Serum Krebs von den Lungen-6 and lung ultrasound B lines as potential diagnostic and prognostic factors for rheumatoid arthritis–associated interstitial lung disease



Rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) (RA-ILD) is a serious systemic RA manifestation with high mortality that needs proper, accurate, and sensitive assessment tools.


Firstly, evaluate serum Krebs von den Lungen-6 (KL-6) levels and lung ultrasound B lines (LUS B lines) score in RA-ILD correlating them with the severity of ILD assessed by high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). Secondly, determine cut-off values for LUS and KL-6 in RA-ILD assessment and outcome prediction.


A case-control study included seventy-five RA-ILD patients with an equal number of matched RA patients without ILD. Clinical assessment includes DAS-28 and PFTs, laboratory assessment of serum KL-6 by latex-enhanced immunoturbidimetric assay, and radiological evaluation of ILD using semiquantitative CT grade and LUS B lines.


RA-ILD patients had significantly higher serum KL6 compared to those without ILD (1025.5 ± 419.6 vs. 237.5 ± 51.9, p ≤ 0.001). Serum KL6 was positively correlated with HRCT and LUS scores (r = 0.93, r = 0.97, respectively) with negative correlation with FVC% and FEV1% (r = − 0.93, r = − 0.91, respectively). LUS was positively correlated with KL6 and HRCT (r = 0.97, r = 0.944, respectively) while, negatively correlated with PFTs. Cut-off values of KL6 and LUS were 277.5 U/ml and < 5.5, with AUC 0.878 and 1, sensitivity 86.7% and 100%, and specificity 88% and 100%, respectively.


The non-invasive, radiation-free LUS with a score < 5.5 combined with serum KL6 could be helpful for RA-ILD assessment correlating with HRCT and disease severity. Serum KL6 combined with LUS is important new and potential prognostic factor predicting poor outcomes in RA-ILD. Further large-scale, multi-center, and prospective studies are needed to confirm these findings.

Key Points

• Combination of the non-invasive, radiation-free LUS with a score < 5.5 and serum KL6 levels of 277.5 U/ml is recommended as prognostic tools for RA-ILD.

• Easily obtainable tests such as serum KL-6, inflammatory markers, and LUS are sensitive for assessing RA-ILD and the risk of poor outcomes in patients with RA-ILD.

• RA-ILD patients with higher KL6 levels, higher LUS scores had a poor prognosis with short survival.

• LUS B lines could be used as the first imaging tool for the evaluation of RA-ILD decreasing the risk of HRCT radiation exposure in asymptomatic or mild RA-ILD patients.

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Fig. 1
Fig. 2

Data availability

On fair request, the data sets are available from the corresponding author during and/or analyzed during the current review.


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Author information




All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Heba Ahmed Esaily, Dina Salem Fotoh, and Asrar Helal. The first draft of the manuscript was written by Dina Salem Fotoh and Mohamed Soliman Rizk, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript; all authors agreed to all aspects of the work.

All authors whose names appear on the submission participated in:

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Corresponding author

Correspondence to Dina S. Fotoh.

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This study was conducted under the Declaration of Helsinki and accepted by our University Hospital Committee’s Institutional Review Board (IRB approval no. 19122018INTPH1). Both participants involved in the study received informed consent.

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Fotoh, D.S., Helal, A., Rizk, M.S. et al. Serum Krebs von den Lungen-6 and lung ultrasound B lines as potential diagnostic and prognostic factors for rheumatoid arthritis–associated interstitial lung disease. Clin Rheumatol (2021).

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  • Interstitial lung disease
  • KL-6
  • Lung ultrasound B lines
  • Rheumatoid arthritis