Juvenile dermatomyositis: association between nail fold capillary end row loop– area under the curve– and disease damage indicators
Pediatric Rheumatology volume 21, Article number: 137 (2023)
Juvenile Dermatomyositis (JDM) is a rare autoimmune disease characterized by skin and muscle inflammation. The loss of nail fold capillary end row loops (ERL) is evidence of small vessel involvement in JDM. This study aimed to examine the specific association of ERL over the disease course with evidence of JDM disease damage.
We analyzed data from 68 initially treatment-naïve JDM children who had been observed for at least five years with multiple ERL density assessments. The JDM disease course were categorized into monocyclic short, monocyclic long, polycyclic, and chronic. The ERL capillary count was cumulatively evaluated using the area under the curve (AUC) method.
The mean ERL density for the treatment-naive JDM was significantly lower than that of their healthy age-matched controls (4.8 ± 1.6 /mm vs. 7.9 ± 0.9 /mm; p < 0.0001). The ERL AUC was significantly lower in children with a chronic disease course compared to those with a monocyclic short (p = 0.001) or monocyclic long disease course (p = 0.013). JDM patients with lipodystrophy had lower ERL AUC than those without lipodystrophy (p = 0.04). There was no association between ERL AUC and calcifications or fractures.
Persistently decreased ERL capillary density, reflected by low ERL AUC, is associated with a chronic disease course and lipodystrophy in JDM. Despite medical therapy, the mean ERL count remained below normal even after five years, particularly in polycyclic and chronic cases. It is not clear that restoring normal capillary density is currently feasible in children with JDM.
Juvenile Dermatomyositis (JDM) is a systemic pediatric autoimmune disease characterized by skin and muscle inflammation . Although it is the most common pediatric inflammatory myopathy, with an incidence rate of approximately 3.2 cases per million children in the United States, JDM remains a rare disease . Its etiology is not entirely understood, but it is believed to involve a combination of specific genetic predisposition and environmental factors, such as viral infections and exposure to ultraviolet rays [3, 4].
One of the key features of JDM is the loss of nailfold capillary end row loops (ERL), which can be evaluated at the bedside using capillaroscopy [5,6,7]. The loss of capillary ERL indicates small vessel vascular injury, which is further supported by elevated levels of von Willebrand factor antigen (vWF antigen) in the treatment-naïve JDM patients . The reduction in ERL is linked to lower bioavailability of oral prednisone compared to IV methylprednisolone making the oral route of medical therapy less effective . Inadequate treatment of JDM can lead to a higher risk of complications such as calcinosis, deposition of insoluble calcium salts in the skin and subcutaneous tissue, and lipodystrophy [10, 11]. Therefore, defining the association between ERL density and disease progression is important for patient care.
This study aims to examine the association between ERL density over time (5 years) using the area under the curve (AUC) method to define the range of various diseases courses (monocyclic short, monocyclic long, polycyclic, and chronic) in addition to indicators of disease damage (lipodystrophy and calcification).
This retrospective chart review study (IRB# 2012–14,858) was conducted at Ann & Robert H. Lurie Children’s Hospital of Chicago. We included all subjects with the JDM diagnosis based on Bohan and Peter criteria [12, 13] who had at least five years of follow-up data and had at least four ERL assessments at a prespecified time point (0,6,12,24,36,48, and 60 months from initiation of medical therapy). Patients who received medical therapy before the initial ERL assessments, those lacking a five-year follow-up, or those with overlap syndrome were excluded from the analysis. The JDM disease activity was evaluated using standardized scoring systems—the Disease Activity Score (DAS)  and Childhood Myositis Assessment Scale (CMAS) . The demographic data of the JDM children are presented in Table 1.
The study included 77 healthy children as a control group after providing appropriate written consent (IRB# 2001–11,715). These healthy controls did not have any autoimmune disease or active infection at time of their enrollment. In appreciation for their participation in nailfold capillaroscopy, they received a $25 gift card. Demographic details of healthy controls are available in the supplementary materials (Supplemental Table 1).
Children with JDM were categorized into four distinct disease courses according to their treatment response: (A) monocyclic short: if the child completed therapy within the first 36 months without a subsequent disease flare; (B) monocyclic long: if the child completed therapy after 36 months without a subsequent disease flare; (C) polycyclic: if the child had completed treatment but had a subsequent relapse of disease requiring re-initiation of medication; (D) chronic: no clinical resolution within 60 months.
Nailfold capillary ERL studies
Standardized images of the nailfold area were obtained using a Nikon Coolpix p6000 digital camera equipped with a Dermlite2 ProHR (18x). The analysis of the nailfold images was performed by a single experienced observer (GM) using Photoshop. The number of ERL per 3 mm section on each of the eight fingers (excluding thumbs) was counted and subsequently divided by three. Each patient’s mean ERL/mm was calculated by averaging the ERL/mm of the eight fingers [5, 16].
ERL area under the curve calculation
GraphPad Prism was used to calculate the AUC to measure the ERL cumulatively across the study duration. First, the curve was created by plotting the ERL data over time. Then, Prism divides AUC into multiple small trapezoid areas, which are measured individually, using the trapezoid rule [area = ½ (base a + base b) x height], and added up to get the total AUC (Fig. 1).
The Person’s correlation coefficient was utilized to assess the relationship between ERL at diagnosis and ERL AUC. The student t-test was used to compare the mean ERL AUC of subjects with and without signs of disease damage. Statistical analyses were conducted using IBM SPSS Statistics® and GraphPad Prism® version 9.4.1 was utilized to generate the figures.
The study included 68 treatment-naive JDM children, the majority of whom were female (84%). The racial and ethnic distribution was as follows: 75% Caucasian, 19% Hispanic, 3% African American and 3% Others. Their MSAs (Myositis-specific antibodies) were as follows: 41% P155/140+, 3% MJ+, 7.5% Mi-2+, 3% MDA-5+, 7.5% multiple MSAs, and 31% MSA negative (Table 1). The mean age of onset for JDM was 6 ± 3.1 years, and the mean duration of untreated disease was 9.6 ± 10.2 months (Table 2). The initial disease activity scores were 11.0 ± 3.6 for DAS total, 5.9 ± 1.5 for DAS skin, and 5.1 ± 1.5 for DAS muscle, and CMAS score was 37 ± 10.3 (Table 2). The disease course distribution was as follows: 17.6% monocyclic short, 42.6% monocyclic long, 20.6% polycyclic, and 19.1% chronic (Table 1).
The mean ERL count for treatment-naive JDM was 4.8 ± 1.6/mm, which is significantly lower than the healthy control, 7.9 ± 0.9/mm (p < 0.0001). Despite the improvement in mean ERL count over time, it still remained below the expected normal level obtained in healthy controls (6.1–9.7/mm), even after five years of medical therapy (Fig. 2). The rate of improvement varied depending on the different disease courses, with the monocyclic short disease course showing more change than the other groups (4.8 ± 1.5/mm at baseline vs. 6.7 ± 1.5/mm at 12 months, p = 0.038 paired T-test).
To evaluate the accumulative effects of chronic ERL capillary loss, the ERL AUC was calculated for each patient (Fig. 1). Although there was a positive correlation between the initial ERL count and ERL AUC, the correlation was not strong (r2 = 0.18, p = 0.001). There was a significant difference between the ERL AUC for monocyclic short vs. chronic (389 ± 46.46 vs. 313 ± 46.69, p = 0.001) and monocyclic long vs. chronic (359 ± 44.53 vs. 313 ± 46.69, p = 0.013) (Fig. 3a). Next, the relationship between ERL AUC and indicators of disease damage (lipodystrophy and calcification) was evaluated. JDM patients with lipodystrophy exhibited a lower ERL AUC than those without lipodystrophy (335.7 ± 52.52 vs. 363.0 ± 47.13, p = 0.04) (Fig. 3b). However, the ERL AUC had no significant association with calcifications (Fig. 3c). Lastly, the relationship between ERL AUC and fractures was assessed, revealing no significant correlation (Fig. 3d).
Next, we evaluated the effect of medical treatment on ERL AUC. There was a negative correlation between the duration of oral steroid use and ERL AUC (r2 = 0.12, p = 0.004). Patients who required multiple immunosuppressive medications (additional immunosuppression more than steroid, hydroxychloroquine, and methotrexate) tended to have a lower ERL AUC (339.9 ± 46.8 vs. 371.0 ± 51.0, p = 0.01) (Fig. 4).
This study provides insight into the association between endothelial dysfunction demonstrated by decreased ERL count and disease progression in children with JDM. Consistent with previous studies, we observed a significantly lower mean ERL density in untreated JDM children compared to healthy controls [6, 7]. This finding supports the concept of endothelial involvement in JDM pathophysiology . Furthermore, the reduction in ERL count often correlates with the severity of skin disease and/or muscle weakness [6, 17], suggesting its possible role as a potential physical exam indicator ofr disease activity. Few studies have evaluated the changes in capillary density and disease activity longitudinally over the disease course [17, 18]. We observed variations in the rate of improvement in ERL count in the different JDM disease courses. Monocyclic disease courses show improvement of the ERL capillary count at a faster rate than that of chronic disease. This finding suggests that the rate of improvement in ERL count may be a more critical factor than the initial ERL count in predicting disease course and outcome.
Despite medical therapy, the mean ERL count in JDM patients remained below normal levels even after five years of treatment, particularly in the polyphasic and chronic disease courses. This implies that the restoration of capillary density might be challenging to achieve and may require additional novel therapeutic strategies to target endothelial dysfunction effectively .
Additionally, we utilized the AUC method to evaluate the cumulative change in ERL capillary density over the study period. Our results demonstrated a correlation between ERL AUC and a more chronic disease course, as well as the presence of complications such as lipodystrophy. Of note, we found a weakly positive correlation between the initial ERL count and ERL AUC, which suggests that factors other than the initial capillary density, including MSAs, may contribute to the cumulative capillary loss. For example, it has been shown JDM with anti-P155/140 antibody tend to have lower ERL capillary count and are less likely to have a monophasic disease course . However, our study was not powered enough to investigate the impact of the type or the duration of different MSAs on ERL AUC.
Circulating endothelial cells and markers of endothelial injury, such as vWF antigen, and thrombomodulin are elevated in JDM, providing further evidence of endothelial involvement in the disease pathophysiology [8, 19, 20]. B cell activation and expansion as well as the formation of anti-endothelial cell antibodies have been demonstrated in JDM [21,22,23,24], suggesting other potential mechanisms for endothelial cell injury. Soluble adhesion molecule markers, such as ICAM-1, ICAM-3, and VCAM1, and inflammatory cytokine and markers like neopterin have been used as possible biomarkers of vasculopathy in JDM [25,26,27]. These findings highlight the complex interplay between immune dysregulation and endothelial dysfunction in JDM, requiring further investigation to elucidate the underlying mechanisms. Furthermore, it is important to recognize the clinical implications of microvascular injury in JDM as it can affect the gastrointestinal system . The reduced nailfold capillary density observed in JDM has been associated with impaired absorption of oral prednisone, potentially leading to suboptimal drug levels and ineffective treatment . Therefore, administering medications by the intravenous or subcutaneous routes might be preferred in patients with persistently low ERL counts.
The study has several limitations. First, the sample size is relatively small, particularly when considering the potential heterogeneity within the JDM population. Second, the diagnosis of lipodystrophy was based on physician assessment, which can introduce some subjectivity. Lastly, the study was conducted at a single center, potentially limiting the generalizability, especially in geographic regions where P155/140 autoantibodies are not the predominant autoantibody.
Persistently decreased ERL capillary density documented by low ERL AUC is associated with both a chronic disease course and lipodystrophy in JDM. Despite medical therapy, the mean ERL count remained below normal, even after five years, particularly in polycyclic and chronic cases. Therefore, restoring normal ERL capillary density might be challenging and require novel therapeutic strategies targeting endothelial dysfunction.
The data that support the findings of this study are available from the corresponding author, [LMP], upon reasonable request.
End row loops
Area under the curve
- vWF antigen:
von Willebrand factor antigen
Disease Activity Score
Childhood Myositis Assessment Scale
Pachman LM, Nolan BE, DeRanieri D, Khojah AM. Juvenile Dermatomyositis: New clues to diagnosis and therapy. Curr Treatm Opt Rheumatol. 2021;7(1):39–62.
Mendez EP, Lipton R, Ramsey-Goldman R, Roettcher P, Bowyer S, Dyer A, et al. US incidence of juvenile dermatomyositis, 1995–1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum. 2003;49(3):300–5.
Pachman LM, Khojah AM. Advances in Juvenile Dermatomyositis: Myositis specific antibodies aid in understanding Disease Heterogeneity. J Pediatr. 2018;195:16–27.
Costin C, Morgan G, Khojah A, Klein-Gitelman M, Pachman LM. Lower NK cell numbers in children with untreated juvenile Dermatomyositis during the COVID-19 pandemic. Clin Immunol Commun. 2023.
Khojah A, Liu V, Savani SI, Morgan G, Shore R, Bellm J, et al. Association of p155/140 Autoantibody with loss of Nailfold Capillaries but not generalized Lipodystrophy: a study of ninety-six children with Juvenile Dermatomyositis. Arthritis Care Res (Hoboken). 2022;74(7):1065–9.
Smith RL, Sundberg J, Shamiyah E, Dyer A, Pachman LM. Skin involvement in juvenile dermatomyositis is associated with loss of end row nailfold capillary loops. J Rheumatol. 2004;31(8):1644–9.
Christen-Zaech S, Seshadri R, Sundberg J, Paller AS, Pachman LM. Persistent association of nailfold capillaroscopy changes and skin involvement over thirty-six months with duration of untreated Disease in patients with juvenile dermatomyositis. Arthritis Rheum. 2008;58(2):571–6.
Gibbs EKA, Morgan G, Ehwerhemuepha L, Pachman LM. The Von Willebrand Factor Antigen reflects the Juvenile Dermatomyositis Disease activity score. Biomedicines. 2023;11(2):552.
Rouster-Stevens KA, Gursahaney A, Ngai KL, Daru JA, Pachman LM. Pharmacokinetic study of oral prednisolone compared with intravenous methylprednisolone in patients with juvenile dermatomyositis. Arthritis Rheum. 2008;59(2):222–6.
Saini I, Kalaivani M, Kabra SK. Calcinosis in juvenile dermatomyositis: frequency, risk factors and outcome. Rheumatol Int. 2016;36(7):961–5.
Bingham A, Mamyrova G, Rother KI, Oral E, Cochran E, Premkumar A, et al. Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity. Med (Baltim). 2008;87(2):70–86.
Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292(8):403–7.
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.
Bode RK, Klein-Gitelman MS, Miller ML, Lechman TS, Pachman LM. Disease activity score for children with juvenile dermatomyositis: reliability and validity evidence. Arthritis Rheum. 2003;49(1):7–15.
Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, Ruperto N, et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: physician and Patient/Parent global activity, manual muscle testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity score (DAS), short form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, myositis damage index (MDI), quantitative muscle testing (QMT), Myositis Functional Index-2 (FI-2), Myositis activities Profile (MAP), inclusion body myositis functional rating scale (IBMFRS), cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), cutaneous Assessment Tool (CAT), Dermatomyositis skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011;63(0 11):118–57.
Pachman LM, Morgan G, Klein-Gitelman MS, Ahsan N, Khojah A. Nailfold capillary density in 140 untreated children with juvenile dermatomyositis: an indicator of Disease activity. Pediatr Rheumatol. 2023;21(1):118.
Schmeling H, Stephens S, Goia C, Manlhiot C, Schneider R, Luthra S, et al. Nailfold capillary density is importantly associated over time with muscle and Skin Disease activity in juvenile dermatomyositis. Rheumatology (Oxford). 2011;50(5):885–93.
Lim LS, Pullenayegum E, Moineddin R, Gladman DD, Silverman ED, Feldman BM. Methods for analyzing observational longitudinal prognosis studies for rheumatic Diseases: a review & worked example using a clinic-based cohort of juvenile dermatomyositis patients. Pediatr Rheumatol Online J. 2017;15(1):18.
Papadopoulou C, Chew C, Wilkinson MGL, McCann L, Wedderburn LR. Juvenile idiopathic inflammatory myositis: an update on pathophysiology and clinical care. Nat Rev Rheumatol. 2023;19(6):343–62.
Kishi T, Chipman J, Evereklian M, Nghiem K, Stetler-Stevenson M, Rick ME, et al. Endothelial activation markers as Disease activity and damage measures in Juvenile Dermatomyositis. J Rheumatol. 2020;47(7):1011–8.
Karasawa R, Tamaki M, Sato T, Tanaka M, Nawa M, Yudoh K, et al. Multiple target autoantigens on endothelial cells identified in juvenile dermatomyositis using proteomics. Rheumatology (Oxford). 2018;57(4):671–6.
Yu HH, Chang HM, Chiu CJ, Yang YH, Lee JH, Wang LC, et al. Detection of anti-p155/140, anti-p140, and antiendothelial cells autoantibodies in patients with juvenile dermatomyositis. J Microbiol Immunol Infect. 2016;49(2):264–70.
Bukhari A, Khojah A, Marin W, Khramtsov A, Khramtsova G, Costin C, et al. Increased otoferlin expression in B cells is Associated with muscle weakness in untreated juvenile dermatomyositis: a pilot study. Int J Mol Sci. 2023;24(13):10553.
Ochfeld E, Hans V, Marin W, Ahsan N, Morgan G, Pachman LM, et al. Coding joint: kappa-deleting recombination excision circle ratio and B cell activating factor level: predicting juvenile dermatomyositis rituximab response, a proof-of-concept study. BMC Rheumatol. 2022;6(1):36.
Khojah A, Morgan G, Pachman LM. Clues to Disease Activity in Juvenile Dermatomyositis: neopterin and other biomarkers. Diagnostics (Basel). 2021;12(1).
McLellan K, Papadopoulou C. Update on biomarkers of Vasculopathy in Juvenile and Adult Myositis. Curr Rheumatol Rep. 2022;24(7):227–37.
Bloom BJ, Miller LC, Blier PR. Soluble adhesion molecules in pediatric rheumatic Diseases. J Rheumatol. 2002;29(4):832–6.
Wang A, Khojah A, Morgan G, Pachman LM. Nailfold capillary dropout precedes the presentation of Pneumatosis Intestinalis and micro-perforation in juvenile dermatomyositis. Clin Immunol Commun. 2023;3:74–6.
The authors acknowledge and appreciate the contributions of the many Pachman Lab members and the Division of Pediatric Rheumatology who enabled the data collection: Dr. Klein-Gitelman cared for the JDM patients over the past 6 years. Drs. Megan Curran, Kaveh Ardalan and Christopher Costin were also involved. Dr. Amer Khojah started the data analysis while he was on the staff of Ann & Robert H. Lurie Children’s Hospital of Chicago, and completed his work while at Umm Al-Qura University.
This study is supported in part by R-21 AR077565, and the CureJM Foundation Center of Excellence (both to LMP). The data in this project is entered in REDCap, which is supported by NUCATS, and funded in part by a Clinical and Translational Science Award (CTSA) grant from the National Institutes of Health (NIH), UL1TR001422. Amer Khojah would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code (23UQU4300201DSR10).
Ethics approval and consent to participate
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Ann & Robert H. Lurie Children’s Hospital of Chicago (IRB# 2012–14,858). Signed informed consent was obtained from all subjects involved in the study.
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Consent for publication was obtained from all study subjects.
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Khojah, A., Morgan, G., Klein-Gitelman, M.S. et al. Juvenile dermatomyositis: association between nail fold capillary end row loop– area under the curve– and disease damage indicators. Pediatr Rheumatol 21, 137 (2023). https://doi.org/10.1186/s12969-023-00919-3