Abstract
Background:
Anemia is considered a risk factor of severity in systemic sclerosis. Yet, limited data are available on the frequency and causes of anemia in systemic sclerosis. The objectives of our study were to determine the frequency and causes of anemia in systemic sclerosis, to analyze the clinical and biological characteristics of patients with anemia, and to assess the association between anemia and systemic sclerosis prognosis.
Methods:
We conducted a prospective single-center study from January 2017 to May 2022. Patients underwent a hemoglobin assay and a standardized etiological workup to determine the causes of anemia at the initial visit. Clinical and biological parameters were compared between patients with anemia and those with normal hemoglobin levels. We followed up patients until May 2023 and compared their survival.
Results:
A total of 502 systemic sclerosis patients, including 107 diffuse cutaneous systemic sclerosis, were included. At enrollment, 100 patients had anemia. The primary cause of anemia was iron deficiency (40%). Among the 32 patients with iron deficiency-associated anemia who underwent gastrointestinal exploration, 56% had digestive bleeding, with upper gastrointestinal tract involvement being the main cause (90%). Patients with anemia at enrollment had higher systemic sclerosis severity scores and more gastrointestinal symptoms compared to patients without anemia (p < 0.05). They exhibited higher systolic pulmonary artery pressure, lower anemia-corrected diffusing capacity for carbon monoxide, and lower forced vital capacity (p < 0.05). During follow-up, 65 patients (14.8%) died. After adjusting for age, systemic sclerosis subtypes, forced vital capacity, and pulmonary arterial hypertension, anemia at inclusion was associated with a higher mortality rate (hazard ratio: 1.94 (95% confidence interval: 1.39–2.48), p = 0.02).
Conclusion:
Our study shows a high frequency of anemia among patients with systemic sclerosis. Most anemias are due to iron deficiency, and gastrointestinal exploration can identify bleeding in the majority of the cases. In addition, our study confirms that systemic sclerosis patients with anemia have a more severe disease and a higher mortality rate.
Keywords: Systemic sclerosis, anemia, iron deficiency, survival
Introduction
Systemic sclerosis (SSc) is a rare and severe connective tissue disease characterized by microvascular damage, specific immunologic abnormalities, and fibrosis of the skin and internal organs. 1 Anemia is common in inflammatory and autoimmune diseases with a frequency of over 30%–50% reported in rheumatoid arthritis and systemic lupus erythematosus.2,3 However, the characteristics and causes of anemia in SSc are not well deciphered, and its association with clinical manifestations of SSc has not been explored extensively. Only studies conducted on small cohorts of patients focused on this subject.4–7 Moreover, anemia in SSc has been considered a factor of poor prognosis in SSc.8,9 Recent research has also indicated that anemia at baseline can predict the progression of organ damage in SSc, 10 suggesting that anemia could serve as a warning sign for more severe damage trajectories in SSc patients.
This study aims to estimate the frequency and describe the main causes of anemia in SSc, and to study the association between anemia characteristics and prognosis in SSc.
Methods
Participants
The study recruited patients diagnosed with SSc in the department of internal medicine at Lille University Hospital between January 2016 and May 2022. All patients met the American College of Rheumatology classification criteria for SSc. 1 After inclusion, we conducted an annual evaluation for each patient until May 2023. After written informed consent, patients were included in the FHU IMMINENT database and biobank gathering patients with immune-mediated inflammatory diseases (ethical appro-val: 2019-A01083-54).
Clinical and biological data
A standardized questionnaire was filled out by the clinician at the time of the inclusion, gathering demographic and disease-related clinical data. This included disease subtypes (diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma),11,12 clinical manifestations, laboratory index, and disease course. The clinical manifestations included (1) gastrointestinal system involvement, which included symptoms of esophagitis, gastritis, transit disorders, or abdominal pain; (2) skin damage with telangiectasia, Raynaud’s phenomenon (RP), fingertip ulcer/gangrene, and modified Rodnan skin score, nailfold capi-llaroscopy scoring system based on Cutolo et al.; 13 (3) symptoms of pulmonary involvement with New York Heart Association (NYHA) functional class 14 and distance walked over 6 min; and (4) musculoskeletal manifestations with arthralgia and myalgia. History of thromboembolic event such as pulmonary embolism, deep vein thrombosis, and arterial thrombosis were recorded. The disease-related laboratory indexes were collected: (1) autoantibodies: antinuclear antibodies (ANAs), anti-topoisomerase I antibody (anti-Scl-70), anticentromere antibody (ACA), and anti-RNA polymerase III antibody; (2) myocardial enzymes: N-terminal pro B-type natriuretic peptide (NT-proBNP); and (3) creatinine. Pulmonary function testing (PFT) included forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO) adjusted for hemoglobin for anemia. Restrictive lung disease (RLD) was defined as FVC <80%. High-resolution computed tomography (CT) of the lungs was performed for all patients and interstitial lung disease (ILD) defined when CT showed ground glass opacity under the pleura or at the base of the lung, or honeycomb or reticular changes in both lungs. Doppler echocardiography screening for pulmonary arterial hypertension (PAH) recorded the following: left ventricular ejection function (LVEF), estimated pulmonary artery systolic pressure (PASP), and tricuspid regurgitant jet velocity (TRV). For patients with suspected PAH, right heart catheterization was performed, and PAH was defined as a mean pulmonary artery pressure (mPAP) ⩾21 mmHg, pulmonary wedge pressure ⩽15 mmHg, and pulmonary vascular resistance >2 WU during cardiac catheterization. The 2001 and 2016 European Scleroderma Trials and Research (EUSTAR) disease activity scores were calculated for each patient as described in reference studies.15,16 The Medsger severity score (MSS) was used excluding the category that used anemia as the parameter: “general organ system evaluation.” 8
Definition of anemia and causes
Anemia was defined by a hemoglobin level below specific thresholds: less than 12 g/dl for women and less than 13 g/dl for men. 17 For all patients with anemia, various laboratory tests were systematically conducted, including mean corpuscular volume (MCV), serum iron, serum ferritin, serum transferrin, total iron-binding capacity (TIBC), calculated transferrin saturation (TSAT = serum iron ÷ TIBC × 100), vitamin B12 level, folate level, lactate dehydrogenase (LDH), bilirubin, haptoglobin, thyroid-stimulating hormone (TSH), and free thyroxine (T4) concentration. The notes for each of these patients were then extensively reviewed to define the nature of their anemia. Anemia was categorized as iron-deficiency anemia (IDA), anemia of chronic disease (ACD), hemolytic, or mixed using a predefined flowchart as detailed below:
IDA if reduced serum ferritin <30 ng/ml, or TSAT <20% 18 ;
ACD if any of the following conditions were present: TSAT <20% and ferritin >100 ng/ml, or ferritin between 100 and 30 ng/ml with transferrin/log(ferritin) ratio <1 18 , 19 or presence of an inflammatory syndrome defined by C-reactive protein (CRP) >5 mg/l or fibrinogen >4 g/l;
Hemolytic if all the following conditions were met: LDH >480 IU/l, haptoglobin <0.34 g/l, total bilirubin >15 mg/l;
B9 deficiency if vitamin B9 <3 ng/ml;
B12 deficiency if vitamin B12 <0.2 ng/ml;
Kidney disease: estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2;
Hypothyroidism: low free thyroxine (T4) concentration according to reference range of our laboratory;
Iatrogenic: if one of the patient’s treatments had an adverse effect of anemia, the temporality was concordant and the anemia disappeared when the treatment was stopped;
Mixed if two or more conditions were associated.
For patients for whom our algorithm failed to diagnose the etiology of the anemia, we consulted the medical record and reported the diagnosis reported by the medical team. The medical team consisted of internists and a hematologist.
For patients with IDA, the investigations were carried out according to clinician judgment. We reviewed all clinical records to determine the cause of IDA. We considered the evaluation complete when the following workup was performed: first, a clinical examination with targeted gastrointestinal and gynecological investigations; if the clinical examination was normal, an upper gastrointestinal endoscopy was proposed, followed by a colonoscopy if the anemia remained unexplained.
Mortality outcome
To collect deaths in May 2023, we consulted the hospital’s database and the national database https://www.data.gouv.fr/fr/reuses/deces-en-france/.
Statistical analysis
First, a cross-sectional study at inclusion was performed to describe the frequency and causes of anemia in our cohort. Investigations for potential blood loss in patients with IDA were recorded in detail. Characteristics of the population were described using mean (standard deviation), or median (interquartile range (IQR)) in case of nonnormality for quantitative variables, and number (percentage) for qualitative variables. Characteristics of patients with and without anemia at inclusion were compared using t tests, or Wilcoxon rank sum tests in case of nonnormality for quantitative variables, and Fisher exact tests for qualitative variables.
Longitudinal data were analyzed using a Cox model 20 to evaluate the association between anemia at inclusion and mortality.
Ethical statement
Our study complied with institutional ethical standards and those of the national research committee. The FHU IMMINENT database and biobanking fulfilled the ethical requirements (RCB 2019-A01083-54), and patients provided written informed consent. All collected data were anonymized in compliance with French regulations. Data collection and archiving were realized in accordance with the Commission Nationale de l’Informatique et des Libertés (CNIL) guidelines
Results
Characteristics of patients
A total of 502 patients were included. Mean age was 58 years, with a predominance of the female sex (85.7%). Three hundred eighty-nine (77.5%) patients presented limited lcSSc, while 107 (21.6%) presented dcSSc. Mean disease duration at the time of evaluation from the first non-RP symptom was 9.28 years.
Frequency and causes of anemia
Out of 502 SSc patients included in this study, 100 patients (20%) had anemia at the first visit according to the prespecified definition (Figure 1). IDA was the most common cause of anemia (40%), followed by mixed anemia (24%), B12 deficiency (7%), and ACD (6%). We could not identify the cause of anemia in 20 patients.
Figure 1.
Percentage distribution of the causes of anemia.
ACD: anemia of chronic disease; B12: B12 deficiency; IDA: iron-deficiency anemia.
Among the 20 patients with mixed anemia, all except three were diagnosed with IDA in addition to another cause of anemia (Figure 2). Regarding the patients with unknown cause of anemia, we observed two distinct patterns. First, there were patients with a near-normal hemoglobin level. In 80% of these cases, when the clinician asked to check the hemoglobin level on a new blood test taken in the following month, the hemoglobin level had returned to normal. So far, further investigation was not pursued. Second, we identified a group of elderly patients with suspected myelodysplastic syndrome (MDS) by the hematologist of the medical team. However, the MDS diagnosis workup was not performed, after collegial discussion, considering that this would have had no impact on patient care. Further details can be found in the appendix (Figure S1).
Figure 2.
Detail of causes for anemias classified as mixed.
ACD: anemia of chronic disease; B9: B9 deficiency; B12: B12 deficiency; IDA: iron-deficiency anemia; MDS: myelodysplastic syndrome.
IDA
Among patients with IDA, investigations for possible blood loss were performed in 32 patients (68% of the patients with IDA). Gastrointestinal investigations were not undertaken in the remaining 32 patients for a variety of reasons, which included the following: blood loss per vagina was reported in 2 (6%) patients, previously normal digestive investigations within the last 2 years in 10 (31%) patients, recommended investigations but eventually not performed in 13 (40%) patients, patient refusal in 2 (7%), or frailty deemed by the clinician to contraindicate such an approach in 5 (16%) patients. Among 32 patients with gastrointestinal investigations, 21 (65%) patients had at least one abnormality. Blood loss from the upper gastrointestinal tract was found in 16 patients, and was due to esophagitis in 5 patients, Barrett’s esophagus in 2 patients, peptic ulceration in 1 patient, gastritis in 3 patients, mixed esophagitis and gastritis in 2 patients, angiodysplasia in 1 patient, and varicose veins in 1 patient. Bleeding from the colon or rectum was found in one patient who had polyps. One patient had a gastroscopy and a colonoscopy during the same period of time and had both gastritis and polyps.
Comparison between SSc patients with and without anemia
Comparisons of clinical characteristics between the SSc patients with and without anemia are shown in Table 1. Patients with anemia were older (mean age: 61.0 vs 57.4 years, p = 0.02) and more likely to have dcSSc (33.7% vs 18.3%, p = 0.005). Symptoms of gastritis were more common in patients with anemia (29.9% vs 17.9%, p = 0.013). They had more pulmonary and cardiovascular involvement as shown by a lower distance of 6-min walk test (65% of theory vs 79%, p < 0.001), lower DLCO corrected for anemia (58% of theory vs 71%, p < 0.001), a higher frequency of FVC <70% (15% vs 6%, p < 0.005), a higher estimated systolic PAP (37.6 mmHg vs 32.7 mmHg, p = 0.004), and higher levels of NT-proBNP (560 ng/ml vs 221 ng/ml, p < 0.001).
Table 1.
Baseline characteristics of the patients with and without anemia.
| Characteristic | Without anemia | With anemia | p |
|---|---|---|---|
| (N = 402) | (N = 100) | ||
| Age—years | 57.39 ± 13.56 a | 60.96 ± 14.89 | 0.021 |
| Male sex—n (%) | 65 (16.2) | 17 (17.0) | 0.960 |
| Tobacco—n (%) | 0.495 | ||
| Active | 52 (13.0) | 9 (9.1) | |
| Never | 238 (59.4) | 64 (64.6) | |
| Weaned | 111 (27.7) | 26 (26.3) | |
| Characteristics of SSc | |||
| Disease duration—years | |||
| from RP symptom | 15.17 ± 12.78 | 15.82 ± 12.85 | 0.672 |
| from first non-RP symptom | 9.38 ± 9.22 | 8.85 ± 7.97 | 0.619 |
| Disease subtypes—n (%) | 0.002 | ||
| dcSSc | 74 (18.6) | 33 (33.7) | |
| lcSSc or Sine scleroderma SSc | 324 (81.4) | 65 (66.3) | |
| ANA—no (%) | 345 (94.8) | 84 (92.3) | 0.512 |
| Antibodies—no (%) | |||
| anticentromere | 200 (49.8) | 41 (41.0) | 0.145 |
| anti-topoisomerase 1 | 71 (17.7) | 22 (22.0) | 0.392 |
| anti-RNA POL3 | 10 (2.5) | 6 (6.0) | 0.141 |
| Severity score | |||
| Medsger b | 3.36 ± 2.46 | 4.13 ± 3.22 | 0.009 |
| EUSTAR_2011 | 1.21 ± 1.27 | 1.81 ± 1.61 | < 0.001 |
| EUSTAR_2016 | 1.29 ± 1.38 | 2.08 ± 1.71 | < 0.001 |
| Gastrointestinal system involvement | |||
| Symptoms of esophagitis—n (%) | 308 (76.6) | 70 (70.7) | 0.274 |
| Symptoms of gastritis—n (%) | 71 (17.9) | 29 (29.9) | 0.013 |
| Transit disorder—n (%) | 139 (34.8) | 34 (34.7) | 1.000 |
| Abdominal, pain—n (%) | 51 (13.9) | 13 (15.1) | 0.904 |
| Skin damage | |||
| Modified Rodnan skin score | 4.63 (5.51) | 6.86 (6.92) | 0.001 |
| Telangiectasia—n (%) | 304 (76.2) | 75 (75.8) | 1.000 |
| Raynaud’s phenomenon—n (%) | 397 (99.0) | 94 (94.9) | 0.022 |
| fingertip ulcer/gangrene—n (%) | 48 (12.0) | 16 (16.2) | 0.342 |
| capillaroscopy (Cutolo)—n (%) | 0.392 | ||
| Active | 72 (52.9) | 14 (53.8) | |
| Early | 45 (33.1) | 6 (23.1) | |
| Late | 19 (14.0) | 6 (23.1) | |
| Pulmonary symptoms | |||
| NYHA—n (%) | < 0.001 | ||
| Class I | 202 (50.5) | 31 (31.6) | |
| Class II | 115 (28.7) | 29 (29.6) | |
| Class III | 65 (16.2) | 22 (22.4) | |
| Class IV | 18 (4.5) | 16 (16.3) | |
| Pulmonary evaluation | |||
| D6WT, meters | 440.76 ± 105.17 | 357.61 ± 135.09 | < 0.001 |
| D6WT, % of theory | 79.47 ± 16.87 | 64.55 ± 22.58 | < 0.001 |
| ILD—n (%) | 135 (33.6) | 44 (44.0) | 0.149 |
| PAH—n (%) | 29 (7.3) | 14 (14.0) | 0.052 |
| FVC < 70 %—n (%) | 22 (5.6) | 15 (15.6) | 0.002 |
| DLCO - % of theory c | 71.23 ± 20.85 | 58.61 ± 16.03 | < 0.001 |
| Cardiovascular evaluation | |||
| NT-proBNP—ng/L | 221.52 ± 512.18 | 560.72 ± 1166.76 | < 0.001 |
| LVEF - % | 64.40 ± 6.00 | 63.38 ± 6.60 | 0.162 |
| PASP—mmHg | 32.70 ± 12.65 | 37.63 ± 16.13 | 0.004 |
| TRV—m/s | 2.55 ± 0.53 | 2.78 (0.62) | 0.001 |
| Vascular event | |||
| Deep vein thrombosis—n (%) | 44 (11.8) | 14 (15.9) | 0.386 |
| Pulmonary embolism—n (%) | 23 (6.2) | 7 (8.0) | 0.710 |
| Arterial thrombosis—n (%) | 36 (9.0) | 18 (18.0) | 0.015 |
| Musculoskeletal symptoms | |||
| Myalgia, n (%) | 73 (18.2) | 21 (21.2) | 0.595 |
| Arthralgia, n (%) | 163 (40.6) | 40 (40.4) | 1.000 |
ANA: antinuclear antibodies; anti-Scl-70: Anti-topoisomerase I; RNAIII: Anti-RNA polymerase III antibody; CK-MD: creatine kinase isoenzyme-MB; D6WT: distance of six-minute walk test; dcSSc: diffuse cutaneous SSc; DLCO: diffusing capacity for carbon monoxide; FVC: forced vital capacity; ILD: interstitial lung disease; lcSSc: limited cutaneous SSc; LVEF: left ventricular ejection function; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PASP: estimated pulmonary artery systolic pressure; RP: Raynaud’s phenomenon; SSc: systemic sclerosis; TRV: tricuspid regurgitant jet velocity.
Plus–minus values are means ± SD.
Excluding general.
The DLCO value was corrected for the hemoglobin level.
Bold values represent significant p values.
Survival analysis
Median follow-up was 5.2 years (IQR: 3.6–5.9). Sixty-five patients died during the follow-up with a median time between inclusion and death of 2.8 years (IQR: 1.6–4.0). The overall survival rate was 86% at 5 years (95% confidence interval (CI): 83%–90%). After adjusting for age, SSc subtypes, FVC, and PAH, anemia was associated with a higher mortality rate (adjusted hazard ratio (HR) for death: 1.94 (95% CI = 1.39–2.48), p = 0.02).
Discussion
In this study, we found that (1) 20% of SSc patients had anemia at inclusion in the database, (2) the main cause of anemia was IDA (66% of patients with anemia, alone or associated with another etiology), while a smaller portion had ACD, (3) half of IDA was due to blood loss from the upper gastrointestinal tract, and (4) anemia at the initial visit was associated with dcSSc, higher severity scores, and a worse prognosis.
The frequency of anemia in our study is in line with previous studies.21,22 Using hemoglobin level <12 g/dl to define anemia, Pokeerbux et al. 22 found that 23% of SSc patients had anemia. The frequency of anemia in our SSc cohort appears to be higher than in the general population of developed countries over the age of 65 years, which is estimated at around 11% 23 and in other rheumatic diseases such as rheumatoid arthritis, which is estimated at around 10%. 24 This higher frequency in SSc may be attributed to the gastrointestinal involvement. Indeed, the majority of anemia was IDA in our study, predominantly resulting from gastrointestinal bleeding. Interestingly, 65% of SSc patients with IDA in our cohort, who had undergone a diagnosis workup to find the cause of IDA, had a final diagnosis, suggesting that this workup is useful in this condition. The majority of IDA was due to upper gastrointestinal tract lesions, and none was malignant. For patients without overt digestive bleeding, we could suspect an undetected digestive blood loss or malabsorption. However, no video capsule endoscopy exploration was performed in our study, nor research for malabsorption. Marie et al. 25 reported that video capsule endoscopy in SSc can identify gastric and/or small intestinal telangiectasia in 27% of patients as well as gastric and/or small intestinal angiodysplasia in 38% of patients.
Our study found several significant associations between anemia and older age, higher frequency of dcSSc, and higher severity scores. Patients with anemia had more gastrointestinal symptoms, which is consistent with the damage to the upper digestive tract revealed by gastrointestinal endoscopy. They also exhibited a higher degree of heart and lung involvement, characterized by a lower distance of 6-min walk test, FVC, DLCO, higher systolic PAP, and higher NT-proBNP. The frequency of patients with a diagnosis of ILD or PAH was similar between the two groups. Our hypothesis to explain these results is that the definition of ILD and PAH is strict. A lower DLCO and PAPs could reflect a more pronounced alteration of the pulmonary microcirculation, without however fulfilling all the criteria for PAH.
These findings are in line with previous studies that have demonstrated a higher incidence of gastrointestinal, cardiopulmonary, kidney, and joint involvement in patients with dcSSc, which is associated with a poorer prognosis and lower survival rates.26,27 In a previous study, anemia was also associated with dcSSc 22 and a poorer prognosis with an adjusted HR of 2.37 (1.54–3.66), 10 which is close to the findings of our study.
The main strength of our study is that it is the largest study exploring anemia in patients with SSc. In addition, the investigation of anemia was standardized, allowing for an etiological diagnosis in over more than 80% of patients. However, the study has limitations. Our center is a referral center. Yet, the characteristics of the patients included are in line with the usual description of SSc patients with more than 80% of lcSSc. We do not anticipate that we have significantly more severe cases but cannot firmly rule it out. We did not perform a video capsule endoscopy in patients with IDA. Due to the small number of deaths in this study, it was not possible to adjust for all confounding factors. Finally, we did not know the precise causes of death.
In conclusion, the study demonstrated that anemia is common in SSc, and is primarily attributed to IDA with upper gastrointestinal bleeding. SSc patients with anemia at inclusion have a more severe clinical presentation and a higher risk of death.
Supplemental Material
Supplemental material, sj-pdf-1-jso-10.1177_23971983241238921 for Prevalence, causes, and clinical associations of anemia in patients with systemic sclerosis: A cohort study by Benoit Gachet, Mathieu Jouvray, Vincent Koether, Aurore Collet, Sandrine Morell-Dubois, Sébastien Sanges, Vincent Sobanski, Eric Hachulla and David Launay in Journal of Scleroderma and Related Disorders
Footnotes
Author contributions: BG, MJ, and DL conceived the study. VK, AC, SM-D, SS, VS, and EH managed the patients and provided clinical data. BG and MJ wrote the manuscript which was approved by all authors.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical statement: Our study complied with institutional ethical standards and those of the national research committee. The FHU IMMINENT database and biobanking fulfilled the ethical requirements (RCB 2019-A01083-54), and patients provided written informed consent. All collected data were anonymized in compliance with French regulations. Data collection and archiving were realized in accordance with the Commission Nationale de l’Informatique et des Libertés (CNIL) guidelines.
ORCID iD: Benoit Gachet 
https://orcid.org/0009-0007-3001-3258
Supplemental material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, sj-pdf-1-jso-10.1177_23971983241238921 for Prevalence, causes, and clinical associations of anemia in patients with systemic sclerosis: A cohort study by Benoit Gachet, Mathieu Jouvray, Vincent Koether, Aurore Collet, Sandrine Morell-Dubois, Sébastien Sanges, Vincent Sobanski, Eric Hachulla and David Launay in Journal of Scleroderma and Related Disorders