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This commentary highlights the present dilemmas surrounding the classification of a patient with interstitial pneumonia who has clinical features suggesting an associated connective tissue disease but the features fall short of a clear diagnosis of connective tissue disease-associated interstitial lung disease under the current rheumatologic classification systems. This commentary illustrates what we perceive to be the limitations in the present approach to the classification of this group of patients and discusses problems with redefining the diagnosis of undifferentiated connective tissue disease to encompass patients with interstitial pneumonia. Finally, we advocate not only for a multidisciplinary approach to evaluation, but also disease classification and offer a proposal to define them as a distinct phenotype--lung-dominant CTD--for which prognostic, therapeutic, and pathobiologic implications can be tested in future, hopefully multiinstitutional, studies.

Rationale: Health-related quality of life (HRQL) is an important outcome in drug trials. Little is known about how the Short Form-36 (SF-36) and Saint George's Respiratory Questionnaire (SGRQ) perform in idiopathic pulmonary fibrosis (IPF). Objectives: To examine the validity of the SF-36 and SGRQ and to determine scores from each that would constitute a minimum important difference (MID). Methods: We analyzed data from a recently completed trial that enrolled subjects with well-defined IPF who completed the SF-36, SGRQ, and Baseline/Transition Dyspnea Index at baseline and six months. We compared mean changes in HRQL scores between groups of subjects whose disease severity changed over six months according to clinical anchors (FVC, DLCO, and dyspnea). We estimated the MID for each domain by using both anchor- and distribution-based approaches. Main results: Results supported the validity of the SF-36 and SGRQ for use in longitudinal studies. Mean changes in domain scores differed significantly between subjects whose clinical status improved and those whose clinical status declined according to the anchors. MID estimates for the SF-36 ranged from 2-4 points and from 5-8 points for the SGRQ. Conclusion: In IPF, the SF-36 and SGRQ possess reasonable validity for differentiating subjects whose disease severity changes over time. More studies are needed to continue the validation process, to refine estimates of the MIDs for the SF-36 or SGRQ, and to determine if a disease-specific instrument will perform better than either of these.

Summary Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. Methods In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials.