Abstract
Objective There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.
Methods A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.
Results The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.
Conclusion Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.
- sex
- scleroderma
- systemic sclerosis
Systemic sclerosis (SSc) is a severe inflammatory autoimmune disease characterized by unpredictable clinical course, inadequate response to treatment, and significant mortality.1,2 Genetic, hormonal, and environmental factors may account for differences in the clinical profile between women with SSc compared to men.3
Some initial studies gathered sex-specific information in small cohorts of patients4,5,6 Later, registries related to SSc have been promoted worldwide to provide large and homogeneous subgroups of patients.7,8,9,10
To date, multicenter national studies have been conducted by cross-sectional analysis, evaluating demographic, clinical, and serological differences between males and females with SSc. Two Canadian studies7,8 included 408 and 1120 patients, respectively, recruited from 15 centers. The Spanish registry RESCLE (Registro de ESCLErodermia) enrolled 1506 patients with SSc from 21 centers.9 A cross-sectional investigation of the prospective European Scleroderma Trial and Research (EUSTAR) group database comprised a mixture of patients from European and non-European countries, including 1027 patients with early SSc.10 The noteworthy nonmulticenter studies with a significant number of patients included single-center retrospective studies11,12 consisting of patients diagnosed according to both American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for SSc. Finally, a large prospective study from the EUSTAR cohort showed evidence of sex influence on SSc heart involvement characteristics.13
These studies yielded mixed results in terms of sex predilection for some relevant clinical manifestations like digital ulcers (DUs), pulmonary hypertension, cardiac involvement, time to diagnosis, and demographic data.3,8,9,10,11,12,13 In fact, many issues may be subject to geographical variations and environmental factors.
In 2015, the Italian Society for Rheumatology (SIR) promoted the creation of the national Systemic sclerosis PRogression INvestiGation (SPRING) registry, which includes both clinical conditions preceding the onset of definite SSc and overt disease variants.14 The overall baseline data have already been published14 and the inclusion of consecutive patients from 37 Italian centers is still in progress to assess short- and long-term prognostic factors.
The purpose of the current study was to thoroughly analyze the sex-specific differences in our cohort of patients with SSc and to evaluate the presence of specific sex-related clinical phenotypes.
METHODS
In 2015, the nonprofit national multicenter cohort study SPRING was started and supported by SIR. The registry currently comprises 37 centers with > 150 items including clinical, immunological, and imaging data, as well as treatments. The ethical committees of each participating center14 approved the study protocol after the coordinating center’s authorization (reference number OSS 15.010, AOU Careggi-Firenze). All patients provided written informed consent to join the study, with guaranteed identity protection. Data were collected and handled using the tool REDCap, a Web-based application to support data collection for research studies. Multicenter registries are highly heterogeneous in how data are collected and entered. Therefore, we sought to minimize the issue by introducing clear definitions of the variables that were followed by the centers. The coordinating center performed periodic quality checks.
Definitions. The SPRING database has been previously described.14 Briefly, it consists of patients aged > 18 years classified into 4 different cohorts: (1) primary Raynaud phenomenon (RP); (2) suspected secondary RP; (3) very early diagnosis of systemic sclerosis (VEDOSS); and (4) definite SSc according to ACR/EULAR 2013 classification criteria for SSc.15 For the purpose of the current study, data concerning patients with definite SSc, enrolled up to December 2020 and comprising the 1538 included in the previous study, were analyzed.14
The data collected at registration included the following: age of disease onset (ie, that of the first non-RP sign[s] and/or symptom[s]), time from SSc onset to diagnosis, time from RP onset to SSc diagnosis, esophageal symptoms (dysphagia, reflux), cardiopulmonary signs and symptoms (dyspnea, heart failure), sicca syndrome (dry eyes/mouth), renal crisis (sudden onset of severe arterial hypertension together with acute renal failure), skin involvement (puffy fingers, telangiectasia), peripheral vascular (digital pitting scars [DPSs], DUs, gangrene), and musculoskeletal (calcinosis, tenosynovitis, arthritis defined as inflammatory changes observed in > 2 joints, joint contractures, tendon friction rubs, osteomyelitis, carpal tunnel syndrome, myositis, muscle atrophy). The first non-RP sign(s)/symptom(s) comprised arthralgia/arthritis, puffy hands, telangiectasias, DUs/pitting scars, and dysphagia.10
Skin subsets were classified as follows: SSc sine scleroderma (ssSSc), limited cutaneous (lcSSc), and diffuse cutaneous SSc (dcSSc). Patients with the ssSSc subset were characterized by the absence of visible skin thickening, and the presence of internal organ involvement and/or serological abnormalities and/or capillaroscopic abnormalities and/or other skin manifestations (ie, calcifications, telangiectasias, pitting scars).16 Further, capillaroscopic patterns were considered according to the data previously described.14 Laboratory findings included antinuclear antibodies (ANA) and antiextractable nuclear antigens (anti-ENA) as earlier described,14 comprising both SSc-related and nonrelated antibodies (anticentromere protein B [CENP-B], antitopoisomerase I/Scl-70, anti–RNA polymerase III, anti-Ro/SSA, anti-La/SSB, anti-RNP, anti-Jo1, antineutrophil cytoplasmic antibodies, anti-dsDNA, and antiphospholipids).14
Noninvasive cardiac diagnostic testing was performed by electrocardiogram and transthoracic echocardiography, collecting the following data: heart conduction block, arrhythmias, bi/trigeminy, pulmonary arterial hypertension (PAH; mmHg), left ventricular ejection fraction (LVEF), anomalous diastolic function, pericardial effusion, and other alterations (heart hypertrophy, valvular heart disease, hypokinesis, and dilated cardiomyopathy). Investigations for lung involvement consisted of pulmonary function tests (total lung capacity [TLC], forced vital capacity [FVC]), including diffusing lung capacity for carbon monoxide (DLCO) and high-resolution computed tomography (HRCT) as the gold standard for the detection and evaluation of lung involvement (ground-glass fibrosis, reticulation, honeycombing). Moreover, the 6-minute walk test (6MWT) with or without pulse oximetry for measuring heart rate and oxygen saturation was assessed.
Finally, information about previous/current treatments included both vasoactive drugs (sildenafil, vardenafil, tadalafil, iloprost, prostaglandin E1, inhaled iloprost, epoprostenol, riociguat, nifedipine, nicardipine, amlodipine, felodipine, diltiazem) and immunosuppressants (cyclophosphamide, methotrexate, leflunomide, azathioprine, mycophenolic acid, cyclosporine, rituximab, imatinib, anti–tumor necrosis factor, tocilizumab, abatacept).
Statistical analysis. Continuous variables are expressed as mean (SD) and categorical variables as n (%). The t test for independent samples was employed for continuous variables when the normality assumption held. Otherwise, the Wilcoxon test was used. The chi-square test was adopted for dichotomous/categorical variables when counts in each cell of the contingency table were > 5. Otherwise, the Fisher exact test was used. Median (IQR) has been provided in place of mean (SD) when significant asymmetry of distributions was present. Analyses were performed using R statistical software (Foundation for Statistical Computing; version 3.6).
RESULTS
Demographic and clinical variables and treatments are reported in Table 1, whereas Table 2 summarizes the prevalence of autoantibodies found in our cohort. Overall data regarding capillaroscopy and internal organ involvement detected by diagnostic procedures are shown in Table 3. Figure 1 provides an overview of the significant clinical, laboratory, and diagnostic categorical variables. The main literature on sex in SSc is indicated in Table 4.
Demographic variables. Up to December 31, 2020, a total of 2281 patients were enrolled in the SPRING registry; 247 (10.8%) were male and the overall female/male ratio was 8.2:1 Moreover, the ratios for lcSSc and dcSSc were 8.7:1 and 4.9:1, respectively. A considerable number of patients (493/2157, 22.9%) presented with the ssSSc variant, markedly prevalent in females (female:male = 10.7:1). No differences between females and males were found for age of onset (P = 0.79); this did not change when patients were separated by age group (P = 0.79). Time from SSc onset to diagnosis was comparable among males and females, whereas time from RP onset to SSc diagnosis was significantly shorter in males (P = 0.003; Table 1).
Clinical variables and treatments. No differences were detected regarding esophageal symptoms, dyspnea, and/or signs of heart failure (New York Heart Association classes). Renal crisis was significantly more frequent in men (2.1% vs 0.7%, P = 0.04), whereas sicca syndrome was more frequent in women (30.3% vs 19.4%, P = 0.001; Figure 1).
Regarding the cutaneous subtypes, dcSSc was significantly more common in males (25.1% vs 15.2%, P < 0.001; Figure 1).
No differences were found for puffy fingers, telangectasia, and calcinosis. Among peripheral vascular manifestations, DPSs and DUs were significantly higher in males than females (49.8% vs 37.8%, P < 0.001, and 25.7% vs 18.9%, P = 0.02, respectively; Figure 1). The frequency of gangrene was similar in both sexes, as were the differences regarding descriptors of musculoskeletal involvement. Immunosuppressive therapies were used significantly more often in males than females (30.0% vs 21.3%, P = 0.003), whereas no difference was recorded for vasoactive drugs (72.9% vs 68.7%, P = 0.21) and corticosteroids (79.2 vs 76.9, P = 0.70; Table 1).
Laboratory variables. Autoantibody profile is detailed in Table 2. A significantly higher percentage was found in females for positive ANA (93.9% vs 89.5%, P = 0.01), anti-ENA (37.2% vs 21.5%, P < 0.001), anti-La/SSB (2.3% vs 0%, P = 0.02), and anti-CENP-B (33.5% vs 16.0%, P < 0.001). Of the anti-SSB–positive patients, only 23 had a concurrent sicca syndrome (1.4%).
Microcirculation and internal organs. The distribution of capillaroscopic patterns was similar in both sexes, since no differences were found regarding early, active, and late pattern. Echocardiographic investigation found no significant differences, except for a lower LVEF in men compared to women. Similarly, conduction defects, specifically conduction blocks (15.9% vs 9.7%, P = 0.03) and cardiac arrhythmias (8.0% vs 3.9% P = 0.05), were more common in males (Table 3).
In male patients, the HRCT of the lungs showed an increased prevalence of ground-glass opacities (24.3% vs 16.1%, P = 0.002) and honeycombing (10.5% vs 3.7%, P < 0.001; Table 3).
Among pulmonary function tests, the mean of the expected values of FVC (91 ± 21.5 vs 103.7 ± 22.1) and TLC (89.8 ± 21.5 vs 99.6 ± 19.6) were significantly lower in men than in women (P < 0.001); no differences were detected in the 6MWT, with values within normal limits17 (Table 3).
Literature review. The clinical and demographic results of the present SSc series and those previously published are summarized in Table 4. The comparison reveals great heterogeneity in the F:M ratio, a significant male prevalence in both the diffuse subset and in visceral involvement, and high variability in autoantibody profiles, with the presence of both SSc-specific and nonspecific antibodies, but with a predominance of anti–Scl-70 in males and anticentromere in females.
DISCUSSION
This study further supports the presence of significant sex-related differences in the demographic, clinical, and serological features of patients with SSc. The disease is more severe in men, who present more frequently with extensive skin involvement, digital vasculopathy, and internal organ involvement, requiring a more aggressive therapeutic approach. In addition, male sex is associated with a significant reduction in the interval between RP onset and SSc diagnosis, which represents a poor prognostic factor.3,14 On the other hand, women show a higher prevalence of sicca syndrome and a particular autoantibody profile characterized by an increased proportion of serum ANA, anti-ENA, anti-CENP-B, and anti-La/SSB antibodies. In addition, the female sex presents a higher percentage of the ssSSc cutaneous variant than males.
Our findings were compared with other observational studies in order to detect any similarities or differences. To date, our study is the largest national registry, to our knowledge. The female/male ratio is 8.2:1, in line with previous Italian series,14,18,19 and almost overlapping with Spanish data.9 However, it differs from the data observed in other countries,3,12,13 reinforcing the assumption of genetic and/or environmental cofactors responsible for epidemiological and clinical heterogeneity among different SSc populations.3 Moreover, we found a considerable proportion of the ssSSc subset in our female cohort, quite higher than expected according to the literature,8,16 which roughly estimates the ssSSc subset as accounting for approximately 5% of all patients with SSc.16 On the basis of the latest classification of ssSSc,16,20 this subgroup can be considered as a mild variant of lcSSc,20 at least in part as a result of earlier diagnosis due to improved diagnostic techniques (ie, autoantibodies, capillaroscopy). Finally, our results are in agreement with the existing literature in reporting that men experience a shorter time to SSc diagnosis following the onset of RP.7,8
Our data confirm and extend previous studies reporting a higher frequency of dcSSc in males,3,10,11,13,21,22 which is considered a risk factor for a poor outcome.9. With regard to DUs, one of the most serious complications of SSc, the literature on sex prevalence is conflicting. Some studies have shown a higher frequency in males,13,14 others in females,12,23 and still others have found no difference,9,10,20 although the concept of an increased likelihood of developing DUs in males with SSc is emerging.24,25 Herein, we may confirm that Italian male patients more frequently have DUs, in line with our previous study,14 while a prospective analysis of our accumulated data will provide further information on sex differences for digital vasculopathy.26
Involvement of internal organs is a common feature in SSc.1,26,27 Among these, the kidneys, heart, and lungs are the main targets of the SSc pathogenic process.26,27
Renal crisis is a life-threatening complication3 and various studies have reported an increased risk in males,3,9,13,25,28 especially during the first 3 years of the disease.25 Our data indicate a significantly higher percentage of renal involvement in males, together with the increased prevalence of DUs. These findings further support the hypothesis of a higher incidence of vasculopathy in males, even if the pathogenic mechanisms still remain to be clarified.1,25,26
In SSc, heart involvement is characterized by an increased prevalence in males,3,9,13,22,29 with frequent abnormalities such as conduction disturbances, arrhythmias,10,19,27,30,31,32 and a reduced LVEF.10,13,25 Our findings regarding a greater occurrence of both arrhythmia and conduction defects in males are partially in agreement with previously data from multicenter studies.9,10 Despite the significant difference found in LVEF between males and females, occurrence is close to 60% and does not suggest severe heart failure, which is observed when LVEF is < 55% or < 45%.13,30 It should be emphasized that our study is ongoing, and we look forward to carrying out specific prospective investigations to identify prognostic markers of heart dysfunction in our patients with SSc, especially in those with mildly reduced LVEF.6,29
In SSc, lung involvement includes interstitial lung disease (ILD) and PAH.33 SSc-associated ILD (SSc-ILD) is one of the prominent causes of morbidity and mortality and is estimated to occur in > 50% of patients.34 Nonspecific interstitial pneumonia, particularly ground-glass opacities, is the most common pattern detected in SSc by HRCT,33 whereas usual interstitial pneumonia such as honeycombing can be observed in about a quarter of cases.35
Our cohort of male patients shows more frequent ILD compared to females, in agreement with the existing literature,9,12,21 particularly for both ground glass and honeycombing observed on HRCT. The significantly lower mean FVC and TLC values in our male cohort are most likely associated with the higher ILD frequency, as this type of pulmonary involvement can reduce measurements during respiratory function tests.34
An interesting observation arising is the significant high rate of sicca syndrome in women, affecting approximately one-third of participants. This peculiar association has only been reported in 1 previous Italian paper19 and in the Spanish population.9 This finding must be taken into account, as there is some promising information from new insights concerning patients with SSc. In fact, a high frequency of xerostomia and xerophthalmia, together with morphological modifications detected by ultrasonography of the major salivary glands, has previously been reported,36 supporting the proposal to include sicca symptoms among the items of the Scleroderma Clinical Trials Consortium Damage Index.37 On this basis, we are therefore confident that further large studies might confirm our findings to disclose whether sicca syndrome is a key manifestation in females with SSc.
Approximately 2% of our female patients showed positive anti-SSB antibodies, and only a few with a concomitant sicca syndrome. Since all the patients enrolled in our database had to accurately meet the 2013 ACR/EULAR criteria for the diagnosis of SSc,15 this subgroup needs to be specifically investigated with parotid ultrasonography and/or biopsy of the minor salivary glands38 to assess the potential overlap between definite SSc and complete or incomplete Sjögren syndrome.38,39 Finally, with regard to other autoantibodies, we confirm a significantly higher presence of ANA, anti-ENA, and SSc-related antibodies— namely the anticentromere CENP-B antibodies in females—in line with data from previous literature.9,10,12,14,40
The common strengths and limitations of SSc registry-based studies have been analyzed previously.9,10,13,14 Additionally, a possible limitation could be that we conducted multiple statistical tests. However, given the exploratory nature of the study, we considered that conservative statistical adjustments would reduce the power of the tests, not least because of the strong correlation between the variables.
The main goal of our study was to provide an overall assessment of sex-related differences in a large multicenter cohort of Italian patients with SSc. Data confirmed and strengthened some aspects of this important issue, namely the shorter time interval from RP onset to SSc diagnosis, a wider extent of skin involvement, major manifestations of SSc vasculopathy, and cardiopulmonary involvement for the male sex; and, conversely, an increased rate of the ssSSc subset, as well as a broader and quite peculiar autoantibody profile, in females. The striking significant association of sicca syndrome with female sex, if supported by other similar studies, may be of great interest in understanding the pathogenic basis of this multifaceted disease. Sex-based medicine is a promising field of research. In our national registry, the ongoing longitudinal study of patients with SSc might confirm and expand our provisional observations on sex-related differences, with important implications for the disease classification, diagnosis, and management.
APPENDIX
The Systemic sclerosis PRogression INvestiGation (SPRING) group of the Italian Society for Rheumatology (SIR). The following are the convenors of the SPRING group: Clodoveo Ferri, Rheumatology Unit, School of Medicine, University of Modena and Reggio Emilia, Modena, Italy; Marco Matucci-Cerinic, Department of Rheumatology, University of Florence, Italy. The following are the investigators for the SPRING group: Giuseppina Abignano, Rheumatology Institute of Lucania (IReL) and Rheumatology Department of Lucania, San Carlo Hospital, Potenza, Italy; Cecilia Agnes, San Lorenzo Hospital, Turin; Giorgio Amato, Rheumatology Unit, A.O.U. Policlinico S. Marco, University of Catania, Catania, Italy; Alarico Ariani, Department of Medicine, Internal Medicine and Rheumatology, Azienda Ospedaliero Universitaria di Parma, Parma, Italy; Gianluca Bagnato, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Gianluigi Bajoicchi, Rheumatology Unit, S. Maria Hospital–IRCCS Institute, Reggio Emilia, Italy; Simone Barsotti, Department of Rheumatology, University of Pisa, Pisa, Italy; Silvia Bellando-Randone, Department of Rheumatology, University of Florence, Florence, Italy; Alessia Benenati, Rheumatology Unit, Policlinico Vittorio Emanuele, Catania, Italy; Lorenzo Beretta, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico di Milano, Milan, Italy; Gerolamo Bianchi, Rheumatology Unit, Department of Musculoskeletal Sciences, Local Health Trust 3, La Colletta Hospital, Genoa, Italy; Silvia Bosello, Institute of Rheumatology and Affine Sciences, Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy; Fabio Cacciapaglia, Rheumatology Unit, Department of Emergency Surgery and Organ Transplantations, University of Bari, Bari, Italy; Francesca Calabrese, Departmental Rheumatology Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy; Maurizio Caminiti, Departmental Rheumatology Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy; Corrado Campochiaro, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Renato Carignola, Internal Medicine, San Luigi Gonzaga Hospital–Orbassano, Turin, Italy; Ilaria Cavazzana, Department of Rheumatology, Spedali Civili di Brescia, Brescia, Italy; Giovanni Ciano, Ariano Irpino Hospital, Local Health Thrust Avellino, Italy; Veronica Codullo, Department of Rheumatology, Policlinico San Matteo, Pavia, Italy; Franco Cozzi, Department of Medicine, Villa Salus Hospital, Venice, Italy; Cuomo Giovanna, University of Campania Luigi Vanvitelli, Naples, Italy; Salvatore D’Angelo, Rheumatology Institute of Lucania (IReL) and Rheumatology Department of Lucania, San Carlo Hospital, Potenza, Italy; Lorenzo Dagna, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Francesca Dall’Ara, Department of Rheumatology, Spedali Civili di Brescia, Brescia, Italy; Ilenia De Andres, Rheumatology Unit, Azienda Ospedaliera di Rilievo Nazionale ed Alta Specializzazione Garibaldi, Catania, Italy; Rossella De Angelis, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy; Angelo De Cata, Unit of Internal Medicine, ‘Casa Sollievo della Sofferenza’ Hospital, IRCCS, San Giovanni Rotondo, Italy; Giacomo De Luca, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Maria De Santis, Humanitas Clinical and Research Center IRCCS, Milan, Italy; Alessandra Della Rossa, Department of Rheumatology, University of Pisa, Pisa, Italy; Andrea Doria, Department of Rheumatology, University of Padova, Padua, Italy; Doveri Marica, Local Health Trust 3, Genoa, Italy; Rosario Foti, Policlinico Vittorio Emanuele, Catania, Italy; Federica Furini, Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera-Universitaria S. Anna di Ferrara, Ferrara, Italy; Enrico Fusaro, Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy; Elena Generali, Milano Humanitas Clinical and Research Center IRCCS, Milan, Italy; Antonietta Gigante, Department of Translational and Precision Medicine, Sapienza University of Rome, Italy; Alessandro Giollo, Rheumatology Section, Department of Medicine, University of Verona, Italy; Francesco Girelli, Department of Medicine, Rheumatology Unit, Ospedale GB Morgagni–L Pierantoni, Forlì, Italy; Dilia Giuggioli, Rheumatology Unit, School of Medicine, University of Modena and Reggio Emilia, Modena, Italy; Marcello Govoni, Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera-Universitaria S. Anna di Ferrara, Ferrara, Italy; Serena Guiducci, Department of Rheumatology, University of Florence, Florence, Italy; Florenzo Iannone, Rheumatology Unit, Department of Emergency Surgery and Organ Transplantations, University of Bari, Bari, Italy; Francesca Ingegnoli, Department of Rheumatology, University of Milan, Milan, Italy; Anna Maria Iuliano, Rheumatology Unit, San Camillo-Forlanini Hospital, Rome, Italy; Maria Grazia Lazzaroni, Department of Rheumatology, Spedali Civili di Brescia, Brescia, Italy; Ennio Lubrano, Department of Rheumatology, University of Molise, Campobasso, Italy; Federica Lumetti, Rheumatology Unit, School of Medicine, University of Modena and Reggio Emilia, Modena, Italy; Luca Magnani, Rheumatology Unit, S. Maria Hospital-USL, IRCCS Institute, Reggio Emilia, Italy; Francesco Masini, University of Campania Luigi Vanvitelli, Naples, Italy; Gianna Mennillo, Rheumatology Institute of Lucania (IReL) and Rheumatology Department of Lucania, San Carlo Hospital, Potenza, Italy; Giuseppe Murdaca, Ospedale Policlinico S. Martino–University of Genoa, Genoa, Italy; Giuseppa Pagano Mariano, Departmental Rheumatology Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy; Simone Parisi, Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy; Greta Pellegrino, Department of Rheumatology, Sapienza–University of Rome, Rome, Italy; Clara Lisa Peroni, Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy; Erika Pigatto, Department of Medicine, Villa Salus Hospital, Venice, Italy; Valeria Riccieri, Department of Rheumatology, Sapienza–University of Rome, Rome, Italy; Anna Maria Risa, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy; Nicoletta Romeo, ASO S. Croce e Carle, Cuneo, Italy; Edoardo Rosato, Department of Translational and Precision Medicine, Sapienza University of Rome, Italy; Gianluca Sambataro, Regional Referral Centre for Rare Lung Diseases, AOU “Policlinico G. Rodolico–San Marco” Dept. of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Marta Saracco, Rheumatology Unit, Mauriziano Umberto I Hospital, Turin, Italy; Giandomenico Sebastiani, Rheumatology Unit, San Camillo–Forlanini Hospital, Rome, Italy; Amelia Spinella, Rheumatology Unit, School of Medicine, University of Modena and Reggio Emilia, Modena, Italy; Rossella Talotta, Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Elisa Visalli, Policlinico– Vittorio Emanuele, Catania, Italy; Licia Vultaggio, Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera–Universitaria S. Anna di Ferrara, Ferrara, Italy; Elisabetta Zanatta, Department of Rheumatology, University of Padova, Padova, Italy; Giovanni Zanframundo, Department of Rheumatology, Policlinico San Matteo, Pavia, Italy.
Footnotes
This study was supported by the Italian Society for Rheumatology (SIR).
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication October 27, 2021.
- © 2022 by the Journal of Rheumatology
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