Lung Findings in Anti-CENP-B Negative CREST Syndrome
Primary Lung Manifestations
Patients with CREST syndrome features but without anti-CENP-B antibodies have a significantly different pulmonary risk profile, with isolated pulmonary arterial hypertension (PAH) being the predominant concern rather than interstitial lung disease (ILD). 1
Isolated Pulmonary Arterial Hypertension
Isolated PAH without significant pulmonary fibrosis is the hallmark pulmonary complication in CREST syndrome, occurring in approximately 9% of systemic sclerosis patients, with the highest prevalence in limited cutaneous disease. 2, 3
The pulmonary hypertension develops independently of other pulmonary or cardiac conditions, characterized by marked intimal fibrosis with hyalinization and smooth muscle hypertrophy in small- and medium-sized pulmonary arteries without significant parenchymal fibrosis. 2, 3
This isolated PAH carries an extremely poor prognosis with a 2-year cumulative survival rate of only 40%, and patients typically do not respond favorably to vasodilators. 2
The time from initial Raynaud's phenomenon to recognition of pulmonary hypertension can be as long as 40 years, making long-term surveillance essential. 3
Interstitial Lung Disease Considerations
Anti-centromere antibodies (CENP-B) are considered protective and actually decrease the likelihood of ILD development in systemic sclerosis. 4
In contrast, anti-topoisomerase 1 (anti-Scl-70) antibodies are strongly associated with ILD risk, independent of disease subset. 4
Patients without anti-CENP-B antibodies who have other autoantibodies (particularly anti-Scl-70) face higher ILD risk and require more aggressive screening. 4
Mandatory Screening Protocol
Initial Baseline Assessment
All patients with suspected CREST syndrome, regardless of antibody status, require comprehensive pulmonary screening at baseline. 4, 1
Pulmonary function tests (PFTs) including spirometry and DLCO measurement are essential, as a DLCO less than 45% of predicted in the absence of pulmonary interstitial fibrosis is an important predictor of subsequent isolated PAH development. 2
In the study cohort with isolated PAH, mean DLCO was markedly reduced at 39% of predicted normal, and in 6 patients, the low DLCO preceded clinical evidence of PAH by 1-6 years. 2
Echocardiography with assessment for PAH is mandatory in all patients, as recommended by the American College of Rheumatology. 1
NT-proBNP levels and 6-minute walking distance testing should be performed as part of PAH screening. 1
High-resolution CT chest with prone images is recommended, particularly in early diffuse cutaneous disease or when clinical suspicion for ILD exists. 4
Specific Screening Thresholds
A threshold of 70% FVC has prognostic value for separating extensive from mild disease in ILD. 4
Serial PFT changes are critical: a 10% decrease in FVC, or 5% decrease with a corroborative 15% drop in DLCO, predict survival and warrant escalation of monitoring. 4
Changes in DLCO or carbon monoxide transfer coefficient are highly predictive of long-term outcome, especially over the next 2 years. 4
Clinical Pitfalls and Red Flags
Antibody Status Implications
Patients with CREST features but negative anti-CENP-B antibodies may have concurrent other disease marker antibodies (anti-SSA/Ro, anti-RNP, anti-Scl-70) in up to 40% of cases, contributing to heterogeneous clinical characteristics including overlap syndromes. 5
The absence of anti-CENP-B does not exclude CREST syndrome, as 30% of patients with anticentromere antibodies have other rheumatic diseases or miscellaneous disorders rather than systemic sclerosis. 5
Five patients with CREST syndrome having both ACA and anti-RNP antibodies demonstrated clinical manifestations compatible with mixed connective tissue disease, suggesting overlap syndromes are common. 5
Timing of Surveillance
Close follow-up every 3-6 months during the first 5 years is recommended for patients with Raynaud's phenomenon, as the risk of developing systemic sclerosis is greatest during this period. 1
In early systemic sclerosis cohorts, 50% showed significant or moderate progression of ILD, and a 2022 EUSTAR registry study reported that ILD progression can occur at any disease duration. 4
PFTs should be performed regularly, particularly in early diffuse cutaneous disease, though they can be unreliable for screening due to range of normal values and test variability. 4
Gastroesophageal Reflux Impact
- Gastroesophageal reflux disease (GERD) with reflux into the lungs worsens ILD and must be aggressively managed. 4
Management Algorithm
For Isolated PAH Without ILD
Right heart catheterization is required to confirm the diagnosis of PAH and assess severity of hemodynamic impairment. 4
Measurement of left ventricular end-diastolic pressure is important to avoid misclassification of patients with elevated pulmonary artery wedge pressure. 4
Patients with isolated PAH historically have not responded favorably to vasodilators, though modern PAH-specific therapies should be considered in consultation with pulmonary hypertension specialists. 2
For ILD Development
Immunosuppressive treatment is supported by cohort studies and placebo-controlled RCTs for systemic sclerosis-ILD. 4
Mycophenolate mofetil (MMF) and cyclophosphamide have demonstrated benefit in clinical trials (SLS I, SLS II, FAST). 4
Nintedanib, an anti-fibrotic agent, was evaluated in the SENSCIS RCT in the context of MMF treatment and showed benefit. 4
Risk Stratification
High-risk patients requiring intensive monitoring include those with:
- DLCO < 45% of predicted without pulmonary fibrosis on imaging 2
- Crackles/rales on auscultation 4
- Abnormal PFTs or chest radiographs 4
- Male gender (higher frequency of diffuse cutaneous disease) 4
- Early disease (within first 3 years, associated with worse prognosis) 4
- Elevated serum IL-6, C-reactive protein, ESR, or thrombocytosis (predictive of lung fibrosis risk) 4