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Restless legs syndrome: A new comorbidity in idiopathic pulmonary fibrosis

Open ArchivePublished:April 22, 2020DOI:https://doi.org/10.1016/j.rmed.2020.105982

      Highlights

      • Current Knowledge/Study Rationale: Sleep quality is compromised in IPF patients.
      • Results: RLS is prevalent and severe in IPF and concurs to worsen sleep quality.
      • Study impact: Treatment of RLS in patients with IPF could ameliorate sleep quality and, in turn, quality of life.

      Abstract

      Objective

      Sleep disorders have a high prevalence among patients with idiopathic pulmonary fibrosis (IPF). The prevalence of restless legs syndrome (RLS) is not known in these patients, neither is its clinical impact as a comorbidity. We investigated the association of RLS with IPF and characterized the clinical features of RLS in a cohort of IPF patients.

      Methods

      Fifty patients with diagnosis of IPF were prospectively enrolled. RLS was diagnosed using the validated 5-item RLS criteria. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. The prevalence of RLS in the IPF group was compared to that observed in a group of 293 patients referred for suspect of sleep disorders. The relationships between RLS and clinical parameters were determined using multivariate logistic regression.

      Results

      Prevalence of RLS in the IPF group was significantly higher than in the control population of patients referred for sleep disorders (IPF: 24%, controls 10%: χ2 6.49, p = 0.011). Higher PSQI score confirmed to be associated with RLS after adjusting for demographics and clinical parameters of disease severity (OR = 1.38, 95%CI 1.08–1.76; p = 0.01).

      Conclusions

      RLS is highly prevalent in IPF and significantly worsen sleep quality in these patients. The benefit/risk ratio of a specific therapeutic intervention for RLS in IPF should be assessed in further prospective research.

      Keywords

      Abbreviations:

      IPF (Idiopathic pulmonary fibrosis), RLS (Restless legs syndrome), COPD (Chronic obstructive pulmonary disease), OSAS (Obstructive sleep apnea syndrome), PSQI (Pittsburgh Sleep Quality Index)

      1. Introduction

      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic lung disease [
      • Richeldi L.
      • Collard H.R.
      • Jones M.G.
      Idiopathic pulmonary fibrosis.
      ]. The disease carries a poor prognosis, with an estimated median survival time of 2–3 years after diagnosis [
      • Raghu G.
      • Remy-Jardin M.
      • Myers J.L.
      • et al.
      Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
      ]. Although IPF is the most common form among the idiopathic interstitial pneumonias, it is still a rare entity; in fact, the prevalence of IPF in Europe is widely variable, ranging between 1.25 per 100,000 in Belgium to 23.4 per 100,000 in Norway [
      • Nalysnyk L.
      • Cid-Ruzafa J.
      • Rotella P.
      • Esser D.
      Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature.
      ]. Several comorbidities have been associated with IPF, including gastro-esophageal reflux, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, lung cancer and obstructive sleep apnea. These conditions and their management may have a relevant clinical impact, and may influence prognosis [
      • Raghu G.
      • Amatto V.C.
      • Behr J.
      • Stowasser S.
      Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review.
      ].
      Sleep disorders, such as nocturnal hypoventilation, particularly during REM sleep, and obstructive sleep apnea syndrome (OSAS) have an increased prevalence in IPF patients and have been recognized as common comorbidities [
      • Milioli G.
      • Bosi M.
      • Poletti V.
      • et al.
      Sleep and respiratory sleep disorders in idiopathic pulmonary fibrosis.
      ]; moreover, a disrupted sleep architecture has also been reported in IPF patients [
      • Perez-Padilla R.
      • West P.
      • Lertzman M.
      • Kryger M.H.
      Breathing during sleep in patients with interstitial lung disease.
      ]. The recognition and the treatment of sleep disorders could improve both quality of life and outcome [
      • Mermigkis C.
      • Bouloukaki I.
      • Schiza S.E.
      Sleep as a new target for improving outcomes in idiopathic pulmonary fibrosis.
      ].
      Restless legs syndrome (RLS) (or Willis-Ekbom disease) is a neurological sensorimotor disorder characterized by an urge to move the legs; it occurs primarily in the evening or night, following a circadian pattern [
      • American Academy of Sleep Medicine
      The International Classification of Sleep Disorders - Diagnostic and Coding Manual.
      ]. RLS is common with a prevalence of 7.2% in the general population and of 2.7% for clinically significant forms [
      • Ohayon M.M.
      • O'Hara R.
      • Vitiello M.V.
      Epidemiology of restless legs syndrome: a synthesis of the literature.
      ]. The prevalence of RLS in IPF is unknown, and so is whether it may represent as a significant comorbidity in these patients. Several IPF patients referred to our ILD Clinic showed complains of poor sleep quality and impulse to move the legs during nighttime.
      In this study we therefore aimed to investigate the link between IPF and RLS and explore its clinical impact in these patients.

      2. Material and methods

      2.1 Study population

      Consecutive IPF patients referred the Interstitial Lung Disease (ILD) Clinic of the University Hospital Fondazione Policlinico “A. Gemelli” IRCCS in Rome, Italy between January and June 2017 were prospectively enrolled in the study. Eligibility criteria were represented by a multidisciplinary diagnosis of IPF according to the ATS/ERS/JRS/ALAT 2011 [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ]. Diagnosis was made on clinical and radiological data in 42 (84%) patients. For 8 patients, an histological confirmation was deemed necessary. 5 patients (10%) underwent surgical lung biopsy (SLB) and 3 patients (6%) transbronchial cryobiopsy (TBLC). Written informed consent was obtained from all patients who accepted to participate. A historical cohort of outpatients referred to the Sleep Disorders Unit of the Department of Neurology at the same hospital between January and December 2016 for any kind of sleep disorder was used as a control population. These patients were matched for age and gender to the IPF population.
      The study was conducted according to the principles of the Declaration of Helsinki and was approved by the local Ethics Committee.

      2.2 Study procedures

      Demographic and clinical data including age, gender, time from diagnosis of IPF, pulmonary function, pharmacological treatment, oxygen therapy, smoking habit were collected. RLS was diagnosed based upon the validated 5-item RLS criteria [
      • Allen R.P.
      • Picchietti D.
      • Hening W.A.
      • et al.
      Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.
      ]. Fulfillment of all criteria and the confirmation by a sleep specialist were required for RLS diagnosis. All the patients with symptoms of RLS underwent to a detailed clinical interview and neurological examination conducted by a sleep specialist with the purpose to rule out behavioral conditions or neurological and non-neurological RLS mimics (e.g. nocturnal leg cramps, painful conditions, positional discomfort, neuropathy, radiculopathy, venous stasis, arthritis). The severity of RLS was determined via the “International Restless Legs Syndrome Study Group rating scale for restless legs syndrome” (IRLSSG) [
      • Walters A.S.
      • LeBrocq C.
      • Dhar A.
      • et al.
      Validation of the international restless legs syndrome study group rating scale for restless legs syndrome.
      ]. The Pittsburgh Sleep Quality Index (PSQI) was used to assess the quality of sleep [
      • Curcio G.
      • Tempesta D.
      • Scarlata S.
      • et al.
      Validity of the Italian version of the Pittsburgh sleep quality index (PSQI).
      ]. A score ≥5 was used as threshold for poor sleep quality [
      • Buysse D.J.
      • Reynolds 3rd, C.F.
      • Monk T.H.
      • Berman S.R.
      • Kupfer D.J.
      The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.
      ].

      2.3 Statistical analysis

      Continuous and categorical data were summarised using means and standard deviations, or counts and percentages respectively. The proportions of RLS diagnoses in IPF patients and controls were compared using the Pearson's χ [
      • Raghu G.
      • Remy-Jardin M.
      • Myers J.L.
      • et al.
      Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
      ]. On univariate analysis, the Mann-Whitney U test was used to compare continuous variables between IPF patients with and without RLS; the Fisher's two-tailed exact test was used to compare categorical variables between the two groups. The relationships of demographics and clinical parameters with the presence of RLS were assessed using multivariate logistic regression. The level of significance was set at p < 0.05.
      All statistics were performed by means of the SYSTAT 12 software version 12.02.00 for Windows® (copyright SYSTAT® Software Inc.)

      3. Results

      3.1 Characteristics of study population

      Fifty IPF patients were enrolled in this study. Thirty-eight (76%) were males with a mean age of 72.0 (SD 7.7) years. Mean time from diagnosis of IPF was 24.8 (SD 19.0) months; 36 patients (76%) were receiving pirfenidone and 14 (24%) nintedanib. Twenty-two (44%) patients were on long term oxygen, 32 patients (64%) were former smokers. Mean forced vital capacity (FVC) was 81,1% (SD 24,6) of the predicted value; mean diffusing capacity for carbon monoxide (DLCO) was 43,3% (SD 21,5) of the predicted value. Eighteen patients (36%) were on gender-age-physiology (GAP) stage 1; 20 patients (40%) were on GAP stage 2; 12 patients (24%) were on GAP stage 3[
      • Ley B.
      • Ryerson C.J.
      • Vittinghoff E.
      • et al.
      A multidimensional index and staging system for idiopathic pulmonary fibrosis.
      ].
      The average score at the Pittsburgh Sleep quality index (PSQI) was 7.80 (SD 4.11); 38 patients (76%) had PSQI scores ≥ 5, considered the cut-off value for poor sleep quality [
      • Buysse D.J.
      • Reynolds 3rd, C.F.
      • Monk T.H.
      • Berman S.R.
      • Kupfer D.J.
      The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.
      ].
      Two hundred and eighty-three patients referred to the Sleep Disorder Centre at the University Hospital Fondazione Policlinico “A. Gemelli” IRCCS in Rome, Italy formed the control population. These were matched per age and sex; 214 (75.3%) were men, mean age was 69.1 (SD 8.8) years.

      3.2 Relationships of RLS with IPF and clinical measurements

      Twelve (24.0%) IPF patients received a diagnosis of RLS. Such prevalence was significantly higher than in the control population, where thirty-one patients (10.9%) were positive for RLS. As such, the prevalence of RLS was approximately 2.5 higher in IPF patients as compared to the controls (χ [
      • Raghu G.
      • Remy-Jardin M.
      • Myers J.L.
      • et al.
      Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
      ], 6.49, p = 0.011) (see Table 1).
      The full characteristics of IPF patients with RLS (RLS+) and without RLS (RLS-) are reported in Table 2. The mean PSQI score in RLS + patients (10.6, SD 3.1) was significantly higher than in RLS- patients (6.9, SD 4.0) p = 0.005). No other significant differences were observed between the two groups (Table 2). RLS + patients were assessed for severity of RLS using a clinical scale (IRLSSG). The average score obtained was 19.57 (SD 6.39), which indicates a moderate degree of severity [
      • Walters A.S.
      • LeBrocq C.
      • Dhar A.
      • et al.
      Validation of the international restless legs syndrome study group rating scale for restless legs syndrome.
      ].
      Table 1Baseline patient characteristics.
      IPF (n = 50)Controls (n = 283)
      Age (years)72.0 (7.7)69.1 (8.8)
      Sex
      Male (%)38 (76)214 (75.3)
      Smoke
      Former n (%)32 (64)
      Never n (%)18 (36)
      FVC L (SD)3.2 (0.7)
      FVC % (SD)81.1 (24.6)
      DLCO ml/min*mmHg10.0 (4.6)
      DLCO % (SD)43,3 (21.5)
      GAP stage
      1 (%)18 (36)
      2 (%)20 (40)
      3 (%)12 (24)
      Long term Oxygen therapy n (%)22 (44)
      Therapy
      Pirfenidone n (%)36 (76)
      Nintedanib n (%)14 (24)
      Table 2Characteristics of study groups. RLS+ = IPF patients with restless leg syndrome. RLS- = IPF patients without restless leg syndrome. PSQI= Pittsburgh Sleep Quality Index; IRLSSG= International Restless Legs Syndrome Study Group Rating Scale.
      RLS+RLS-
      MEAN (SD)N (%)MEAN (SD)N (%)P VALUE
      Gender9 (18)29 (58)1.00
      Age (years)72.4 (9.7)71.8 (7.2)0.794
      Time from IPF diagnosis (months)30.3 (19.6)23.1 (18.7)0.214
      Treatment with Pirfenidone8 (16)28 (56%)0.718
      Treatment with Nintedanib4 (29)10 (71)0.718
      O2 therapy6 (12)16 (32)0.51
      Smoke9 (18)23 (46)0.729
      PSQI10.6 (3.1)6.9 (4.0)0.005
      IRLSSG Scale19.6 (6.4)
      On multivariate analysis, higher PSQI score (OR = 1.38, 95%CI 1.08–1.76; p = 0.01) showed to be independently associated with the presence of RLS (Table 3).
      Table 3Relationships between presence of Restless Legs Syndrome and clinical measurements in IPF patients. PSQI: Pittsburgh Sleep Quality Index; FVC: forced vital capacity; DLCo: diffusion capacity for carbon monoxide.
      OR (95% CI)P VALUE
      Male sex0.33 (0.04–2.56)0.289
      Age1.03 (0.93–1.13)0.583
      FVC % pred1.01 (0.97–1.05)0.561
      DLco % pred0.98 (0.94–1.02)0.318
      PSQI score1.38 (1.08–1.76)0.01

      4. Discussion

      In this study, we sought to determine the prevalence and characterize the clinical features of RLS in a cohort of patients with a diagnosis of IPF. The first important finding was that the RLS had prevalence (24%) much higher than the one reported in the general population (7.2%) [
      • Ohayon M.M.
      • O'Hara R.
      • Vitiello M.V.
      Epidemiology of restless legs syndrome: a synthesis of the literature.
      ]. Notably, such prevalence was two and half times higher as compared to a control group evaluated for sleep disorders. While RLS has been described in association with a variety of conditions, including kidney diseases, cardiovascular diseases, metabolic and endocrine disorders, it has never been associated to pulmonary disorders [
      • Trenkwalder C.
      • Allen R.
      • Hogl B.
      • Paulus W.
      • Winkelmann J.
      Restless legs syndrome associated with major diseases: a systematic review and new concept.
      ]. As such, our data represent the first evidence suggesting an association between RLS and IPF.
      The second main finding of our study was that the that IPF patients have poor sleep quality and that RLS is associated to poorer sleep quality in IPF. In our IPF sample, the average PSQI score was 7.8 and 76.0% of patients had a score above 5, indicating poor quality of sleep in population [
      • Buysse D.J.
      • Reynolds 3rd, C.F.
      • Monk T.H.
      • Berman S.R.
      • Kupfer D.J.
      The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.
      ]. A poor sleep quality in IPF patients could be explained by several reasons, including the presence of sleep disordered breathing associated to the underlying lung disorder [
      • Bosi M.
      • Milioli G.
      • Fanfulla F.
      • et al.
      OSA and prolonged oxygen desaturation during sleep are strong predictors of poor outcome in IPF.
      ], older age and concomitant drug therapies [
      • Ohayon M.M.
      Epidemiology of insomnia: what we know and what we still need to learn.
      ]. Our study suggests that RLS could be also implicated in the poorer sleep quality in IPF patients; in fact PSQI was significantly higher in IPF patients with RLS (average PSQI 10.6) with respect to IPF patients without RLS (average PSQI 6.9). It is known that RLS commonly affects the patients sleep [
      • Cavalcante A.G.
      • de Bruin P.F.
      • de Bruin V.M.
      • et al.
      Restless legs syndrome, sleep impairment, and fatigue in chronic obstructive pulmonary disease.
      ]. Insomnia is the most common reason for a patient with RLS to search for consultation in clinical practice. Although initially the symptoms occur at bedtime or during the night, as the syndrome progresses, symptoms start to occur earlier in the day and become more intense at night. Even when they occur throughout the day, the symptoms are typically worst in the evening or during the night. In our cohort of IPF patients RLS was rated moderate to severe and was independently associated with higher PSQI score, suggesting that sleep quality is further worsened in the presence of RLS. Interestingly, presence of RLS was not associated with functional impairment or gas exchange in our cohort, suggesting that development of RLS is not influenced by disease severity.
      RLS can be effectively treated with low-doses of dopaminergic drugs (pramipexole, especially in the slow-release formulation). Drug treatment induces a prompt amelioration of both subjective symptoms (sensory discomfort and restlessness) and motor associated phenomena (periodic limb movements during wake and sleep). As such, drug treatment should be considered in all patients with severe RLS associated with sleep difficulties or disruption. However, whether these treatment are safe and beneficial in IPF patients should be eventually clarified by properly designed trials.
      Our study has several limitations. First, it represents a single centre experience including a small number of patients. Second, concomitant sleep disorders and their relative contribution to impaired sleep quality have not been assessed. Third, the impact of the presence of RLS on quality of life has not been evaluated in our cohort. Fourth, we enrolled as a control population, outpatients coming to a sleep clinic. Therefore, we obtained a control population in which the prevalence of RLS is likely much higher than in normal healthy controls. The result of this selection bias is a possible underestimation of the association between RLS and IPF.
      In conclusion, our findings provide first evidence that RLS is a frequent comorbidity in IPF and concurs to further deterioration of sleep quality in these patients. The association between the two conditions and the clinical impact of RLS in IPF deserves further investigation in larger, prospective studies.

      CRediT authorship contribution statement

      Francesco Varone: Conceptualization, Methodology, Formal analysis, Writing - original draft. Ludovica Friello: Data curation, Writing - original draft. Chiara Di Blasi: Data curation. Giacomo Sgalla: Methodology, Formal analysis, Writing - original draft. Marco Luigetti: Conceptualization. Bruno Iovene: Formal analysis. Luca Richeldi: Supervision. Giacomo Della Marca: Conceptualization, Methodology. Valerio Brunetti: Methodology, Formal analysis, Writing - original draft.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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