Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort

Abstract

Objective:

To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis.

Methods:

Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months.

Results:

One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement.

Conclusion:

In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Introduction

Juvenile systemic sclerosis (jSSc) is an orphan disease with an estimated prevalence of three in 1,000,000 children. ¹ The female to male ratio is approximately 4:1^2,3 and in age under 10 years it is 3:1. ² In adult-onset systemic sclerosis (SSc), the female to male ratio ranges from 3:1 to 7–8:1.^4,5 Although adult males are less frequently affected, they have a difference in SSc organ manifestations and demonstrate a more severe disease course in cohort studies.^4–9 To address if these or other differences are present in jSSc patients we reviewed our patients’ data enrolled in the juvenile systemic sclerosis inception cohort (jSScC) at their baseline visit and after 12 months regarding organ involvement and disease severity, including physician and patient-reported outcomes, between male and female sex.

Methods

The jSScC, as previously described,^2,3,10 is an international prospective observational cohort study, including 25 centers from Europe, five from Asia, six from North America, and six from South America, representing 42 academic institutions. The Medical Council in Hamburg, Germany was the overarching Ethics Committee that approved the research protocol (No. 2894). All participants gave written informed consent. Data were queried January 31, 2021 and include jSSc patients initially enrolled in January 2008–January 2021. All patients met 2013 ACR/EULAR adult classification criteria for SSc, ¹¹ and had standard data collection every 6 months, including demographics, organ involvement, laboratory evaluation, patient-reported outcomes, and physician assessment.^2,10 Baseline visit and data after 12 months after enrollment were analyzed for this report. Regarding assessment of the organ systems, we refer to our previous publication ² and we attached the case report form (CRF) of the baseline/follow-up visit (attachment 1).

Statistical analyses were conducted using SAS software version 9.4. Categorical variables were reported by absolute and relative frequencies and continuously distributed variables by median and interquartile range (25th and 75th percentiles). Comparison between male and female patients of jSSc was performed using chi-square test for categorical variables and Mann–Whitney U test for continuously distributed variables. A p-value of < 0.05 was considered to be statistically significant.

Results

At the time of data query, 175 jSSc patients were enrolled in the international cohort across 42 academic institutions. Thirty-three (19%) of the patients were male, and the female-to-male ratio was 4:1. Diffuse cutaneous SSc was the most common subtype in both female and male subjects, approximately 3/4 in both sexes. Approximately, 80% of the patients were Caucasian in both groups. The median disease duration at time of inclusion in the cohort was comparable, 2.6 years in male and 2.5 in female patients. The mean disease duration was at time of enrollment in the cohort was comparable, 3.4 (±2.8) years in male and 3.1 (±2.7) in female patients. Mean age at enrollment in years (standard deviation): 13.3 (±2.7), 13.7 (±2.8) years in male and 3.1 (±2.7) in female. The median age of onset of Raynaud’s and non-Raynaud’s symptoms was similar in both sexes, at approximately 11 years old. The majority of jSSc patients (88%) were on disease-modifying agents at enrollment (Table 1).

Table 1.

Demographic, serological, and disease manifestations ^ǂ of the 175 juvenile systemic sclerosis patients in the inception cohort at time of enrollment, compared by gender.

	Whole group, N = 175	Female, N = 142	Male, N = 33	Comparison between female and male p-value (bold values significant)
Female-to-male ratio	4.3:1 (142/33)			-
Cutaneous subtype
Diffuse subtype	73% (128/175)	73% (103/142)	76% (25/33)	0.802
Limited subtype	27% (47/175)	27% (39/142)	24% (8/33)
Ethnicity
Caucasian	81% (141/175)	81% (115/142)	79% (26/33)	0.991
African	6% (10/175)	6% (8/142)	6% (2/33)
Indian	9% (15/175)	9% (13/142)	6% (2/33)
Other	5% (9/175)	4% (6/142)	9% (3/33)
Disease duration (years), median (IQR)	2.5 (1–4.4)	2.5 (1–4.4)	2.6 (1.1–5.1)	0.260
Disease duration (years), mean (standard deviation)	3.1 (± 2.7)	3.1 (± 2.7)	3.5 (± 2.8)
Age at onset of Raynaud’s (years), median (IQR)	10.4 (7.2–12.9)	10.3 (7.3–13.1)	10.8 (7.1–12.6)	0.643
Age at onset of non-Raynaud’s (years), median (IQR)	10.9 (7.4–13.4)	10.9 (7.5–13.4)	10.9 (6.5–13.4)	0.535
Mean age at enrollment in years (standard deviation)	13.5 (+3.5) Range, 4.2–17.9	13.2(+ 3.5) Range, 4.3–17.9	13.7 ( + 3.7) Range, 4.2–17.9	0.712
On disease-modifying drugs	88% (154/175)	89% (126/142)	85% (28/33)	0.536
On corticosteroids	49% (84/171)	54% (72/138)	36% (12/33)	0.103
Autoantibody positivity
ANA	91% (156/171)	91% (125/138)	94% (31/33)	0.540
Anti-Scl-70	35% (59/169)	35% (48/136)	33% (11/33)	0.832
Anti-centromere	4% (5/119)	3% (3/93)	8% (2/26)	0.316
Anti-PMScl	18% (12/68)	19% (10/52)	13% (2/16)	0.537
RNA polymerase III	5% (3/65)	6% (3/48)	0% (0/17)	0.561
Laboratory values
ESR elevated (> 20 mmHg)	26% (42/164)	27% (36/135)	21% (6/29)	0.503
CRP elevated (> 5 mg/l)	11% (17/148)	13% (15/120)	7% (2/28)	0.423
Elevated CK	25% (30/122)	23% (23/98)	29% (7/24)	0.561
Pro-BNP increased	18% (4/22)	17% (3/18)	25% (1/4)	0.696
Cutaneous
Modified Rodnan skin score, median (IQR)	12.0 (5–21) (173/175)	10.0 (5–20) (141/142)	17.5 (8–30) (32/33)	0.150
Gottron papules	27% (46/171)	29% (40/139)	19% (6/32)	0.249
Puffy fingers	31% (47/152)	33% (41/126)	23% (6/26)	0.342
Calcinosis	17% (15/86)	15% (11/72)	29% (4/14)	0.230
Sclerodactyly	78% (126/162)	75% (100/133)	90% (26/29)	0.090
Vascular
Raynaud’s phenomenon	90% (158/175)	89% (127/142)	94% (31/33)	0.431
Nailfold capillary changes	75% (120/161)	75% (98/130)	71% (22/31)	0.612
Telangiectasia	36% (56/154)	36% (45/126)	39% (11/28)	0.722
History of ulceration	53% (91/173)	54% (75/140)	48% (16/33)	0.599
Active ulceration	18% (31/173)	14% (20/140)	33% (11/33)	0.010
DUCAS, median (IQR)	0.8 (0–5), n = 82	0 (0–0), n = 70	0.5 (0–2.6), n = 12	0.286
Pulmonary
FVC < 80%	33% (41/125)	30% (30/100)	44% (11/25)	0.182
DLCO < 80%	44% (39/88)	43% (29/68)	50% (10/20)	0.561
Abnormal findings on HRCT	34% (45/133)	33% (36/108)	36% (9/25)	0.595
Six-minute walk test under the normal range (<10th percentile of normal range)	71% (39/55)	70% (32/46)	78% (7/9)	0.620
Composite pulmonary involvement	46% (81/175)	44% (62/142)	58% (19/33)	0.149
Cardiac
Cardiac involvement	6% (10/175)	6% (8/142)	3% (1/33)	0.461
Pulmonary hypertension assessed by US	5% (9/175)	6% (8/142)	3% (1/33)	0.542
Renal
Renal involvement assessed by urinalysis	4% (7/175)	4% (5/142)	6% (2/33)	0.502
Hypertension assessed by RR	1% (1/175)	1% (1/142)	0% (0/33)	0.629
Renal crisis	0% (0/175)	0% (0/142)	0% (0/33)	–
Gastroenterology
Total gastrointestinal involvement	40% (70/175)	42% (60/142)	30% (10/33)	0.207
Total esophageal involvement	38% (66/175)	39% (56/142)	30% (10/33)	0.329
BMI ⩽ −1 z-score	32% (53/167)	29% (39/134)	42% (14/33)	0.141
BMI ⩽ −2 z-score	15% (25/167)	12% (16/134)	27% (9/33)	0.027
Musculoskeletal
Overall	63% (111/175)	64% (91/142)	61% (20/33)	0.709
Presence of swollen joints	18% (32/175)	20% (28/142)	12% (4/33)	0.309
Presence of joints with decreased range	57% (99/175)	58% (83/142)	49% (16/33)	0.298
Presence of joints with pain on motion	21% (37/175)	23% (32/142)	15% (5/33)	0.349
Contractures	49% (85/173)	48% (67/140)	55% (18/33)	0.489
Muscle weakness	21% (31/149)	21% (26/124)	20% (5/25)	0.913
Tendon friction rub	7% (12/164)	5% (7/136)	18% (5/28)	0.019
Neurologic
Overall neurological involvement	3% (5/175)	2% (3/142)	6% (2/33)	0.220

^ǂClinical parameter variables and organ system involvement listed in Table 1 are defined in detail in earlier international juvenile systemic sclerosis cohort (jSScC) publications (Foeldvari et al.^2,3).

HRCT: high-resolution chest tomography; IQR: interquartile range, 25th–75th% ANA: anti-nuclear antibody; Scl: scleroderma; PMScl: polymyositis-scleroderma; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CK: creatine kinase; BNP: B-type natriuretic peptide; DUCAS: Digital Ulcer Clinical Assessment Score; FVC: functional vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; US: ultrasound; RR: assessed by Riva Rocci method; BMI: body mass index.

Serological comparison between male and female groups a time of enrollment

Serologic analyses of auto-antibody positivity, including anti-nuclear antibody, anti-Scl-70, anti-centromere, and anti-RNA polymerase III, did not reveal any significant differences. Evaluation of inflammatory markers, cardiac, and muscle biomarkers did not identify differences between male and female sex (Table 1).

Clinical variable comparison between male and female groups at enrollment

Cutaneous and vascular involvement

The mean-modified Rodnan skin score was slightly higher, but not significantly, in males than in females, 17.5 versus 10.0 (p = 0.150), respectively. Sclerodactyly occurred in 90% of males and 75% of the females (p = 0.090). Regarding microvascular involvement, we found a significantly higher rate of active ulceration in male patients, 33% versus 14% (p = 0.010). The median Digital Ulcer Clinical Assessment Score (DUCAS) ¹² was 0.5 in males and 0.0 in females (p = 0.286). Occurrence of calcinosis was 29% in male patients, compared with 15% in females (p = 0.230) (Table 1).

Cardiopulmonary involvement

Male patients had higher, but not significant, rate of forced vital capacity (FVC) < 80% on pulmonary function testing compared to females, 44% and 30% (p = 0.182), respectively. The composite pulmonary involvement variable (the presence of FVC < 80%, diffusing capacity of the lung for carbon monoxide (DLCO) < 80% or pathologic high-resolution chest tomography (HRCT)) was 58% in the male and 44% in the female patients (p = 0.149). Pulmonary hypertension was infrequent in both sexes (Table 1).

Cardiac involvement was infrequent 6% (n = 8) in female and 3% (n = 1) in male. The only male patient with cardiac involvement had sinus bradyarrhythmia. In the female patients, five of nine had some kind of arrhythmia, one perimyocarditis, one tricuspidal regurgitation, and one mitral prolapse each.

Renal and gastrointestinal involvement

No renal crisis was observed, and only one female patient had hypertension. There were six patients identified with proteinuria and one with microscopic hematuria, with no significant difference between sexes. Although the overall gastrointestinal involvement, including esophageal involvement, was more frequent in females (though not statistically significant), the frequency of those with severe low body mass index (BMI), indicated by age-specific z-scores less than −2 standard deviations (SDs), was significantly higher in males compared to females, 27% and 12 % (p = 0.027), respectively (Table 1).

Musculoskeletal and neurologic involvement

There was no difference in the number of joints with decreased range of motion between males and females (49% vs 58%, p = 0.298). Muscle weakness occurred in approximately 20% in both sexes. The presence of tendon friction rubs was significantly more frequent in males compared with females, 18% and 5% (p = 0.019), respectively. There were only five jSSc patients with neurologic involvement, with no difference of occurrence between sexes (Table 1).

Physician and patient-reported outcomes comparison between male and female groups

Physician rated global disease activity on a 100-point visual analogue scale (VAS) was higher, but not significantly, in males, 40 versus 30 in females (p = 0.154) (Table 2). Physician rated ulceration activity was significantly higher in males (15 vs 0; p = 0.003). Global disease damage rated by the physician VAS demonstrated statistically significantly higher scores in males compared to females (40 vs 25; p = 0.031). Interestingly, patient-reported outcomes did not reveal any significant differences between the sexes, although patient rated ulceration activity was 10 in males compared to 0 in females (p = 0.089). The mean Child Health Assessment Questionnaire (CHAQ) scores were 0.6 in males and 0.5 in females (Table 2).

Table 2.

Patient- and physician-related outcomes of the 175 juvenile systemic sclerosis patients in the cohort, compared by gender.

	Whole group, N = 175	Female, N = 142	Male, N = 33	Comparison between female and male p-value
Physician reported* (median, IQR)
Physician global disease activity	30 (20–45) n = 141	30 (20–45) n = 116	40 (30–60) n = 25	0.154
Physician global disease damage	30 (15–40) n = 140	25 (15–40) n = 115	40 (17–60) n = 25	0.031
Physician ulceration activity	0 (0–20) n = 161	0 (0–10) n = 132	15 (5–25) n = 29	0.003
Patient reported* (median, IQR)
Patient global disease activity	40 (20–55) n = 129	40 (20–50) n = 103	40 (23–68) n = 26	0.827
Patient global disease damage	40 (20–60) n = 128	37.5 (20–54) n = 102	50 (20–60) n = 26	0.613
Patient Raynaud activity	30 (10–50) n = 153	25 (0–50) n = 125	30 (15.3–50) n = 28	0.387
Patient ulceration activity	5 (0–30) n = 154	0 (0–27.8) n = 124	10 (0–30) n = 30	0.089
CHAQ, median IQR	0.3 (0–0.8) n = 108	0.3 (0–0.8) n = 88	0.3 (0–0.7) n = 20	0.930
CHAQ, mean (range)**	0.5 (0–2.6)	0.5 (0–2.6)	0.6 (0–2.5)	0.841

IQR*: interquartile range; CHAQ**: Child Health Assessment Questionnaire.

Clinical variable comparison between male and female groups at 12-month follow-up

Our preliminary analyses at 12-month follow-up comparing males (n = 23) to females (n = 78) are shown in Table 3. The physician’s global disease activity significantly declined in males (beta = −19.7, p < 0.001) and females (beta = −11.1, p < 0.001), whereas the magnitude of change between males and females did not differ significantly (p = 0.113). The magnitude of improvement in physician’s ulceration activity was significantly (p = 0.037) more pronounced in males (beta = −11.6, p = 0.001) than females (beta = −3.3, p = 0.080). The patient-reported outcomes, like patient global disease damage and global disease activity, did not significantly differ between males and females, but in both groups improved significantly compared at the time of enrollment. Females showed more often (37%) abnormal DLCO (< 80%) than males (17%, p = 0.047) at month 12. The overall pulmonary involvement (composite pulmonary index ³ ) was also more frequent in females than in males at 12-month follow-up (59% vs 35%, p = 0.042).

Table 3.

Patient- and physician-related outcomes between baseline and 12-month follow-up, compared by gender.

	Change in 12-month FU in male patients				Change in 12-month FU in female patients				Difference in change during 12-month FU between male and female patients				Difference at 12-month FU between male and female patients
	Beta	p-value	LCL	UCL	Beta	p-value	LCL	UCL	Beta	p-value	LCL	UCL	Beta	p-value	LCL	UCL
Physician global disease activity	−19.7	< 0.001	−29.1	−10.2	−11.1	< 0.001	−16.0	−6.1	8.6	0.113	−2.0	19.2	0.7	0.886	−9.2	10.7
Physician global disease damage	−6.4	0.126	−14.6	1.8	−4.3	0.053	−8.6	0.1	2.1	0.652	−7.1	11.4	10.0	0.036	0.6	19.3
Physician ulceration activity	−11.6	0.001	−18.5	−4.7	−3.3	0.080	−6.9	0.4	8.3	0.037	0.5	16.1	1.8	0.614	−5.2	8.8
Patient global disease activity	−15.5	0.020	−28.7	−2.4	−13.4	< 0.001	−20.4	−6.5	2.1	0.778	−12.7	17.0	0.2	0.975	−12.3	12.7
Patient global disease damage	−10.8	0.048	−21.5	−0.1	−15.6	< 0.001	−21.5	−9.7	−4.8	0.437	−17.1	7.4	7.3	0.240	−4.9	19.6
Patient Raynaud activity	−10.9	0.069	−22.7	0.9	−10.7	0.001	−16.8	−4.7	0.2	0.976	−13.0	13.5	3.0	0.634	−9.5	15.6
Patient ulceration activity	−12.8	0.011	−22.6	−2.9	−7.7	0.004	−12.9	−2.4	5.1	0.368	−6.0	16.3	−1.5	0.758	−10.8	7.8
CHAQ	−0.2	0.078	−0.4	0.0	−0.1	0.072	−0.2	0.0	0.1	0.533	−0.2	0.3	0.0	0.889	−0.3	0.3

FU: follow-up; CHAQ: Child Health Assessment Questionnaire.

Discussion

This is the first large jSSc cohort study to focus on comparisons between juvenile male and female patients. Overall, our findings in the jSScC suggest male gender is associated with more severe disease at timepoint of enrollment, which is compatible with adult-onset SSc cohort findings.^4,6,7 In the jSScC at the time of enrollment cohort, this was reflected across a few organ systems, such as vascular, with more active fingertip ulceration, and pulmonary, with more frequent involvement using the composite pulmonary index in males compared with females. Although the recorded gastrointestinal involvement in the jSScC was not as frequent in males, they were notably underweight, with BMI z-scores lower than −2SD, likely reflecting more active and severe gastrointestinal involvement.^13,14 In the musculoskeletal domain, male jSSc patients had a significantly higher frequency of tendon friction rubs, which has been associated with active ¹⁵ and more severe disease course ¹⁶ in adult SSc cohorts. Joint contractures were more frequent, but not statistically significant, in male patients at enrollment in the jSScC.

In the post hoc analysis of the patients, we saw a change of pattern regarding the number of patients with decreased DLCO under 80%. The physician’s global disease activity significantly declined in both sexes over 12 months. The magnitude of improvement in physician’s ulceration activity was significantly more in male patients. After 12 months, we could not see differences in patient-related outcome between male and female patients regarding global disease damage and activity ulceration activity, but in both groups, it improved significantly compared to enrollment. This is amazingly unique finding compared to adult data. We could already demonstrate this when we assessed the 12-month outcome comparing diffuse and limited subset (Foeldvari et al., Abstract presented at EULAR 2022). Around 90% of our patients were treated with a disease-modifying anti-rheumatic drugs (DMARDs), only around 10% of them with a biologic DMARD. It seems to be, that the applied treatment led to this stabilization of the organ pattern, but to a significant improvement in patient-related outcomes. The mean disease duration was around 3 years, and normally in an adult cohort, the mean progression is expected in the first 3–5 years of the disease, this improvement in this phase of the disease is more unique.

Even in the larger adult population, it is not clear, what predicts improvement. ¹⁷

Matching the cumulative effect of these organ systems at time of enrollment, physicians rated the global damage to be more severe in male jSSc patients and it equalize after 12 months. The patients themselves did denote the males had higher disease damage impact, but not in a statistically significant manner. Digital ulceration did impact both physician and patient rated ulceration VAS, but again with significance on the physician rated but not patient-reported numbers and again it shows an improvement after 12 months. Additional patient-reported outcome measures and questionnaires that are SSc specific may be able to better capture the impact of SSc on children and are currently being piloted in the jSScC and Pittsburgh National Registry of Childhood Onset Scleroderma cohorts. These include tools, such as the scleroderma gastrointestinal tract (GIT) instrument ¹⁸ and the scleroderma-specific VAS, which are derived from the scleroderma-HAQ (S-HAQ). ¹⁹ The S-HAQ scales include pain overall, hand pain, intestinal problems, breathing problems, Raynaud’s severity, finger ulcer severity, and patient global, to capture the patient’s perspective on the level of interference. The S-HAQ and GIT are some of the few patient related outcomes (PROs) developed for SSc with patient input, including cognitive interviewing of patients supporting the face validity of the VAS questions.^18,19

The female predominance, female-to-male ratio, median age of onset, and diffuse cutaneous SSc predominant subtype presented is typical of the other published jSSc cohorts;^13,20 therefore, findings should be representative of jSSc and generalizable. In addition, this is a relatively balanced comparison between male and female groups since race, age of onset, disease duration at time of assessment, disease subtype (diffuse cutaneous 70% in both), and auto-antibody status were not significantly different between the groups, eliminating some potential confounders.

Reviewing adult SSc studies evaluating gender differences in large cohorts or scoping literature reviews, we observe some similarities and differences to our findings. Comparing the jSScC data to the EULAR scleroderma trials and research (EUSTAR) database (n = 9182; 1321 men), we have similar findings regarding the increased rate of digital ulcerations in males ⁶ but only at time of enrollment. It is notable, that in children, we do not have cofounding factors of smoking or occupational exposure influencing differences in digital ulcer frequency between sex. Different from the adult studies, in our jSScC, we did not see any association of male sex with pulmonary arterial hypertension, likely due to the low rate in jSScC (5%), and no association with heart failure, which are possibly due to both age-related and infrequency in jSSc, this observation persists over 12 months. The diffuse subtype in our cohort was similar between males and females, whereas it was predominant in males in the EUSTAR database. ⁶

In another study in the United States evaluating the large (n = 2686; 542 men) Pittsburgh adult SSc cohort for gender difference, Peoples et al. ⁷ determined males to have a more frequent diffuse cutaneous subtype, as in the EUSTAR cohort, with associated topoisomerase auto-antibody. Organ assessment comparison found more severe peripheral vascular involvement and severe interstitial lung disease in males. Hughes et al. ⁴ reviewed the literature regarding gender differences and found similar findings as the EUSTAR and the Pittsburgh cohort.^6,7 To note, age of onset of disease was significantly higher in males and disease duration was significantly lower in males in the two large adult SSc cohorts evaluating sex differences, this may impact some of the organ involvement.^6,7 The jSScC has the advantage of not having these confounders influence our findings given the more homogeneous age of onset, disease duration, and disease subtype, and lot of patients are prepubertal.

Finally, a smaller Asian cohort study in Thailand (n = 115; 46 males) by Wangkaew et al. ⁸ compared male and female adult SSc patients with early disease onset, with similar age of onset and disease duration between sexes, eliminating some of these potential biases. At the last visit, male patients had a higher prevalence of active digital ulceration, interstitial lung disease, joint contracture, and tendon friction rub; these were also observed in our cohort at enrollment, some significantly, while others trending. We could not confirm increased rate of telangiectasia, decreased left ventricular ejection fraction and right ventricular dysfunction in male SSc patients which they observed.

Our study provides a comprehensive evaluation of demographic, organ manifestation, and physician and patient-reported outcomes in a large jSSc international cohort, providing an initial comparison between sexes in pediatric-onset disease at time of enrollment in the cohort and after 12-month follow-up. However, the study should be interpreted in light of some potential limitations. This is an observational study, and the participating clinicians report according to their standard of care in jSSc using a clinical research form. Performance of additional organ evaluation was not mandatory due to the observational study design and for ethical reasons limiting the completeness of the data. In consequence, the results of specific organ manifestation screening include a proportion of missing data and may be slightly biased to patients with a more severe organ involvement. However, the general organ involvement pattern in our cohort is very similar to other previously published pediatric cohorts^20,21 and each published evaluation^2,10 of the jSScC the distribution of the organ involvement remained similar.

We report the first jSSc cohort study dedicated to the evaluation of sex differences in regards to organ assessment and disease impact. Male patients at time of enrollment show more severe microvascular involvement, increased rate of tendon friction rub, higher frequency of very low BMI (z-score < 2), reflecting more active disease and possibly more severe gastrointestinal involvement, and more severe global disease damage and digital ulcerations according to the rating of the treating physicians. They show a significant improvement after 12-month follow-up. A unique finding is the patient global disease damage and activity improved significantly compared to enrollment in both sexes. Male patients with jSSc and female patients should be followed closely with continued organ surveillance and clinical evaluations, and with the same index of suspicion. Future assessment should include more formal longitudinal evaluation to identify if jSSc males are at more risk for pulmonary arterial hypertension and heart failure as they age, as in adult-onset SSc.