in the group of patients with rheumatoid arthritis" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96410-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96410-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 8. Pathological changes of the capillary bed in the group of patients with rheumatoid arthritis</strong></p>
<p><strong>Рис. 8. </strong><strong>Патологические изменения капиллярного русла в группе пациентов с ревматоидным артритом</strong></p>
<p><strong></strong></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 9. Pathological changes of the capillary bed in the group of patients with dermato/polymyositis" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96411-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96411-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 9. Pathological changes of the capillary bed in the group of patients with dermato/polymyositis</strong></p>
<p><strong>Рис. 9. </strong><strong>Патологические изменения капиллярного русла в группе пациентов с дермато/полимиозитом</strong></p>
<p></p>
<p>In 13 patients with idiopathic pulmonary hypertension, NFC revealed capillary dilatation (<em>n</em> = 7) and pathological tortuosity and microhemorrhages (<em>n</em> = 4) in all study fields. These abnormalities may be associated with microangiopathy that occurs with endothelial dysfunction or damage due to an imbalance between vasodilation and vasoconstriction.</p>
<p>In 20 patients with osteoarthritis, NFC showed dilatation and pathological tortuosity of the capillaries (<em>n</em> = 2 each) in all study fields. These abnormalities are clinically insignificant and may be caused by angiopathy in nodular osteoarthritis.</p>
<p>In 20 patients with rheumatoid arthritis, NFC revealed capillary dilatation (<em>n</em> = 3) and pathological tortuosity (<em>n</em> = 4) in all study fields. These abnormalities are clinically insignificant and may be associated with the initial manifestations of digital vasculitis.</p>
<p>In 12 patients with primary dermatomyositis/polymyositis, NFC revealed capillary dilatation (<em>n</em> = 8) and pathological tortuosity (<em>n</em> = 6) in all study fields. Three alterations of each type, namely, non-parallel capillaries, microhemorrhages, and avascular areas, were detected. Capillary dilatation, pathological tortuosity, microhemorrhages, non-parallel capillaries, and avascular areas in two patients formed a pathognomonic presentation caused by Raynauds syndrome, which is detected in this rheumatological disease. In other patients, the alterations were clinically insignificant.</p>
<p>Compared with the patients in the comparison groups, patients with SS showed a decrease capillary density (<em>p</em> = 0.0003) (Fig. 10).</p>
<p></p>
<center>
<div class="preview fancybox" style="text-align: center;"><a title="Fig. 10. Comparison of capillary density in different groups ( mean; mean error; mean deviation, p relative to the group with systemic scleroderma). The patient groups: 1 with systemic scleroderma; 2 with idiopathic pulmonary hypertension; 3 control group; 4 with osteoarthritis; 5 with rheumatoid arthritis; 6 with dermato/polymyositis" href="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96412-1-SP.jpg" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="https://journals.eco-vector.com/files/journals/20/articles/43996/supp/43996-96412-1-SP.jpg" /></a></div>
</center>
<p><strong>Fig. 10. Comparison of capillary density in different groups ( mean; mean error; mean deviation, p relative to the group with systemic scleroderma). The patient groups: 1 with systemic scleroderma; 2 with idiopathic pulmonary hypertension; 3 control group; 4 with osteoarthritis; 5 with rheumatoid arthritis; 6 with dermato/polymyositis</strong></p>
<p><strong>Рис. 10.</strong><strong> Сравнение плотности капилляров в разных группах ( среднее; средняя ошибка; среднее отклонение, <em>p</em> относительно группы пациентов с системной склеродермией). Группы пациентов: 1 с системной склеродермией; 2 с идиопатической легочной гипертензией, 3 группа контроля; 4 с остеоартритом; 5 с ревматоидным артритом; 6 с дермато/полимиозитом</strong></p>
<p></p>
<h2>Discussion</h2>
<p>In this study, specific changes in the capillary network (i.e., capillaroscopic patterns) were found in the group of patients with SS. Moreover, significant differences were found in the capillary network density in patients with SS when compared with the patients of the comparison groups (<em>p</em> = 0.0003). This confirms the high diagnostic value of NFC. In 2001, LeRoy and Medsger proposed the criteria for the early diagnosis of SS with Raynauds syndrome as the only major clinical manifestation that were included in the ACR/EULAR criteria in 2013. These criteria are SS-specific autoantibodies and specific sclerodermic abnormalities detected by capillaroscopy.</p>
<h2>Conclusions</h2>
<p>The results of this study suggest that NFC is the safest, most atraumatic, and easy-to-perform technique of microvasculature morphological examination in patients with Raynauds syndrome. NFC is characterized by high diagnostic specificity and sensitivity in the measures for the differential diagnosis of SS and other rheumatic and immunoinflammatory diseases. The capillary density in patients with SS was significantly lower than those of patients of the comparison groups (<em>p</em> = 0.0003).</p>[Maricq HR, LeRoy EC. Patterns of finger capillary abnormalities in connective tissue disease by “wide-field” microscopy. Arthritis Rheum. 1973;16(5):619-628. https://doi.org/10.1002/art.1780160506.][Bollinger A, Jäger K, Roten A, et al. Diffusion, pericapillary distribution and clearance of Na-fluorescein in the human nailfold. Pflugers Arch. 1979;382(2):137-143. https://doi.org/10.1007/bf00584215.][Bukhari M, Herrick AL, Mooreet T, al. Increased nailfold capillary dimensions in primary Raynaud’s phenomenon and systemic sclerosis. Br J Rheumatol. 1996;35(11):1127-1131. https://doi.org/10.1093/rheumatology/35.11.1127.][Grassi W, Core P, Carlino G, et al. Labial capillary microscopy in systemic sclerosis. Ann Rheum Dis. 1993;52(8): 564-569. https://doi.org/10.1136/ard.52.8.564.][Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 2000;27(1):155-160.][Smith V, Pizzorni C, De Keyser F, et al. Reliability of the qualitative and semiquantitative nailfold videocapillaroscopy assessment in a systemic sclerosis cohort: A two-centre study. Ann Rheum Dis. 2010;69(6):1092-1096. https://doi.org/10.1136/ard.2009.115568.]