Original article
Risk factors of damage in early diagnosed systemic
lupus erythematosus: results of the Italian
multicentre Early Lupus Project inception cohort
Matteo Piga
1, Alberto Floris
1, Gian Domenico Sebastiani
2,
Imma Prevete
2, Florenzo Iannone
3, Laura Coladonato
3, Marcello Govoni
4,
Alessandra Bortoluzzi
4, Marta Mosca
5, Chiara Tani
5, Andrea Doria
6,
Luca Iaccarino
6, Franco Franceschini
7, Micaela Fredi
7, Fabrizio Conti
8,
Francesca Romana Spinelli
8, Mauro Galeazzi
9, Francesca Bellisai
9,
Anna Zanetti
10,11, Greta Carrara
10, Carlo Alberto Scire`
10and
Alessandro Mathieu
1Abstract
Objective.
To investigate risk factors for damage development in a prospective inception cohort of early diag-nosed SLE patients.Methods.
The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to 1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors independently associated with the risk of dam-age development.Results.
Overall, 230 patients with a mean (S.D.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P¼ 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P¼ 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P¼ 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P ¼ 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development dif-fered for glucocorticoid-related and -unrelated damage. HCQ use (P¼ 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage.Conclusion.
We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.Key words: SLE, organ damage, glucocorticoids, early diagnosis, BILAG, SLICC/ACR Damage Index, dyslipi-daemia, HCQ
1
Rheumatology Unit, University of Cagliari and AOU University Clinic, Cagliari,2
UOC di Reumatologia, Azienda Ospedaliera San Camillo-Forlanini, Rome,3
Dipartimento dell’Emergenza e dei Trapianto di Organi – Sezione di Reumatologia, Universita` di Bari, Bari,4
UOC e Sezione di Reumatologia – Dipartimento di Scienze Mediche, Universita` degli Studi di Ferrara, Ferrara,5
UOC di Reumatologia, Dipartimento di Medicina Clinica e Sperimentale, Universita` di Pisa, Pisa,6
Rheumatology Unit, Department of Medicine, University of Padova, Padova,7
UOC di Reumatologia e Immunologia Clinica, Dipartimento di Scienze Cliniche e
Sperimentali, Universita` degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy,8
Reumatologia, Dipartimento
di Medicina Interna e Specialita` Mediche, Sapienza Universita` di Roma, Roma,9
UOC di Reumatologia, Azienda Ospedaliera Universitaria Senese, Siena,10
Societa` Italiana di Reumatologia, Unita` Epidemiologica, Milano, and11
Divisione di Biostatistica,
Epidemiologia e Salute Pubblica, Dipartimento di Statistica e Metodi Quantitativi, Universita` degli Studi di Milano-Bicocca, Milano, Italy Submitted 26 July 2019; accepted 25 October 2019
Correspondence to: Matteo Piga, Dipartimento di Scienze Mediche e Sanita` Pubblica, Universita` di Cagliari, SS 554, 09042 Monserrato (CA), Italy. E-mail: [email protected]
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Introduction
SLE is a multisystem autoimmune disease with a wide range of clinical manifestations and a relapsing–remitting course. Although short-term survival of SLE patients has improved substantially in the past five decades, irrevers-ible organ damage accrual contributing to impaired health-related quality of life and increased long-term mortality remain major challenges [1].
The SLICC/ACR Damage Index (SDI) is a validated instrument that was designed to measure irreversible damage in SLE patients [2]. Early damage development measured by SDI is associated with further damage ac-crual and a higher mortality rate [3,4]. Moreover, SDI progression has a negative impact on perceived phys-ical and mental health [4]. It is therefore important to understand factors associated with organ damage and address these factors from an early stage of the dis-ease, as any interventions that can reduce damage de-velopment and accrual are also likely to improve health-related quality of life and survival in patients with SLE.
The early diagnosis of SLE can be beneficial for long-term outcomes by allowing early intervention and potentially reducing damage development and accrual [5]. New tools for classification and diagnosis will allow earlier recognition of SLE [6], whereas targeted treatment strategies for SLE offer the opportunity to reduce damage, thus improving long-term outcomes [7]. However, limited data are available for early diag-nosed SLE patients, and it is conceivable that the risk profiles for damage differ according to disease stage. In fact, despite a good level of agreement that patients at risk of damage can be identified from demographic factors, disease activity states and glucocorticoid (GC) exposure, the rate of damage de-velopment and the patterns of damage accrual are variable across different cohorts and dependent on patient characteristics, including disease duration, re-gional socioeconomic and health care-related factors [1,8].
This study aimed to evaluate the rate of damage de-velopment and accrual over the first few years of follow-up in newly diagnosed patients enrolled in the inception cohort of the Italian Early Lupus Project. We investigated the contribution of disease-related factors, clinically use-ful biomarkers, therapeutic agents and comorbidities to damage development in a cohort of early diagnosed SLE patients. Finally, we analysed the risk profiles for the development of GC-related and GC-unrelated damage.
Methods
Early Lupus inception cohort
The Early Lupus Project comprises nine Italian centres with experience in the diagnosis and management of SLE [9,10]. An inception cohort of consecutive patients, who were enrolled within 12 months since recognition of four or more 1997 ACR classification criteria for SLE [11], was recruited from January 2012 to December 2017. Patients were followed up every 6 months. The study was approved by the Ethics Committee of each participating centre, and all patients provided written informed consent.
Patients and clinical assessment
Patients who were followed up for at least 6 months (e.g. two visits) were included in the present study. The only exclusion criterion was >12 months elapsed since recognition of four or more 1997 ACR classification cri-teria for SLE.
Demographic features, including age, gender, ethni-city, years of school education and socioeconomic sta-tus (e.g. low, intermediate or high), were recorded. The time elapsed since the onset of the first symptom related to SLE was also noted at baseline. Disease ac-tivity based on the validated ECLAM [12] and cumulative damage according to the SDI [2] were measured every 6 months. Clinical manifestations defined according to items and domains of the validated BILAG-2004 index glossary were recorded [13]. Disease biomarkers includ-ing anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-Sm, anti-RNP, aCL (IgM and IgG), anti-B2-glycoprotein I (IgM and IgG), LA, 24-h proteinuria, and C3 and C4 comple-ment fractions were tested in the local laboratories at each centre. Ongoing treatment with GCs, antimalarials, immunosuppressants, biologics or a combination of these agents was recorded at each visit, together with the cumulative prednisone equivalent dose.
Hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg), dyslipidae-mia (blood cholesterol and/or triglycerides outside nor-mal limits), smoking (current or past), diabetes and obesity (BMI >30 kg/m2) were comorbidities noted at every visit and included in the analysis.
Statistical analysis
Continuous variables are indicated as the mean (S.D.) or median and interquartile range as appropriate. Damage development was defined as any increase from SDI 0 to
Rheumatology key messages
. We depicted damage development in SLE at an earlier disease phase than reported thus far. . Glucocorticoids had little impact as determinants of damage in early diagnosed SLE patients.
. Addressing comorbidities, using HCQ and minimizing glucocorticoids may reduce early damage development in SLE.
1 during the time of follow-up for any participant included in the study. Damage items were a priori subdi-vided (Table 1) according to whether they were consid-ered to be definitely dependent on GCs (e.g. cataract, avascular necrosis), possibly dependent on GCs (e.g. dia-betes, cardiovascular) and unrelated to GCs (e.g. renal, pulmonary), taking into account previous definitions [14– 17]. Items of damage possibly or definitely dependent on GC were categorized together as GC related.
Sample size was calculated, estimating a prevalence of damage equal to 25% after 2 years of follow-up, according to previous studies. A sample size of 240 patients was considered sufficient to precisely estimate a multivariate model for risk of damage development with six independent factors (rule of thumb).
A univariate analysis was performed to assess the contribution, expressed as the exponent of the
regression coefficient (Exp coeff), of baseline and time-varying covariates to damage. Covariates with a frequency 10 for each cell of the 2 2 outcome fre-quency table were included in the multivariate models. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors inde-pendently associated with an increased risk of damage development. The hazard ratios (HRs) with 95% CIs were calculated. A P-value <0.05 was considered statis-tically significant.
Results
Overall, 279 patients were enrolled in the Early Lupus in-ception cohort through 31 December 2017; 230 patients [mean number of visits 5.3 (2.7)] with at least 6 months
TABLE 1 SDI items were categorized in definitely or possibly GC-related and GC-unrelated according to previous definition
Damage domain Item
Definitely GC-related Possibly GC-related GC-unrelated
Ocular Cataract – Retinal change
Neuropsychiatric – Cognitive impairment Seizures
Psychosis Transverse myelitis
Cerebrovascular accident Cranial or peripheral neuropathy
Renal – – Glomerular filtration rate <50%
Proteinuria3.5 g/24 h
End-stage renal disease
Pulmonary – – Pulmonary hypertension
Pulmonary fibrosis Shrinking lung Pleural fibrosis Pulmonary infarction
Cardiovascular – Angina or coronary artery bypass Cardiomyopathy
Myocardial infarction Valvular disease
Pericarditis for 6 months, or pericardiectomy
Peripheral vascular – Claudication for 6 months Venous thrombosis
Minor tissue loss (pulp space) Significant tissue loss
Gastrointestinal – – Infarction or resection of bowel
below duodenum, spleen, liver or gall bladder ever
Mesenteric insufficiency Chronic peritonitis
Stricture or upper gastrointestinal tract surgery ever
Musculoskeletal Avascular necrosis Osteomyelitis Deforming or erosive arthritis
Osteoporosis with fracture or vertebral collapse
Muscle atrophy or weakness
Skin – – Scarring chronic alopecia
Extensive scarring or panniculum Skin ulceration
Miscellanea – Diabetes Malignancy
Menopause SDI: SLICC/ACR Damage Index; GC: glucocorticoid.
of follow-up (median 27.4 months; interquartile range 7.2–48.0) were eligible for this study. Depending on their time since entry in the Early Lupus Project inception co-hort, 210 patients had at least 1 year of follow-up, 150 had at least 2 years of follow-up and 115 had at least 3 years of follow-up. The characteristics of the inception cohort at study entry are summarized inTable 2. Rate of damage development and accrual
At enrolment, 6 months or more had passed since diag-nosis and SDI was scored for 69 out of 230 patients; 11
of these patients (15.9%) had an SDI1. There were 43 (18.7%) patients with SDI 1 after 6 months of follow-up, 51 (22.2%) after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months (Fig. 1). After 1 year of follow-up, 27 (11.7%) patients had SDI items exclusively for GC-unrelated damage and 9 (3.9%) had SDI items exclusively for GC-related (definitely or pos-sibly) damage; 15 (6.5%) patients had at least one SDI item of both types of damage. At the end of follow-up, 73 (31.7%) patients had damage, 35 (15.2%) had exclu-sively GC-unrelated damage, 15 (6.5%) had excluexclu-sively GC-related (definitely or possibly) damage and 23 (10.0%) patients had both types of damage. The median cumulative dose of prednisone was 1.0 g (0.1–2.1) at baseline, 2.9 g (1.8–5.0) after 1 year, 4.1 g (1.7–6.3) after 2 years and 5.4 g (1.5–8.0) after 3 years. The median daily prednisone dose progressively reduced from 15 mg (5.9–30.0) at baseline to 7.0 mg (4.2–13.0) at 6 months, 4.9 mg (3.5–8.8) at 12 months, 4.1 (0.8–5.5) at 24 months and 3.2 mg (0.9–4.9) at 36 months (Fig. 2).
At the end of follow-up, individual organ system dam-age was as follows: 21 (9.1%) ocular, 20 (8.7%) neuro-psychiatric, 12 (5.2%) musculoskeletal, 11 (4.8%) pulmonary, 10 (4.3%) cardiovascular, 10 (4.3%) others, 9 (3.9%) peripheral vascular, 8 (3.5%) renal, 6 (2.6%) skin and 3 (1.3%) gastrointestinal (Fig. 3).
The mean SDI reported over time was 0.33 (0.77) after 6 months, 0.45 (1.02) after 12 months, 0.56 (1.32) after 24 months and 0.78 (1.69) after 36 months of follow-up. At the end of follow-up, 61.9% of the morbidities described in the SDI could be attributed to GC-unrelated factors, whereas 38.1% were possibly or definitely related to GCs. The number of patients with in-dividual items of damage at the end of follow-up are reported inTable 3.
Factors associated with increased risk for damage development
According to the univariate analysis, factors significantly associated with increased risk of developing damage were older age (>35 years) at diagnosis (P < 0.001; Exp coeff 4.0), lower socioeconomic status (P¼ 0.013; Exp coeff 2.7), hypertension, (P¼ 0.021; Exp coeff 1.6), dysli-pidaemia (P < 0.001; Exp coeff 4.1), higher number of BILAG-2004 domains (P < 0.001; Exp coeff 1.5), cardio-respiratory BILAG-2004 domain (P < 0.001; Exp coeff 3.5) and higher cumulative prednisone (equivalent) dose (P¼ 0.001; Exp coeff 1.1). The multivariate model for the development of damage confirmed dyslipidaemia (P¼ 0.001; HR 2.9; 95% CI 1.5, 5.6), older age at diag-nosis (P¼ 0.001; HR 3.0; 95% CI 1.6, 5.5), higher num-ber of BILAG-2004 domains (P¼ 0.002; HR 1.4 for each domain; 95% CI 1.1, 1.8) and cardiorespiratory BILAG-2004 domain (P¼ 0.041; HR 1.9; 95% CI 1.0, 3.7) as independently associated with an increased risk of damage development.
TABLE 2 Baseline characteristics of the Italian Early Lupus Project cohort at entry into the study
Features Value
Age, mean (S.D.), years 36.5 (14.6)
Female 199 (86.5)
Caucasian 206 (89.6)
Time since first symptom (<1 year), n (%) 156 (68.4)
Time since 4 ACR criteria, median (IQR), months
1.1 (0.0–4.8) Clinical phenotypes according
to BILAG domains Constitutional 80 (34.9) Mucocutaneous 113 (49.3) Neuropsychiatric 18 (7.8) Musculoskeletal 141 (61.3) Cardiorespiratory 46 (20) Gastrointestinal 11 (4.8) Ophthalmic 5 (2.2) Renal 71 (30.9) Haematological 99 (43.0) Serologic features ANA 229 (99.6) Anti-dsDNA 177 (79.4) Anti-Ro/SSA 89 (38.7) Anti-La/SSB 35 (15.2) Anti-RNP 47 (20.4) Anti-Sm 46 (20.0)
Low C3 and/or C4 complement fractions 143 (65.0)
aPLa 69 (30.0)
Triple positivity (LA and aB2GPI and aCL) 20 (8.7)
ECLAM, mean (S.D.) 3.1 (2.3) Comorbidities Smoking (ever) 92 (40.4) Diabetes 8 (3.5) Hypertension 35 (15.2) Dyslipidaemia 31 (13.5)
Familial history for CV events 31 (13.7)
Obesity (BMI >30 kg/m2) 13 (5.6) Medicationsb Prednisone 203 (90.2) HCQ 181 (80.4) Immunosuppressants 144 (62.6) Biologics 14 (6.1)
Unless otherwise expressed, numbers are absolute values
(percentage). aLA and/or aCL IgM/IgG and/or aB2GPI IgM/
IgG.bTreatment prescribed at baseline visit. IQR:
interquar-tile range; CV: cardiovascular; aB2GPI: anti-B2-glicoprotein I.
Risk profiles for the development of GC-related and GC-unrelated damage
The multivariate models showed that neuropsychiatric BILAG-2004 domain (P < 0.001; HR 5.3; 95% CI 2.3, 12.5), older age (P¼ 0.013; HR 3.2; 95% CI 1.3, 7.8) and cumulative dose of GCs measured both at base-line (P¼ 0.013; HR 1.7 per 5 g of prednisone equivalent dose; 95% CI 1.1, 2.6) and during follow-up (P¼ 0.024; HR 1.2 per 5 g of prednisone equivalent dose; 95% CI 1.0, 1.4) were independent risk factors for developing GC-related damage. Dyslipidaemia (P < 0.001; HR 7.0;
95% CI 3.3, 14.8) and cardiorespiratory BILAG-2004 domain (P < 0.001; HR 4.3; 95% CI 2.1, 8.5) were factors independently associated with an increased risk of GC-unrelated damage. HCQ was the only antimalarial prescribed in this cohort and was inde-pendently associated with a reduced risk of GC-unrelated damage (P¼ 0.005; HR 0.4; 95% CI 0.2, 0.8). See supplementary Tables S1–S3, available at Rheumatology online, for details regarding the univari-ate and multivariunivari-ate analyses.
FIG. 1 Kinetics of damage development
(A) Grey dots represent the time a single patient developed her/his first item of SDI damage. (B) Green and violet dots represent the time a single patient developed her/his first item of unrelated and glucocorticoid-related damage, respectively, regardless of previous damage. SDI; SLICC/ACR Damage Index.
Discussion
The present study aimed to estimate damage and iden-tify factors contributing to its development in a pro-spective inception cohort of early diagnosed SLE patients. We observed a high rate of damage develop-ment within the first year, followed by a linear rate of in-cident damage and steady damage accrual over the next few years. This pattern of damage accrual was similar to that reported by other groups [16–19], but we
found a lower proportion of GC-related damage than previously reported. Possible explanations for this differ-ence are the shorter disease duration and lower daily dose of prednisone observed in our early SLE cohort, whereby their limited use of GCs reduced the impact as a determinant of damage. One could hypothesize that early diagnosis allows for minimizing GC use, but this should be confirmed in specifically designed studies. Prospective studies that reported a higher proportion of
FIG. 2 Trends of damage and glucocorticoids dose over time
Trends of the median daily prednisone dose (square, blue line), median cumulative prednisone dose (circle, red line) and percentage of patients with at least one SDI item of damage (triangle, grey line) over follow-up. SDI; SLICC/ACR Damage Index.
FIG. 3 The pattern of accrual of SDI organ system damage over time
GC-related damage tended to follow cohorts for 5 years or more, suggesting that the cumulative dose and longer GC exposure may have a greater impact on damage than the current daily dose [15–20]. In our cohort, the cumulative prednisone dose measured at baseline was associated with a higher risk of development of GC-related damage than the entire cumulative dose, sug-gesting that GCs influence damage development from the very early stage of the disease. Remarkably, the cu-mulative prednisone dose was independently associated with GC-related incident damage, which steadily increased over time despite the progressive reduction in the daily prednisone dose. It remains unclear which, if any, GC maintenance daily dose best prevents damage. To reduce the risk of damage due to GCs, the maintenance dose of prednisone (equivalent) should be tapered to <7.5 mg/day and withdrawn, whenever possible, aiming at remission or low disease activity [21–23], which have been proven to prevent damage accrual from the early disease phase [24, 25]. Rapid and effective tapering or discontinuation of GCs could be pursued by using pulses of i.v. methylpredniso-lone, especially in acute and organ-threatening disease, and favouring prompt initiation of HCQ and immunosup-pressive agents, including biologics in selected cases [26–28]. Previous studies demonstrated that high disease activity and flares are major risk factors for the development of damage [29–32]. Using the ECLAM score as both a quantitative (from 0 to 10) or categorical (3 or >3) covariate, we did not observe any indication of the latter suggestion in our cohort. Nevertheless, we observed that patients suffering from a higher num-ber of actively involved organs or systems, especially in the cardiorespiratory and neuropsychiatric domains, were more prone to develop damage over time. aPL have been associated with increased risk of overall damage [32–34], mainly in long-standing SLE, but did not predict damage in a large prospective early SLE co-hort [4]. Similarly, in our cohort, aPL were not associated with an increased risk of damage development when considered as single variables (e.g. LA, aCL, anti-B2-glycoprotein I) or as a combination of them (e.g. triple positivity).
Notably, older age and dyslipidaemia showed the highest HR for global damage development in our early cohort. The latter is a novel finding of our study, as dys-lipidaemia is usually believed to affect long-term lupus damage through its negative impact on heart, brain and kidney disease [35]. On the other hand, dyslipidaemia has been directly related to disease activity, and it had a greater impact on GC-unrelated damage, which most-ly depends on inflammation and is independent of the long-term sequelae of atherosclerosis (e.g. myocardial infarction, stroke). Our results emphasized the need to assess dyslipidaemia and promptly address it from the time of SLE diagnosis. Further studies are needed to prove the effectiveness of statins on SLE outcomes, as the randomized controlled trials conducted thus far were
TABLE 3 Number of patients with individual item of dam-age at the end of follow-up
Domain N (%)
Item
Ocular 21 (9.1)
Cataract 18 (7.8)
Retinal change or optic atrophy 6 (2.6)
Neuropsychiatric 20 (8.7)
Cerebrovascular accident 8 (3.5)
Seizures requiring therapy for 6 months 7 (3.0)
Cognitive impairment 5 (2.2)
Psychosis 4 (1.7)
Cranial or peripheral neuropathy (excluding optic)
4 (1.7)
Transverse myelitis 0
Renal 8 (3.5)
Proteinuria >3.5 g/24 h 5 (2.2)
Estimated or measured glomerular filtration rate <50%
4 (1.7)
End-stage renal disease 0
Pulmonary 11 (4.8)
Pulmonary fibrosis (physical and radiographical)
6 (2.6)
Pleural fibrosis (radiograph) 3 (1.3)
Shrinking lung (radiograph) 2 (0.9)
Pulmonary hypertension (right ventricular prominence, or loud P2)
2 (0.9) Pulmonary infarction (radiograph) or resection
not for malignancy
0
Cardiovascular 10 (4.3)
Valvular disease (diastolic murmur, or systolic murmur >3/6)
5 (2.2)
Myocardial infarction ever 2 (0.9)
Cardiomyopathy (ventricular dysfunction) 2 (0.9)
Pericarditis for 6 months or pericardiectomy 2 (0.9)
Angina or coronary artery bypass 0
Peripheral vascular 9 (3.9)
Venous thrombosis with swelling, ulceration or venous stasis
8 (3.5)
Claudication for 6 months 1 (0.4)
Minor tissue loss (pulp space) 1 (0.4)
Significant tissue loss ever (excluding loss of digit or limb)
0
Gastrointestinal 3 (1.3)
Infarction or resection of bowel below duode-num, spleen, liver or gallbladder, for any cause
3 (1.3)
Mesenteric insufficiency 0
Chronic peritonitis 0
Stricture or upper gastrointestinal tract surgery 0
Chronic pancreatitis 0
Musculoskeletal 12 (5.2)
Deforming or erosive arthritis 5 (2.2)
Avascular necrosis 3 (1.3)
Osteoporosis with fracture or vertebral collapse
2 (0.9)
Muscle atrophy or weakness 2 (0.9)
Osteomyelitis 0
Others 10 (4.3)
Malignancy (excluding dysplasia) 7 (3.0)
Diabetes (regardless of treatment) 2 (0.9)
Premature gonadal failure 1 (0.4)
characterized by significant limitations and reported contradictory results [36]. Meanwhile, statins should be considered in SLE patients presenting with dyslipidae-mia as part of an integrated strategy aimed at minimiz-ing damage. Antimalarials must be part of the same strategy; in fact they effectively prevent both the devel-opment of new damage and damage accrual in SLE patients [37, 38]. In our early cohort, HCQ showed a significant protective effect on the risk of developing GC-unrelated damage during the first few years of ob-servation. It is conceivable that, given the early disease phase, we mainly observed the anti-inflammatory and immunomodulatory effect of HCQ in preventing damage rather than its effect as an atheroprotective agent, which most likely has a higher impact on the prevention of later damage [39]. We reported a higher proportion of patients (over 80%) receiving HCQ alone or in combin-ation with immunosuppressants since baseline. Considering the widespread use of HCQ in our cohort, it is unlikely that the reduced risk of damage represented a bias arising from the propensity to prescribe HCQ in milder disease.
Our study has a number of strengths. The Early Lupus Project enrolled a large inception cohort of patients within 12 months of SLE classification, almost 70% of whom had experienced the first symptom onset less than a year before enrolment, thus providing information on damage development at an earlier disease phase than reported thus far. The sample size calculated a pri-ori and patient assessments every 6 months allowed us to satisfactorily model time-varying covariates, including disease activity and GC exposure. These unique charac-teristics of our cohort have helped provide an under-standing of the dynamics of incident damage in newly diagnosed SLE patients and to identify risk factors for early damage development.
Some limitations of our study need to be acknowl-edged. Because our main goal was to investigate risk factors for the development of early damage, we con-sidered a relatively brief observation time to be appro-priate. Such a short follow-up prevented us from investigating risk factors of late-occurring damage and damage accrual, as well as the association between early damage and long-term outcomes. However, this seems unnecessary given that previous studies have provided high-level evidence of early damage as re-sponsible for further damage accrual and increased mortality in SLE patients [3, 4]. Additionally, the Italian Early Lupus cohort patients are enrolled in Rheumatology Units, which are tertiary referral and teaching centres, and these patients might have been selected due to disease severity and phenotype. Finally, the small number of patients of non-Caucasian descent limits the relevance of our observations to other popula-tions; thus, our results need further confirmation in other ethnic groups.
In conclusion, the present study describes different risk profiles that could help physicians better identify early diagnosed SLE patients at higher risk for damage.
We also recognized modifiable risk factors that should be targeted from the time of diagnosis. An integrated approach addressing comorbidities, adding HCQ and minimizing GC use from the early stages of the disease, with the goal of remission or low disease activity, may help reduce damage. These observations are of clinical interest and may support the design of effective damage prevention strategies.
Acknowledgements
The start of the Early Lupus Project was supported by a specific grant from the Italian lupus patient association Gruppo LES Italiano – ONLUS.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
Supplementary data
Supplementary dataare available at Rheumatology online.
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