Assessment of long-term damage and cardiovascular risk in juvenile systemic lupus erythematosus compared to juvenile dermatomyositis in adulthood

This study compares adult outcomes of juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM), revealing that while damage accumulation is similar between the two groups, JSLE patients exhibit significantly higher traditional cardiovascular risk factors and PDAY scores, underscoring a distinct long-term cardiovascular burden in JSLE.

The Gist

The Big Picture: A Race Against Time

Imagine two groups of young people who started a long, difficult marathon as children. One group has Juvenile Systemic Lupus Erythematosus (JSLE), and the other has Juvenile Dermatomyositis (JDM). Both are autoimmune diseases, meaning their immune systems accidentally attack their own bodies, like a security guard who starts locking the doors from the inside.

This study followed these two groups into their early 20s to answer two big questions:

1. How much "wear and tear" (damage) did their bodies accumulate over the years?
2. How likely are they to have heart trouble later in life?

The Main Findings: The "Heart Risk" Gap

1. The Damage Score: A Tie, but Different Scars
Surprisingly, both groups ended up with a similar total amount of physical damage to their bodies (about 50-60% of people in both groups had some damage). However, the type of damage was different, like two houses that both got damaged in a storm but in different ways:

• The JDM Group: Their "damage" was mostly on the outside and the muscles—think skin rashes, muscle weakness, and joint issues.
• The JSLE Group: Their damage was more internal and deep—kidneys, brain, and blood vessels. They also had a slightly higher rate of serious complications like cancer and death, though the numbers were still small.

2. The Heart Risk: The Silent Danger
This is where the study found a major difference.

• The JDM Group: Their hearts looked relatively healthy. They had low cholesterol and low blood pressure.
• The JSLE Group: Their hearts were under much more stress. They had higher blood pressure, higher "bad" cholesterol, and more inflammation. It's as if the JSLE group was driving a car with a engine that was running hotter and with grittier oil than the JDM group.

The Problem: The Wrong Map for the Journey

The researchers tried to use standard "Heart Risk Maps" (tools doctors use to predict heart attacks) to see who was in danger.

• The Old Maps (Adult Tools): They used tools like the Framingham Risk Score and QRISK. These are like maps designed for 50-year-olds. When they tried to use these maps on these young people (ages 20–24), the maps said: "No danger here! You're safe."
• The Reality: The maps were lying. Because these young people are so young, the math in the old maps ignores them. It's like trying to measure the depth of a swimming pool with a ruler meant for a bathtub; the tool just doesn't fit the job.

The Solution: The "Arterial Age" Clock
The researchers tested a different tool called the PDAY score. Instead of asking, "What are your chances of a heart attack in the next 10 years?" (which is low for a 20-year-old), it asks, "How old does your blood vessel look right now?"

• The Result: The PDAY score was a game-changer. It revealed that many young JSLE patients had "arterial ages" that were 10 to 20 years older than their actual age. It was like finding out a 20-year-old's heart was actually aging like a 40-year-old's. The JDM group, however, still looked healthy on this clock.

The Culprits: What Made the Damage Worse?

The study found two main "villains" that made things worse for both groups:

1. The Inflammation: The more active the disease was (the more the immune system was attacking), the more damage occurred.
2. The Weight (BMI): This was a surprise finding. Being overweight was a major predictor of damage in both groups. It's like adding extra weight to a car that is already struggling with a broken engine; the heavier the car, the faster the parts wear out.

The Takeaway: Why This Matters

1. Stop Using the "Adult" Tools:
Doctors need to stop using the standard heart-risk calculators for these young people. They are blind to the real danger. We need "teen/young adult" specific tools (like PDAY) to catch the risk early.

2. Watch the Weight:
Since body weight was a huge factor in damage, managing weight isn't just about looking good; it's about protecting the organs from permanent damage.

3. The "Treat to Target" Approach:
The study suggests that doctors need to be very aggressive in keeping the disease quiet (low activity). If the disease is active, it's like leaving a fire burning in the house; eventually, the house burns down (damage). Keeping the fire out prevents the damage.

In a Nutshell

This study is a wake-up call. Young people with Lupus (JSLE) are carrying a much heavier burden of heart risk and internal damage than their peers with Dermatomyositis (JDM). The tools we currently use to check their hearts are too blunt to see the danger. We need new, sharper tools and a focus on keeping inflammation low and weight healthy to ensure these young adults don't face heart trouble decades too early.

Technical Summary

1. Problem Statement

Juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM) are severe childhood-onset autoimmune rheumatic diseases (RMDs) associated with chronic inflammation, organ damage, and an elevated risk of cardiovascular disease (CVD). While both conditions share pathogenic mechanisms (e.g., interferon pathway activation) and therapeutic overlaps, there is a lack of comparative data regarding their long-term outcomes in adulthood.

Key gaps identified include:

• Lack of Comparative Data: No previous studies have directly compared long-term damage accrual and CVD risk profiles between JSLE and JDM cohorts transitioning into adulthood.
• Inadequate Risk Stratification Tools: Standard CVD-risk scores (e.g., Framingham Risk Score, ASCVD, QRISK3) are validated for general adult populations but have been shown to underperform in RMD patients, often failing to identify high-risk young adults due to their reliance on age as a primary driver.
• Unknown Predictors: The specific drivers of damage and CVD risk in these young populations, particularly the role of modifiable factors like Body Mass Index (BMI), require further elucidation.

2. Methodology

Study Design:

• Type: Single-centre, longitudinal cohort study with both retrospective and prospective data collection.
• Population: Two cohorts of Adolescents and Young Adults (AYA) transitioning from paediatric to adult rheumatology services at University College London (UCL).
  • JSLE Cohort: $n=76$ (Mean age at follow-up: 24.3 ± 4.2 years).
  • JDM Cohort: $n=79$ (Mean age at follow-up: 20.1 ± 5.0 years).
• Follow-up: Mean disease duration was comparable between groups (~10–11 years).

Data Collection & Measures:

• Damage Assessment: Evaluated using validated indices:
  • JSLE: Paediatric SLE Damage Index (Ped-SDI).
  • JDM: Myositis Damage Index (MDI).
• CVD Risk Assessment: Evaluated using multiple scoring tools:
  • Adult Scores: Framingham Risk Score (FRS), ASCVD risk calculator, and QRISK3 (which includes SLE as a risk enhancer).
  • Paediatric/Young Adult Score: PDAY (Pathobiological Determinants of Atherosclerosis in Adolescence) score, which estimates "arterial age" and cumulative risk burden rather than 10-year event probability.
• Statistical Analysis: Descriptive statistics, t-tests/Mann-Whitney U tests for continuous variables, Chi-square/Z-tests for categorical variables, and multivariable logistic regression to identify independent predictors of damage and high CVD risk (defined as PDAY $\ge$ 8).

3. Key Contributions

• First Comparative Evaluation: This is the first study to directly compare long-term organ damage and CVD risk trajectories between JSLE and JDM in young adulthood.
• Validation of PDAY Score: It provides evidence that the PDAY score is superior to traditional adult risk calculators (FRS, ASCVD, QRISK3) for stratifying CVD risk in young RMD patients, as the latter consistently underestimated risk (classifying nearly all patients as "low risk").
• Identification of BMI as a Universal Predictor: The study identifies BMI as an independent predictor of damage accumulation in both JSLE and JDM, highlighting a modifiable target for intervention.
• Disease-Specific Risk Profiles: It delineates distinct risk profiles, showing that while overall damage prevalence is similar, JSLE carries a significantly higher burden of traditional CVD risk factors and vascular aging compared to JDM.

4. Key Results

Demographics and Disease Characteristics:

• JSLE patients were significantly older at follow-up and had a longer diagnostic delay (median 1.2 years vs. 0.4 years for JDM).
• JSLE showed higher rates of renal, CNS, and gastrointestinal involvement, whereas JDM had higher rates of musculoskeletal, cutaneous, and pulmonary damage.
• JSLE patients had significantly higher rates of hypertension, dyslipidemia, and elevated LDL-cholesterol at the last assessment.

Damage Accrual:

• Prevalence: Similar overall damage prevalence (JSLE: 51.3% vs. JDM: 59.4%; $p=0.307$).
• Predictors of Damage:
  • JSLE: Independently predicted by cumulative cyclophosphamide dose and BMI.
  • JDM: Independently predicted by BMI and physician damage VAS.
• Mortality: Two JSLE patients died (ages 20–25) due to severe flares and infections; no JDM deaths occurred.

Cardiovascular Risk Assessment:

• Adult Scores (FRS, ASCVD, QRISK3): Failed to identify high-risk individuals. Median 10-year risk scores were extremely low for both cohorts (e.g., JSLE median FRS ~0.2%), with almost no patients reaching the $\ge$10% high-risk threshold.
• PDAY Score: Successfully stratified risk.
  • JSLE: Median score 5 (IQR 4–13). 43.5% of JSLE patients had a PDAY $\ge$ 8 (moderate-to-high risk), and 32.8% had a score >10 (very high risk).
  • JDM: Median score 0 (IQR 0–3). Only 15.1% had a PDAY $\ge$ 8.
• Predictors of High PDAY in JSLE: Multivariable regression identified four independent predictors for PDAY $\ge$ 8:
  1. Older age.
  2. Longer disease duration.
  3. Higher LDL cholesterol.
  4. Active disease (BILAG A/B or SLEDAI $\ge$ 6).
  • Note: While glucocorticoid (GC) exposure >1 year was common, it was not an independent predictor in the final model, likely because its effect is mediated through lipid profiles and disease activity.

Validation with Imaging:

• In a small sub-cohort with vascular imaging, high PDAY scores correlated with increased carotid intima-media thickness (CIMT) in JSLE and endothelial dysfunction (reduced FMD) in JDM, whereas adult risk scores remained near 0% for these same individuals.

5. Significance and Clinical Implications

• Limitations of Current Guidelines: The study confirms that standard adult CVD-risk tools are clinically useless for risk stratification in young adults with RMDs, potentially leading to a false sense of security and delayed preventive interventions.
• Need for Age-Appropriate Tools: The PDAY score demonstrates superior utility in capturing cumulative vascular aging in this demographic. Clinicians should consider adopting PDAY or similar tools for AYA with RMDs.
• Modifiable Risk Factors: The strong association between BMI and damage in both cohorts underscores the critical need for aggressive lifestyle interventions and weight management alongside immunosuppressive therapy.
• Disease Control: Tighter disease control (achieving low disease activity states) is essential to prevent damage and reduce CVD risk, particularly in JSLE where active disease drives vascular aging.
• Future Directions: The authors call for multicenter, longitudinal studies to validate these findings and establish specific CVD-risk stratification guidelines for paediatric and young adult rheumatology.

Conclusion:
Young adults with JSLE face a significantly higher burden of cardiovascular risk and vascular aging compared to those with JDM, a disparity missed by traditional risk calculators. The study advocates for a shift toward using pediatric-specific risk scores (like PDAY) and prioritizing modifiable factors like BMI and disease activity to improve long-term outcomes.