PROF Laurent Misery

D R Christelle Ianotto

C Devergne

H Kerspern

F Poizeau

Eveillard

J L Carré

L Misery

C Le Gall-Ianotto

E Brenaut
email: emilie.brenaut@chu-brest.fr

Frequency and characteristics of pruritus in patients with monoclonal gammopathy: a casecontrol study

Keywords: pruritus, itch, monoclonal gammopathy, monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström's macroglobulinemia

Frequency and characteristics of pruritus in patients with monoclonal gammopathy: a case-control study

Dear Editor, Chronic pruritus (CP) is a frequent symptom in many skin and systemic diseases(1), including haematological malignancies. It is described in 30% of Hodgkin lymphoma patients and in patients with myeloproliferative disorders, particularly in polycythaemia vera [START_REF] Gall-Ianotto | Clinical characteristics of aquagenic pruritus in patients with myeloproliferative neoplasms[END_REF][START_REF] Lelonek | Aquagenic Pruritus in Polycythemia Vera: Clinical Characteristics[END_REF]. Serum protein electrophoresis (SPEP) is recommended in laboratory screening for CP [START_REF] Weisshaar | European S2k Guideline on Chronic Pruritus[END_REF]. However, the literature about pruritus in monoclonal gammapathies (MGs) is scarce [START_REF] Zelicovici | Pruritus as a presentation of myelomatosis[END_REF][START_REF] Erskine | Pruritus as a presentation of myelomatosis[END_REF][START_REF] Woo | Cutaneous comorbidities in patients with multiple myeloma[END_REF]. The aim of this study was to determine the frequency and clinical characteristics of pruritus in patients with MGs in comparison to controls with normal SPEP results.

Cases and controls were selected on SPEP performed at the University Hospital of Brest between 2014 and 2018. The inclusion criteria for cases were to have a monoclonal spike of at least 15 g/L for IgG, 10 g/L for IgA and 5 g/L for IgM (rates choosen because they are associated with higher risk of multiple myeloma (MM), Waldenström's macroglobulinemia (WM) and monoclonal gammopathy of clinical significance [START_REF] Kyle | Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management[END_REF][START_REF] Fermand | Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications[END_REF]). Controls had qualitative and quantitative normal SPEP results. Cases and controls were matched for the year of birth and sex. Patients with another haematological disease producing a monoclonal protein were excluded.

A questionnaire was sent out by post to patients, asking them if they suffered from pruritus. If yes, they answered to the Brest Questionnaire [START_REF] Brenaut | Itch Characteristics in Five Dermatoses: Non-Atopic Eczema, Atopic Dermatitis, Urticaria, Psoriasis and Scabies[END_REF][START_REF] Brenaut | Pruritus: an underrecognized symptom of small-fiber neuropathies[END_REF], the 5-D Itch Scale [START_REF] Elman | The 5-D itch scale: a new measure of pruritus[END_REF] and the ItchyQoL questionnaire [START_REF] Desai | A pilot quality-of-life instrument for pruritus[END_REF]. The study protocol was approved by a Jurisdictional Ethics Committee. The trial was registered on ClinicalTrials.gov (NCT03832140).

One hundred forty-one cases and 141 controls answered the questionnaire with a respective response rate of 48% and 50%. The characteristics of patients with an MG are presented in Table I. For controls, SPEP was prescribed in various conditions: stroke (41.8%), inflammatory rheumatism (10.6%), pre-biotherapy check-up (7.1%), dyspnoea (6.4%), bone pain (5%), anaemia (2.9%), and tumours (2.9%). CP without any skin disease was present in 32 cases (22.7%) and in 12 controls (8.5%). The difference was significant with an OR of 2.46 [1.14 -5.32] (p=0.023). Only 20% of cases with CP had consulted a dermatologist for their pruritus. CP was present for a few years for 72% of patients with MGs, a few months for 24% and a few weeks for 4%. Most cases (48.3%) had started experiencing pruritus after the diagnosis of their gammopathy, 31% had started experiencing pruritus before the diagnosis, and 20.7% had started experiencing pruritus at the same time as the diagnosis. Pruritus was triggered by contact with water in only 4 cases Accepted Article (12.9%). The most frequently reported associated symptoms were stinging (45.1%) and burning (38.8%). The mean 5-D Itch Scale score was 11.0 ± 5.9 (range 6 to 21) for cases. The intensity of pruritus was mild for 24.1% of cases, moderate for 6.9% and severe for 65.5%. The mean ItchyQol score was 38.7 ± 18.2 (range 22 to 73) for cases. Univariate and multivariate logistic regression analyses were performed to identify factors associated with the presence of pruritus in MGs (Table II). The only association found was with MM, which was less associated with CP than MG of undetermined significance (MGUS) and WM. No association was found between pruritus and monoclonal protein levels in MM (OR 0.97 [0.90-1.03), WM (OR 1.00 [0.93-1.06]) or MGUS (OR 1.01 [0.88-1.15]).

Our study demonstrated a significant association between MGs and pruritus. It is not an aquagenic pruritus, contrary to myeloproliferative disorders [START_REF] Gall-Ianotto | Clinical characteristics of aquagenic pruritus in patients with myeloproliferative neoplasms[END_REF], which suggests different pathophysiological mechanisms. The impairment in the quality of life evaluated by the ItchyQol showed the same impairment as in patients with polycythaemia vera (37.3)(3) but a lower impairment than in haemodialysis patients (48.4) [START_REF] Plewig | The Course of Chronic Itch in Hemodialysis Patients: Results of a 4-year Follow-Up Study of GEHIS (German Epidemiological Hemodialysis Itch Study)[END_REF].

To conclude, our study highlighted that CP is 2.5 times more frequent in patients with MGs than in controls. Thus, SPEP is useful in the check-up to find the aetiology of unexplained CP.

Accepted Article

  hal.archives-ouvertes.fr/hal-02890960Submitted on 16 Jul 2020

Table I .

 I Demographic and clinical baseline characteristics of patients with monoclonal gammopathy (MG) and controls and a comparison of features in cases with or without chronic pruritus (CP).

		Cases	Cases with CP	Cases	Controls
		(n=141)	without skin	without CP	(n=141)
			disease (n=32)	(n=96)*
	Sex n (%) Men	76 (53.9)	17 (53.1)	52 (54.2)	76 (53.9)
	Women	65 (46.1)	15 (46.9)	44 (45.8)	65 (46.1)
	Age (years) Mean (SD)	71 (10.4)	73 (10.1)	71 (10.3)	71 (10.4)
	Median	72	74	72	72
	Range	44-92	44-88	50-92	45-91
	Type of gammopathy n (%) MGUS	45 (31.9)	14 (43.7)	26 (27.1)
	IgG	13	5	6
	IgA	9	3	5
	IgM	23	6	15
	Myeloma	63 (44.7)	8 (25.0)	48 (50.0)
	IgG	50	7	38
	IgA	12	1	9
	IgM	1	0	1
	Waldenström

33 (23.4) 10 (31.3) 22 (22.9)

	(IgM) Type of light chain Kappa n (%) Lambda Kappa/lambda ratio Median at diagnosis Range Monoclonal protein levels (g/l) Mean (SD) IgG Median Range Accepted Article IgA Mean (SD) Median Range IgM Mean (SD) Median Range Diagnosis of an MG < 1 year 1-5 years 6-10 years > 10 years Missing value MGUS: Monoclonal gammopathy of undetermined significance. 101 (71.6) 23 (71.9) 40 (28.4) 9 (28.1) 2.9 1.7 0.01-2882 0.09-573 29.6 (15.8) 24.4 (10.1) 24.4 22.3 13-98 13-47.3 18.5 (7.4) 12.6 (2.6) 17 11.4 7.0-31.5 10.6-17 16.5 (11.2) 15.9 (10.2) 14.2 15 3.4-68 3.4-39.1 17 (12.2) 6 (18.8) 67 (47.8) 15 (46.9) 37 (26.4) 7 (21.9) 19 (13.6) 4 (12.4) 1 0 Accepted Article	71 (73.9) 25 (26.0) 3.8 0.01-2882 30.3 (16.2) 24.7 14-98 21.2 (7.3) 21.3 10.2-31.5 16.8 (11.8) 13.9 4.5-68 10 (10.4) 51 (53.1) 21 (21.9) 14 (14.6) 0

* Patients who had had pruritus and patients with CP with skin disease were excluded.

Table II .

 II Factors associated with the presence of pruritus in monoclonal gammapathies. Univariate and multivariate logistic regression models were used to assess the association of covariates with the presence of pruritus. The covariates examined were sex, age, the type of gammopathy, the type of heavy chain, the type of light chain, heavy chain levels at diagnosis, and the kappa/lambda ratio at diagnosis. An adjustment on age and sex was then added because of a known association with pruritus.

			Odds Ratio (95% CI)	p-value
		Univariate logistic regression
	Sex (male)		0.96 (0.43-2.16)	0.92
	Age		1.02 (0.98-1.06)	0.41
	Gammopathy	Ref MGUS
		Myeloma	0.31 (0.11-0.82)	0.02
	Waldenström	0.84 (0.31-2.26)	0.74
	Heavy chain	Ref IgA
		IgG	0.95 (2.28-3.84)	0.94
		IgM	1.47 (0.45-5.81)	0.54
	Monoclonal protein levels	0.97 (0.93-1.002)	0.10
	Light chain lambda*		1.11 (0.44-2.67)	0.82
	Kappa/lambda ratio		0.998 (0.994-1.000)	0.28
		Multivariate logistic regression
	Sex (male)		0.96 (0.41-2.27)	0.93
	Age		1.01 (0.97-1.06)	0.61
	Gammopathy
		Myeloma	0.31 (0.11-0.83)	0.02
	Waldenström	0.81 (0.28-2.30)	0.69

This article has no funding source.


N Champtiaux

V Cottin

G Chassagnon

B Chaigne

G Bussone

Dr Luc Mouthon
email: luc.mouthon@aphp.fr

Combined pulmonary fibrosis and emphysema in systemic sclerosis

Keywords: systemic sclerosis, combined pulmonary fibrosis and emphysema, prognosis, survival, pulmonary hypertension

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Systemic sclerosis (SSc) is a rare multisystemic disease characterized by vascular hyper-reactivity and fibrosis in the skin and other organs. Fifty to 70% of SSc patients develop interstitial lung disease (ILD) [START_REF] Dumoitier | Pathophysiology of systemic sclerosis: state of the art in 2014[END_REF] which represents one of the two main causes of death in SSc [START_REF] Steen | Changes in causes of death in systemic sclerosis, 1972-2002[END_REF]. In this setting, we recently reported 36 patients, including 10 with SSc, with CTD-associated combined pulmonary fibrosis and emphysema (CPFE) (3), a recently described entity of severe prognosis [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF].

CPFE is defined by the association of centrilobular and/or paraseptal emphysema in upper lung zones and pulmonary fibrosis in lower lobes [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF][START_REF] Akagi | Coexistent emphysema delays the decrease of vital capacity in idiopathic pulmonary fibrosis[END_REF][START_REF] Jankowich | Combined pulmonary fibrosis and emphysema alters physiology but has similar mortality to pulmonary fibrosis without emphysema[END_REF][START_REF] Lee | The impact of combined pulmonary fibrosis and emphysema on mortality. The international journal of tuberculosis and lung disease[END_REF][START_REF] Mejia | Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension[END_REF][START_REF] Kitaguchi | Annual changes in pulmonary function in combined pulmonary fibrosis and emphysema: Over a 5-year follow-up[END_REF][START_REF] Todd | Centrilobular emphysema combined with pulmonary fibrosis results in improved survival[END_REF][START_REF] Ryerson | Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis[END_REF]. In addition to connective tissue disease (CTD)-associated ILD [START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease[END_REF][START_REF] Antoniou | Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung[END_REF][START_REF] Antoniou | Combined pulmonary fibrosis and emphysema in scleroderma lung disease has a major confounding effect on lung physiology and screening for pulmonary hypertension[END_REF], a number of etiologies have been reported to contribute to the CPFE syndrome including tobacco smoking, pneumoconiosis like asbestosis [START_REF] Jankowich | Combined pulmonary fibrosis and emphysema alters physiology but has similar mortality to pulmonary fibrosis without emphysema[END_REF] or siderosis [START_REF] Roshan | Combined pulmonary fibrosis and emphysema in a welder[END_REF] and familial pulmonary fibrosis [START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in a patient age 28 years with severe systemic sclerosis[END_REF][START_REF] Epaud | Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations[END_REF][START_REF] Nunes | Is telomeropathy the explanation for combined pulmonary fibrosis and emphysema syndrome?: report of a family with TERT mutation[END_REF]. Because of the opposing effects of emphysema and fibrosis on lung mechanics, the lung function profile is characterized by subnormal dynamic and static lung volumes despite significant reduction in carbon monoxide diffusing capacity (DLCO) and severe exercise hypoxemia. Approximately 30% of patients with idiopathic ILD also have significant emphysema and therefore present with CPFE. Most patients with CPFE are male smokers or ex-smokers. Pulmonary hypertension (PH), often severe, occurs in nearly 50% of CPFE patients, and seems tightly linked to increased mortality [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF][START_REF] Mejia | Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension[END_REF][START_REF] Sugino | Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone[END_REF]. SSc-associated CPFE may exhibit unique characteristics that might not apply to other CTDs. Thus, in our study performed in CTD-associated CPFE, 5 out of 10 patients with SScassociated CPFE, but none of the others, developed PH [START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease[END_REF]. Furthermore, increased susceptibility to emphysema has been suggested in SSc patients [START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in a patient age 28 years with severe systemic sclerosis[END_REF][START_REF] Antoniou | Pulmonary fibrosis is associated with emphysema in systemic sclerosis: indirect support for a smoking pathogenesis hypothesis [Abstract[END_REF].

In order to describe the specificities of SSc-associated CPFE (CPFE-SSc), we conducted a retrospective multi-center case-control study, and compared the clinical characteristics, pulmonary function tests (PFTs), and outcome of 36 patients with CPFE-SSc with those of 72 control patients with SSc and ILD without emphysema (ILD-SSc).

PATIENTS AND METHODS

Selection of cases and controls

Physicians belonging to the National reference and the Regional competence centers for rare For each CPFE-SSc patient, two control SSc patients corresponding to criteria 2, 3 and 4 but without emphysema were randomly selected from the Cochin database that included 773 patients at the end of the study period. This database collects socio-demographic, clinical, morphological, biological, and PFT characteristics of patients with SSc referred to this tertiary care center.

Details about data collection and thoracic HRCT scan analysis are described in the supplementary appendix.

Ethical considerations

Our study was approved by the Hotel Dieu Ethics Committee (Paris, France), the CCTIRS and the CNIL (French National Committee for Informatics and Liberties).

Statistical analysis

Statistical analysis was performed using XLSTAT 2013 software. Comparisons between discrete variables were made using Chi 2 or Fisher Exact Test. For continuous variables, comparisons were performed using an unpaired 2-tailed Student t-test or a Mann Whitney U test as appropriate. Survival analysis was performed with the Kaplan-Meier method using a Log Rank test. The effect of tobacco on survival was examined using a cox-model regression analysis Patients were censored if they were lost to follow-up. P values less than 0.05 were considered significant.

RESULTS

Patient population

Thirty-six patients with CPFE-SSc were identified, including 10 who had been previously reported [START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease[END_REF][START_REF] Cottin | Combined pulmonary fibrosis and emphysema syndrome in a patient age 28 years with severe systemic sclerosis[END_REF]. Representative examples of HRCT scans from patients with CPFE-SSc are shown in Figure 1.

Out of 276 SSc patients from the Cochin cohort with HRCT scans readily available for review, ILD was detected in 131 patients (47.4%), of whom 10 also had significant emphysema. Thus, the rate of CPFE for all SSc patients evaluated on CT was 3.6%, and 7.6% among SSc patients with ILD. Although the difference did not reach statistical significance, emphysema seemed to be more frequent in SSc-ILD patients compared to SSc patients with no ILD (7.6% versus (vs) 2.7%, respectively, p=0.06), despite a similar proportion of smokers (35.5% and 40.0%, respectively).

Demographic characteristics and exposure to smoking and to aerocontaminants (Table 1)

Median age at the diagnosis of SSc was similar in ILD-SSc controls and CPFE patients.

However, CPFE-SSc patients were more likely than ILD-SSc to be males (75% vs 18%, p<0.0001), smokers or former smokers (83% vs 33%, p<0.0001), and to report occupational exposure to dusts (35% vs 5%, p<0.0001). Among smokers, tobacco consumption was more important in CPFE patients (mean 31.7±20.2 pack-years) as compared to ILD-SSc controls (mean 19.3±12.6 pack-years, p=0.02). Interestingly, when analysis was restricted to smokers from each group, male gender remained strikingly more prevalent in CPFE-SSc patients (83% vs 25%, p<0.0001). Unadjusted OR for male gender was 13.6 (95% confidence interval: 5.2-35.7), or 9.5 (3.4-26.2) after adjustment for smoking status.

SSc clinical and immunological characteristics (Table 1)

The SSc subtype differed between CPFE-SSc and ILD-SSc patients (p<0.01). Namely, most CPFE-SSc patients exhibited a limited cutaneous form of SSc (53% vs 24% of ILD-SSc controls). Accordingly, the mean modified Rodnan skin score was higher in ILD-SSc controls. The proportion of patients with extra-pulmonary complications and autoantibody specificity did not differ between groups.

Lung disease clinical characteristics and symptoms (Table 1)

The delay between SSc diagnosis and the radiological evidence of CPFE was 3.2±5.4 years. In most cases (n= 24), emphysema and ILD were diagnosed simultaneously whereas ILD preceded emphysema in 9 patients by 3.6±3.5 years on average. In the remaining 3 patients, emphysema was detected before ILD. In the control group, ILD was identified 3.1±5.9 years after the diagnosis of SSc.

At the time of diagnosis, most patients reported dyspnea on exertion (97% and 86% of CPFE and ILD-SSc controls, respectively), but with increased dyspnea in CPFE-SSc as compared to ILD-SSc patients (p<0.05, Chi 2 for NYHA functional classes).

Pulmonary function tests (PFT) (Table 2)

At diagnosis, a restrictive ventilatory defect was observed in 21/36 CPFE patients (58%) and 37/72 ILD-SSc controls (53%, p=0.6). Forced vital capacity (FVC) and total lung capacity (TLC) were similar between groups (Table 2). CPFE-SSc patients exhibited a more severe decrease in DLCO (39±13 vs 51±12%, p<0.0001) and transfer coefficient of the lung (KCO 60±17% vs 74±15%, p<0.0001) than ILD-SSc controls. The composite physiologic index (CPI), calculated as described by Wells et al. [START_REF] Wells | Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography[END_REF], was significantly higher in the CPFE group.

Forty-eight percent of CPFE patients and 23% of ILD-SSc controls had hypoxemia at rest (PaO 2 < 80 mmHg, p=0.01). At the end of the 6-minute walk test, 73% of CPFE patients, and 41% of ILD-SSc controls (p=0.01) exhibited a decrease in percutaneous saturation greater than 4%.

Upon follow-up, the presence of emphysema was surprisingly associated with a greater decline rate of FVC and TLC values, whereas the decline rate of DLCO was similar in both groups. Indeed, FVC decreased by a mean of 3.1±4.8% per year in CPFE patients, vs 1.1±4.5% per year in ILD-SSc controls (p<0.05). The mean interval from the diagnosis of CPFE or ILD to the last PFT available was comparable in both groups (4.8±3.3 years vs 5.7±4.0 years in CPFE and ILD-SSc controls, respectively).

Thoracic HRCT scans (Table 3)

Twenty-eight of the 32 patients analysed (88%) and 94% of ILD-SSc controls had CT features typical for non-specific interstitial pneumonia. CPFE patients had a significantly lower mean disease extent (28% (range: 5-55%) vs 19% (2-71%), p<0.01) although the mean traction bronchiectasis score was similar in both groups. Emphysema was predominantly paraseptal in 20 (62%) patients. Mean emphysema extent was 15% (range: 2-50%) with only 7 patients with emphysema extent of more than 20%. The CPFE pattern (as defined in [START_REF] Brillet | Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary function tests[END_REF]) was that of "distinct entities" in 10 patients, "progressive transition" between emphysema and fibrosis in 7 patients, "predominantly paraseptal" emphysema associated with fibrosis in 6 patients, and unclassifiable in the remaining 9 patients. Interestingly, the proportion of patients with main pulmonary artery diameter enlargement above 34 mm was significantly higher in CPFE patients than in the control group (22 (7%) vs 4 (3%), p=0.01).

Pulmonary hypertension (Table 4)

Systolic pulmonary arterial pressure (sPAP) could be estimated by echocardiography in 34 CPFE-SSc patients and in 67 ILD-SSc controls. Elevated sPAP> 40 mmHg or right heart cavities dilation was detected in 55% and 25% of CPFE-SSc patients, respectively (vs 20% and 3% of ILD-SSc controls, p<0.001 in both cases). The mean estimated sPAP was significantly higher in the CPFE-SSc group (43±13 mmHg vs 36±13 mmHg, p <0.01).

Precapillary pulmonary hypertension (PH

Treatment

Approximately half of the patients in both groups (53% of CPFE-SSc and 49% of ILD-SSc controls) received intravenous cyclophosphamide (6 to 12 infusions of 0.7 g/m² each) in association with low dose glucocorticoids (10-15 mg per day) followed by oral mycophenolate mofetil or azathioprine as a maintenance therapy. One additional patient with CPFE received oral cyclophosphamide for 6 months. At the end of cyclophosphamide treatment, FVC improved (by more than 10%) in 13% of CPFE-SSc patients, was stable in 47 %, and worsened (by more than 10%) in 40%. Comparable results were obtained in ILD-SSc controls (FVC improved in 22%, remained stable in 56%, and worsened in 22% of cases, p=0.51)

Prognosis

The mean follow-up after the first SSc symptom was 10.1±6. [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF] Thirteen patients (36% of CPFE-SSc patients and 18% of ILD-SSc controls, p=0.04) died in each group. The mean survival time from the first manifestation of SSc was 13.0±1.0 and 27.6±3.9 years in CPFE-SSc and control patients, respectively (p<0.01, LogRank Test, Figure 2b). Similar results were obtained when the survival time was estimated from the date of ILD/CPFE diagnosis (not shown) or after adjustment for CPI to take into account the confounding effect of fibrosis extension (not shown). In CPFE-SSc patients, in univariate analysis, the existence of PH was the only parameter significantly associated with mortality (p=0.05; LogRank test, Figure 2c), whereas gender, scleroderma subtype and auto-antibody specificity were not (not shown). Using the Cox model, in univariate analysis: the CPFE and smoking status are both associated with survival (p = 0.013 for CFPE, p = 0.03 for active or weaned smoking). However, neither of them remains significant on multivariate analysis (p = 0.13 for CFPE, p = 0.29 for tobacco).

DISCUSSION

We present a large case series of patients with SSc-associated CPFE. We confirmed the pulmonary function hallmark of the CPFE syndrome, with markedly reduced DLCO, disproportionate to the preserved lung volumes and mild or absent airflow obstruction. The prevalence of precapillary PH (44%) was comparable to that observed in "idiopathic" CPFE, but much greater than the 8-20% prevalence observed in SSc with or without ILD [START_REF] Antoniou | Combined pulmonary fibrosis and emphysema in scleroderma lung disease has a major confounding effect on lung physiology and screening for pulmonary hypertension[END_REF][START_REF] Hachulla | Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study[END_REF][START_REF] Launay | Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease[END_REF]. Recently, in a cohort of SSc patients with ILD, Antoniou et al. [START_REF] Antoniou | Combined pulmonary fibrosis and emphysema in scleroderma lung disease has a major confounding effect on lung physiology and screening for pulmonary hypertension[END_REF] reported an even greater prevalence of the CPFE syndrome (12.5%) but a somewhat lower prevalence of PH in CPFE-SSc patients (24%). The difference between our two studies might be explained by a difference in the definition of significant emphysema (in their report, mean emphysema extent represented 5.5% of lung surface vs 15% in the present study). At last, we could demonstrate that patients with CPFE-SSc had a decreased survival as compared to ILD-SSc controls.

Altogether, our findings establish CPFE in patients with SSc as a serious distinct condition with increased morbidity and mortality when compared to ILD-SSc without emphysema.

As reported in patients with CPFE without CTD (4), male gender and tobacco smoking were the main risk factors associated with CPFE in SSc patients, and OR for male gender after adjustment for smoking status was 9.5. Moreover, using the Cox model, in univariate analysis: the CPFE and smoking status were both associated with survival. However, neither of them remained significant on multivariate analysis, probably because these two variables are not independent.

In addition, although none of the patients met the criteria for the diagnosis of pneumoconiosis, we observed a significant association with CPFE syndrome and exposure to dusts. This finding is consistent with previous reports suggesting a role for agrochemical compounds [START_REF] Daniil | Combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds[END_REF], iron dusts [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF][START_REF] Roshan | Combined pulmonary fibrosis and emphysema in a welder[END_REF], or talc [START_REF] Karkhanis | Combined pulmonary fibrosis and emphysema in a tyre industry worker[END_REF] in the pathogenesis of CPFE.

The pathophysiology of CPFE outside the setting of CTD is poorly understood [START_REF] Cottin | The syndrome of combined pulmonary fibrosis and emphysema[END_REF]. In SSc-associated CPFE, emphysema might be related to inflammatory processes dependent on the CTD itself. Our observation that CPFE was more frequently associated with limited cutaneous SSc highlights the importance of pathological processes specific to the underlying CTD. Moreover, the average tobacco consumption was lower in SSc-associated CPFE than that reported in idiopathic CPFE (31 pack-years vs 40-70 pack-years in idiopathic CPFE). Six patients (17%) denied any exposure to tobacco smoke. We also found a trend for a greater frequency of emphysema in patients with ILD-SSc (7.6%), compared to patients with SSc without evidence of ILD on CT scan (2.7%). Our data are in agreement with the findings of Antoniou et al., who found a high prevalence of emphysema in ILD-SSc patients, even in never smokers [START_REF] Antoniou | Combined pulmonary fibrosis and emphysema in scleroderma lung disease has a major confounding effect on lung physiology and screening for pulmonary hypertension[END_REF][START_REF] Antoniou | Pulmonary fibrosis is associated with emphysema in systemic sclerosis: indirect support for a smoking pathogenesis hypothesis [Abstract[END_REF]. The reasons for this apparent increased susceptibility to develop emphysema are unclear. Interestingly, a relative α1-antitrypsin deficiency, or an excess of neutrophil elastase levels in the serum of SSc patients were reported [START_REF] Barnes | Relative alpha(1)-antitrypsin deficiency in systemic sclerosis[END_REF][START_REF] Hara | Elevated serum concentrations of polymorphonuclear neutrophilic leukocyte elastase in systemic sclerosis: association with pulmonary fibrosis[END_REF]. In Tsk-1 mice, a murine model of SSc with a duplication of the fibrillin 1 gene and anti-topoisomerase-1 antibodies, lung emphysema develops spontaneously [START_REF] Gardi | Lung collagen synthesis and deposition in tight-skin mice with genetic emphysema[END_REF]. We could not demonstrate a specific link between anti-topoisomerase-1 detection and CPFE in our patients, but autoantibodies with other specificities might play a role. Indeed, high levels of anti-elastin autoantibodies have been described in patients with SSc [START_REF] Hong | Serum elastin-derived peptides and anti-elastin antibody in patients with systemic sclerosis[END_REF], or tobacco induced emphysema [START_REF] Lee | Antielastin autoimmunity in tobacco smoking-induced emphysema[END_REF], but not in idiopathic CPFE [START_REF] Cottin | Anti-elastin autoantibodies are not present in combined pulmonary fibrosis and emphysema[END_REF]. Interestingly, increased susceptibility to tobacco induced emphysema was also reported in patients with rheumatoid arthritis and ILD [START_REF] Antoniou | Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung[END_REF].

The functional profile of CPFE-SSc patients was similar to that usually reported in "idiopathic" CPFE, with subnormal mean FVC and TLC values and little evidence of airway obstruction despite the existence of radiologic emphysema. In contrast, DLCO and KCO values were markedly reduced and significantly lower than in ILD-SSc control patients despite similar lung volumes. However, the lack of significant difference between the two groups for TLC and FVC values and the lower predicted RV values in patients with CPFE are unexpected. Due to the absence of emphysema (and subsequent air-trapping mechanism), we expected higher FVC and lower RV values in the group of ILD-SSc controls. This finding may reflect a more advanced fibrosing disease mitigating the expected gas-trapping effect of emphysema in CPFE patients. Such hypothesis could be the consequence of a delay in the diagnosis of lung fibrosis in these patients. Emphysema distant from the ILD may not have an effect on FVC, as opposed to emphysema admixed to the fibrotic process [START_REF] Jacob | Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis[END_REF], which was not analyzed in the present study. Alternatively, patients with CPFE might be affected by a more rapidly progressive disease. Thus, the rate of FVC and TLC decline was greater in CPFE patients than in ILD-SSc controls, contrasting with other studies in "idiopathic" CPFE which demonstrated a slower decline in lung volumes as compared to patients with idiopathic ILD (5) especially in individuals with emphysema extent greater than 15% at HRCT [START_REF] Cottin | Effect of emphysema extent on serial lung function in patients with idiopathic pulmonary fibrosis[END_REF].

Identifying CPFE in SSc patients with ILD is highly relevant. CPFE was associated with increased mortality. Compared to ILD-SSc controls, CPFE-SSc patients appeared more symptomatic, with increased dyspnea, more frequent hypoxemia at rest, and more frequent desaturation upon exercise. During follow-up, CPFE patients more frequently required emergency hospitalization for cardio-pulmonary reasons, and long-term nasal oxygen therapy.

The cumulative frequency rate of precapillary PH (44%) was four times greater than in patients with isolated ILD-SSc. Importantly, the presence of PH in CPFE patients was associated with decreased exercise capacity, and decreased survival, as reported outside the setting of CTD [START_REF] Cottin | Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity[END_REF][START_REF] Mejia | Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension[END_REF].

Our study has several limitations, including its retrospective design. Patients from the control group were randomly selected from a large cohort of SSc patients emanating from a single center, whereas CPFE patients were identified in several university hospitals. This allowed random selection of ILD-SSc controls among a very large group of SSc patients to constitute a representative sample of the condition of interest and avoid important selection bias associated with the non-random selection of ILD-SSc controls in smaller centers.

In conclusion, CPFE is a distinct, still under-recognised, pulmonary complication of SSc.

Patients with SSc-associated CPFE more frequently develop PH and show increased morbidity and mortality as compared to those with SSc and ILD without emphysema.

LEGEND TO FIGURES

  pulmonary diseases, to the Groupe d'Etudes et de Recherche sur les Maladies « Orphelines » pulmonaires (GERM « O »P), the Club Rhumatismes et Inflammation (CRI), and the Groupe Francophone de Recherche sur la Sclérodermie (GFRS), were asked to report all cases of CPFE occurring in a patient with SSc. The databases from the Centre de Référence Maladies Systémiques Autoimmunes Rares d'Ile de France (Cochin Hospital) and from the GERM « O »P were also screened for potential cases included between 1998 and June 2013. In order to estimate the prevalence of CPFE in SSc, all thoracic high resolution computed tomography (HRCT) scans of patients from the Cochin cohort readily available on digital support (from 2006 on) were reviewed (n= 276 patients). Inclusion criteria were the following: 1) evidence of emphysema on HRCT scan, defined as areas of decreased attenuation, without visible walls, of non-uniform distribution and predominantly located in upper lung zones (20); 2) evidence of ILD, characterized by presence of ground glass opacities, reticulations, traction bronchiectasis or bronchiolectasis, and/or honeycombing; 3) SSc defined by the 2013 ACR-EULAR classification criteria (21); 4) Patients with ILD related to another etiology and patients with a diagnosis of mixed connective tissue disease were excluded.

  ) was confirmed by right heart catheterization in 16 (44%) SSc patients and 8 (11%) ILD-SSc controls (p<0.0001). The mean survival time without PH from the onset of SSc was 15.4±2.1 years in CPFE vs 24.2±1.4 years in ILD-SSc controls, (p<0.0001 Log Rank test, Figure 2a). Among CPFE-SSc patients, those who developed PH had significantly decreased PaO2 at rest, greater desaturation during the sixminute walk test, and lower DLCO at the time of diagnosis of CPFE as compared to patients without PH (not shown).

  and 11.2±7.3 years in CPFE-SSc and control patients, respectively. During follow-up, 50% of CPFE-SSc patients and 25% of ILD-SSc controls required at least one emergency hospitalization for cardiorespiratory failure (p<0.01). Causes for emergency hospitalization in CPFE patients were right heart failure (n=13), infectious pneumonia (n=11, including 1 case of Pneumocystis jiroveci pneumonia), exacerbation of ILD (n=5), pneumothorax (n=4), hemoptysis (n=2) and pulmonary embolism (n=2).Twenty (56%) CPFE-SSc patients and 13 (18%) ILD-SSc controls (p<0.0001) received long term nasal oxygen therapy. One patient in each group was diagnosed with lung cancer. Two CPFE-SSc patients underwent pulmonary transplantation.

Figure 1 :

 1 Figure 1:

Figure 2 :

 2 Figure 2: a) Occurrence of precapillary pulmonary hypertension (PH) in CPFE-SSc and ILD-

FIGURES Figure 1

 1 FIGURES

Table 1

 1 Clinical and immunological characteristics in CPFE-SSc patients and ILD-SSc controls. Dust exposure was inferred from our knowledge of patients' profession and included exposure to flour, metal, wood, and concrete dusts. SSc subtype corresponds to the Leroy and Medsger 2001 classification (L= limited, LC=limited cutaneous, D=Diffuse). ANA: antinuclear antibody. BMI: body mass index; CFPE: combined fibrosis and pulmonary emphysema; ILD: interstitial lung disease; MRSS: modified Rodnan Skin Score; NYHA: New York Heart Association; Pm/Scl: polymyositis/scleroderma. RNP: ribonucleoprotein. RNA: ribonucleic acid; SD: standard deviation; SSc: systemic sclerosis. Unless specified, data are presented as patient number (percentage)

	CPFE-SSc (n=36)	ILD-SSc (n=72)	p

Acknowledgements

Pr. Luc Mouthon is the guarantor of the content of the manuscript, including the data and analysis.

All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. All authors had full access to all of the data in the study.

Financial/non-financial disclosures: none.

Sponsors: none

We acknowledge the help of Drs Chahera Khouatra, Julie Traclet, and Jean-François Mornex (Lyon, France) for patient care, Mrs Raphaele Guelminger and Sabrina Zeghmar who contributed to data entry, and Matt Kostura for English proofreading.