|Ahead of print publication
Nailfold capillaroscopy in early stages of mixed connective tissue disease in a sample of Egyptian patients
Yasser A Elmotaleb Gazar1, Hesham Salah Hamoud1, Sherif Mohamed Ismail2
1 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 National Research Center, Cairo, Egypt
|Date of Submission||01-Aug-2021|
|Date of Acceptance||14-Nov-2021|
|Date of Web Publication||19-Mar-2022|
Yasser A Elmotaleb Gazar,
Department of Rheumatology and Rehabilitation, Faculty of Medicine, AL-Azhar university Hospitals, Cairo
Source of Support: None, Conflict of Interest: None
Introduction: Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with a high titer of anti-U1 small nuclear ribonucleoprotein particles and a number of clinical pictures, mainly Raynaud's phenomenon. Nailfold capillaroscopy (NFC) is a noninvasive diagnostic tool for patients with different connective tissue diseases that permit detection of local microvascular changes that correlate with systemic vascular involvement.
Aim of the Study: The aim of this study was to compare the results of NFC in patients with systemic sclerosis (SSc) and MCTD to determine the chief characteristics of skin microangiopathy in early MCTD and attempt to describe a characteristic MCTD pattern in Egyptian patients.
Methodology: This cross-sectional study included forty patients diagnosed with MCTD according to Alarcón-Segovia and Villareal criteria and twenty patients with confirmed systemic sclerosis according to the American College of Rheumatology and the European League against Rheumatism classification criteria for Systemic Sclerosis. Nailfold examination for the study subjects was performed describing architectural derangement, capillary density changes, mega capillary and enlarged loops, microhemorrhages, and angiogenesis.
Results: Of the sixty patients studied, 49 (81.7%) patients were females and 11 were males with a mean age of 31 years with a median of 29.5 and range 16–52 years. Three of the twenty patients diagnosed with systemic sclerosis had arthritis. Out of sixty patients, 53.3% had thickened skin, 19 patients exhibited puffy fingers, six patients showed rash, and none had swollen joints. The skin was significantly thicker in systemic sclerosis patients (85%) compared to 37.5% in the MCTD population. Patients presented with various features, the most common of which was fatigue (26.7%) and myositis (23% of patients). There is a significant negative correlation of −0.508 (P = 0.022) between the enlargement scores and illness duration in systemic sclerosis patients. Those patients also exhibited a statistically significant positive correlation of 0.520 (P = 0.019) between hemorrhage score and the number of tender joints. Alternatively, patients diagnosed with MCTD exhibited a significant positive correlation between the architectural changes scores of their joints and both the duration of their illness (0.347; P = 0.028) and the number of swollen joints (0.424; P = 0.006). MCTD patients also showed a significant correlation of 0.423 (P = 0.007) between their hemorrhage scores and their age at the time of the study.
Conclusion: In this study, the results obtained were qualitatively satisfactory for clear delineation of the nailfold capillaries features in MCTD. Therefore, it aids in the recognition of alternations in nailfold capillaries making an early prediction of course of illness in MCTD patients possible and suggests a potential ability to differentiate from early SSc, thus helps in preventing morbidities and sequelae of the disease.
Keywords: Mixed connective tissue disease, nailfold capillaroscopy, Raynaud's phenomenon, systemic sclerosis
|How to cite this URL:|
Elmotaleb Gazar YA, Hamoud HS, Ismail SM. Nailfold capillaroscopy in early stages of mixed connective tissue disease in a sample of Egyptian patients. Indian J Rheumatol [Epub ahead of print] [cited 2022 Aug 12]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=339939
| Introduction|| |
Mixed connective tissue disease (MCTD) is a systemic autoimmune disease characterized by high titers of autoantibodies targeting the U1 small nuclear ribonucleoprotein particle (U1RNP) and the simultaneous presence of several clinical features, namely Raynaud's phenomenon (RP), “puffy hands,” arthritis, myositis, pleuritis, pericarditis, lung fibrosis, and skin lesions.
Nailfold capillaroscopy (NFC) is a noninvasive diagnostic tool for patients with different connective tissue diseases that permit the detection of local microvascular changes that correlate with systemic vascular involvement. The patterns of systemic sclerosis (SS) and systemic lupus erythematosus (SLE) revealed by NFC are clearly defined.
In systemic diseases, as MCTD, whose prominent feature is microvasculature damage, abnormalities of nailfold capillaries can be detected before the onset of clinical disease. In those patients, changes in the nailfold capillaries may reflect internal organ involvement and therefore help clinicians determine the stage of the disease.
Despite that, few investigators have studied the NFC pattern in MCTD and its correlation with the course of the disease.
In this study, we compared the results of NFC in patients of MCTD with systemic sclerosis in Egyptian patients to determine the main characteristics of skin microangiopathy in early disease which might help predict its course.
| Methodology|| |
This cross-sectional study included forty patients diagnosed with MCTD according to Alarcón-Segovia and Villareal criteria and twenty patients with confirmed systemic sclerosis according to the American College of Rheumatology and the European League Against Rheumatism classification criteria for Systemic Sclerosis published in 2013 (SSc) Those sixty patients were assessed at Al Hussein University Hospital between March 2019 and August 2019. The study protocol was approved by the National Research Center Ethics Committee (IEC approval number 19090, date of approval JAN /2019). Written informed consent was obtained from each participant. The study was conducted in accordance with the principles of the Declaration of Helsinki. None of the patients included in this study had other rheumatic or systemic diseases.
Nailfold examination for the study subjects was done using the Dino-Lite Capillaroscopy Pro (MEDL4N Pro) ×200 magnification and performed by the same researcher for all patients. The following points were scored for the little and ring fingers of each hand for each subject:
- Architectural derangement
- Capillary density changes
- Mega capillary and enlarged loops
Architectural derangement was defined as any changes in the findings for orientation, size, or shape of capillaries and was scored from 0 to 3 with 0 meaning no change. Changes below 33% of all capillaries were given a score of 1. If one-third to two-third (33%–66%) of the capillaries were involved, they were given a score of 2, whereas more than two-third (66%) involvement of the capillaries was scored 3.
Capillary density changes were also given a score between 0 and 3 depending on the intensity of the capillary reduction. Nine or more capillaries per mm were given a score of 0, 6–9 capillaries/mm were scored as 1, 3–6 capillaries/mm are scored as 2, and <3 capillaries were given the score of 3.
Capillaries more than 3–5 times the normal size (between 20 and 50 μm) and 10 times the normal size (above 50 μm) were categorized as enlarged loops and mega capillaries, respectively. The scoring system of abnormalities is exactly like the scoring system where changes below 33% of all capillaries were given the score of 1; if one-third to two-third (33%–66%) of the capillaries are involved, they were given the score of 2; and more than two-third (66%) involvement of the capillaries was scored 3.
Microhemorrhage is described as bleeding beyond the papillae in the distal pulp. This finding was also scored from 0 to 3, where 0 indicates no evidence of bleeding. If one line of bleeding was observed, the patient was given a score of 1; similarly, if two lines of bleeding were observed, a score of 2 was given. Three or more lines of bleeding were given a score of 3.
The last observation is angiogenesis, described in four types as follows:
- Mixed, branched, and turn and twist capillaries (extremely tortuous)
- Existence of four or more capillaries in one papilla
- Very enlarged loops
- And finally, thin and connected capillaries branching of a single loop.
Angiogenesis, too, was given a score from 0 to 3 where no change was scored as 0. Involvement of <1/3 (33%) of capillaries was scored as 1, involvement of between (33% and 66%) of capillaries was scored as 2, and involvement of two-third (66%) or more was scored as 3.
The score of each category was summed for each patient to provide a final total score.
The collected data were coded, tabulated, and statistically analyzed using IBM SPSS statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp., Chicago, Illinois, USA, 2013.
Descriptive statistics was done for quantitative data as minimum and maximum of the range as well as mean ± standard deviation for quantitative normally distributed data, median, and first and third interquartile range for quantitative nonnormally distributed data, whereas it was done for qualitative data as number and percentage.
Inferential analyses were done for quantitative variables using Shapiro–Wilk test for normality testing, independent t-test in cases of two independent groups with normally distributed data, and Mann–Whitney U in cases of two independent groups with nonnormally distributed data. In qualitative data, inferential analyses for independent variables were done using the Chi-square test for differences between proportions and Fisher's exact test for variables with small, expected numbers, while correlations were done using Spearman rho test for numerical nonnormally distributed and qualitative data. Receiver operating characteristic curve was used to evaluate the performance of different tests differentiate between certain groups. The level of significance was taken at P < 0.05.
Diagnostic characteristics were calculated as follows:
- Sensitivity = (True positive test/Total positive golden) × 100
- Specificity = (True negative test/Total negative golden) × 100
- Diagnostic accuracy =
([True positive test + True negative test]/Total cases) × 100
- Youden's index = sensitivity + specificity − 1
- Predictive positive value = (True positive test/Total positive test) × 100
- Predictive negative value = (True negative test/Total negative test) × 100
- LR+ = (Sensitivity/1-specificity)
- LR-= (1-sensitivity/specificity)
- LR = LR+/LR-
| Results|| |
Of the sixty patients studied, 49 (81.7%) patients were females and 11 were males with a mean age of 31 years with a median of 29.5 and range (16–52 years). Three of the twenty patients diagnosed with systemic sclerosis had arthritis. Out of sixty patients, 53.3% had thickened skin, 19 patients exhibited puffy fingers, 6 patients showed rash, and none had swollen joints. Demographic and clinical characteristics were comparable between patients with confirmed systemic sclerosis and patients with MCTD. However, skin thickening was significantly higher in systemic sclerosis patients (85%) compared to 37.5% in the MCTD population.
Patients presented with various features [Table 1], the most common of which was fatigue (26.7%) and myositis (23% of patients).
|Table 1: Demographic and clinical characteristics among the studied cases|
Click here to view
[Table 2] presents laboratory findings. Anti-RNP antibodies were significantly less frequent in Systemic Sclerosis patients at 20%, compared with MCTD patients who all (100%) presented with anti-U1RNP antibodies. Alternatively, antinuclear antibodies and anti-SCL70 were significantly more frequently observed in Systemic Sclerosis patients (80% and 35%) than patients with MCTD. Overall, the total capillaroscopy scores were higher in patients diagnosed with systemic sclerosis as opposed to patients with MCTD [Table 3]. Moreover, median architectural change, density, enlargement, and hemorrhage scores were higher in systemic sclerosis patients. There was no difference in the median neoangiogenesis scores between both groups. As such, only the total capillaroscopy score showed significant differentiation between systemic sclerosis and mixed connective tissue patients [Table 4] and [Figure 1].
|Table 4: Diagnostic performance of capillaroscopy scores in differentiating systemic sclerosis from mixed types|
Click here to view
|Figure 1: ROC curve for capillaroscopy scores in differentiating SSc from mixed types|
Click here to view
Across most patient subgroups, categorized by clinical findings [Table 5], there was no statistically significant difference in any of the five capillaroscopy scores. Only patients testing positive for ANA exhibited statistically significant higher total, density, and enlargement scores than patients testing negative for ANA [Table 6].
|Table 5: Capillaroscopy scores according to some clinical findings among the mixed type|
Click here to view
|Table 6: Capillaroscopy findings according to some laboratory findings among the studied cases|
Click here to view
As shown in [Table 7], there is a significant negative correlation of −0.508 (P = 0.022) between the enlargement scores and illness duration in systemic sclerosis patients. Those patients also exhibited a statistically significant positive correlation of 0.520 (P = 0.019) between hemorrhage score and the number of tender joints. Alternatively, patients diagnosed with MCTD exhibited a significant positive correlation between the architecture scores of their joints and both the duration of their illness (0.347; P = 0.028) and the number of swollen joints (0.424; P = 0.006). MCTD patients also showed a significant correlation of 0.423 (P = 0.007) between their hemorrhage scores and their age at the time of the study.
| Discussion|| |
Early diagnosis is of utmost significance for patients with MCTD, as it often takes years to confirm a diagnosis. As such, the understanding of outcome and how this disease develops is essential.
To our knowledge, few studies discussing NFC in MCTD have been published, none of which identified any capillaroscopic patterns specific for MCTD.
In our study, we tried to add some context to the use of NFC in the diagnosis of the MCTD that may support in the early identification of patients. To achieve that, we compared MCTD findings with a known clinical diagnosis (Systemic sclerosis) that has already established clinical, laboratory, and NFC characteristics.
The results of this study confirm previously reported data that all patients with MCTD exhibit high titers of anti-U1RNP. Despite that, Ungprasert et al. also described high titers of anti-RNP antibodies in 46% of their 264 anti-RNP-positive population, but only 29% of the high anti-RNP pool (35/121) were diagnosed with MCTD.
None of the patients with MCTD in our study exhibited a normal NFC pattern. There are many similarities between NFC findings in MCTD and SS. As our study demonstrates, various capillaroscopy scores were significantly higher in SSc type, except for density scores [Figure 2], [Figure 3] and [Figure 4]. Therefore, the combined presence of an SSc pattern and more dense capillaries can be used as an indicator of MCTD. This finding is consistent with Granier et al. who noted that 12 of the 14 patients (85.7%) in the MCTD subgroup with an SS pattern also exhibited dense capillaries.
|Figure 2: Capillary elongation: Multiple capillaries are seen in this MCTD patient that are elongated in this field (had visible measured length more than 300 nm)|
Click here to view
|Figure 3: Normal capillary density: Picture of one of the MCTD patients showing normal capillary density (more than 9 can be seen within 1 mm in this field)|
Click here to view
|Figure 4: Low capillary density: Picture of one of the SSc patients showing low capillary density (only 3 per 1 mm are seen in this field)|
Click here to view
In our study, we found no significant difference in capillaroscopy findings within the MCTD group which can lead to a conclusion that NFC is similar in all patients with different clinical presentations of MCTD.
The picture is different with regard to laboratory findings since density, enlargement, and total scores were significantly higher in MCTD cases with positive ANA. The latter abnormality was only previously suggestive of SLE and not specific to this disease. Furthermore, enlargement of the capillary loop observed in patients with positive ANA which has not been seen in Systemic Sclerosis should be considered as part of the pattern indicative of a possible future progression to SLE.
Our study showed that in patients diagnosed with MCTD, there were significant positive correlations between architectural change scores and both illness duration and number of swollen joints. This positive correlation was also seen between hemorrhage score and age. In contrast, in SSc patients, a significant negative correlation between enlargement score and illness duration was found. A significant positive correlation between hemorrhage score and number of tender joints was also seen in these patients. Those findings indicate that NFC findings may indicate disease activity or remission.
As our study demonstrated, only the total score had significant moderate diagnostic performance in differentiating SSc from MCTD, and the combination of laboratory and capillaroscopy findings did not yield better diagnostic characteristics. Furst et al. compared the clinical courses of SSc patients with anti-SCL70 versus those of SSc patients without and were able to establish differences.
Therefore, the authors believe that the presented NFC results strengthen the hypothesis that MCTD is more of a clinical subset of SSc rather than a distinct, separate entity.
The limitations of this study were the small sample size, absence of follow-up during disease, and treatment details. Furthermore, the presence of some comorbidities such as diabetes or hypertension which may affect NFC findings was not excluded.
| Conclusion|| |
In this study, the results obtained were qualitatively satisfactory for clear delineation of the nailfold capillaries features in MCTD. Therefore, it aids in the recognition of alternations in nailfold capillaries making early prediction of course of illness in MCTD patients possible and suggests a potential ability to differentiate from early SSc, thus helps in preventing morbidities and sequelae of the disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol 2016;30:95-111.
Grassi W, De Angelis R. Capillaroscopy: Questions and answers. Clin Rheumatol 2007;26:2009.
Etehad Tavakol M, Fatemi A, Karbalaie A, Emrani Z, Erlandsson BE. Nailfold capillaroscopy in rheumatic diseases: Which parameters should be evaluated? Biomed Res Int 2015;2015:974530.
Ciang NC, Pereira N, Isenberg DA. Mixed connective tissue disease-enigma variations? Rheumatology (Oxford) 2017;56:326-33.
Alarcon Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Mixed Connective Tissue Disease and Anti-nuclear Antibodies, Kasukawa R, Sharp G (Eds), Elsevier, Amsterdam 1987. p.33.
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al
. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013;65:2737-47.
Gayraud M. Raynaud's phenomenon. Joint Bone Spine 2007;74:e1-8.
Sulli A, Secchi ME, Pizzorni C, Cutolo M. Scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients. Ann Rheum Dis 2008;67:885-7.
Ingegnoli F, Zeni S, Gerloni V, Fantini F. Capillaroscopic observations in childhood rheumatic diseases and healthy controls. Clin Exp Rheumatol 2005;23:905.
Pavlov-Dolijanovic S, Damjanov NS, Stojanovic RM, Vujasinovic Stupar NZ, Stanisavljevic DM. Scleroderma pattern of nailfold capillary changes as predictive value for the development of a connective tissue disease: A follow-up study of 3,029 patients with primary Raynaud's phenomenon. Rheumatol Int 2012;32:3039-45
Cutolo M, Sulli A, Secchi ME, Olivieri M, Pizzorni C. The contribution of capillaroscopy to the differential diagnosis of connective autoimmune diseases. Best Pract Res Clin Rheumatol 2007;21:1093-108.
Cortes S, Cutolo M. Capillarosecopic patterns in rheumatic diseases. Acta Reumatol Port 2007;32:29-36.
Aringer M, Smolen JS. Mixed connective tissue disease: What is behind the curtain? Best Pract Res Clin Rheumatol 2007;21:1037-49.
Granier F, Vayssairat M, Priollet P, Housset E. Nailfold capillary microscopy in mixed connective tissue disease. Comparison with systemic sclerosis and systemic lupus erythematosus. Arthritis Rheum 1986;29:189-95.
Lee P, Leung FY, Alderdice C, Armstrong SK. Nailfold capillary microscopy in the connective tissue diseases: A semiquantitative assessment. J Rheumatol 1983;10:930-8.
Redisch W, Messina EJ, Hughes G, McEwen C. Capillaroscopic observations in rheumatic diseases. Ann Rheum Dis 1970;29:244-53.
Furst DE, Obrodovic M, Barnett EV, Clements PJ, Paulus HE. Case control study of antibodies to ENA in progressive systemic sclerosis patients. J Rheumatol 1984;11:298-305.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]