Journal Pre-proof

First diagnosis of systemic lupus erythematosus in hospitalized

patients: Clinical phenotypes and pitfalls for the non-specialist

Noemin Kapsala MD , Dionysis Nikolopoulos MD ,

Sofia Flouda MD, MSc , Aikaterini Chavatza MD ,
Dimitrios Tseronis MD , Michail Aggelakos MD ,
Pelagia Katsimbri MD , George Bertsias MD, MSc, PhD ,
Antonis Fanouriakis MD, MSc, PhD ,
Dimitrios T Boumpas MD, FACP

PII: S0002-9343(21)00500-3
DOI: https://doi.org/10.1016/j.amjmed.2021.07.015
Reference: AJM 16410

To appear in: The American Journal of Medicine

Please cite this article as: Noemin Kapsala MD , Dionysis Nikolopoulos MD ,

Sofia Flouda MD, MSc , Aikaterini Chavatza MD , Dimitrios Tseronis MD , Michail Aggelakos MD ,
Pelagia Katsimbri MD , George Bertsias MD, MSc, PhD , Antonis Fanouriakis MD, MSc, PhD ,
Dimitrios T Boumpas MD, FACP , First diagnosis of systemic lupus erythematosus in hospitalized
patients: Clinical phenotypes and pitfalls for the non-specialist, The American Journal of Medicine
(2021), doi: https://doi.org/10.1016/j.amjmed.2021.07.015

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

First diagnosis of systemic lupus erythematosus in hospitalized patients: Clinical

phenotypes and pitfalls for the non-specialist

Noemin Kapsala, MD,1 Dionysis Nikolopoulos, MD,1, 4 Sofia Flouda, MD, MSc,1 Aikaterini

Chavatza, MD,1 Dimitrios Tseronis, MD,1 Michail Aggelakos, MD,1 Pelagia Katsimbri, MD,1

George Bertsias, MD, MSc, PhD,2, 5 Antonis Fanouriakis, MD, MSc, PhD,1,3 Dimitrios T

Boumpas, MD, FACP 1, 4, 6

1
"Attikon" University Hospital of Athens, Rheumatology and Clinical Immunology, Medical

School, National and Kapodistrian University of Athens, Athens, Greece

2
Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine,

Heraklion, Crete, Greece

3
Department of Rheumatology, "Asklepieion" General Hospital, Voula, Athens, Greece

4
Laboratory of Immune Regulation and Tolerance, Autoimmunity and Inflammation,

Biomedical Research Foundation of the Academy of Athens, Athens, Greece

5
Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-

Hellas, Heraklion, Crete, Greece

6
Medical School, University of Cyprus, Nicosia, Cyprus

1
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Corresponding author: DT Boumpas, MD, FACP, Professor of Medicine, Affiliated

Investigator

T: +30 210 65 97 516, +30 210 65 97 133; Mobile 00306937212025; F: +30 210 65 97 516;

E: dboumpas@bioacademy.gr, boumpasd@uoc.gr, boumpasd@med.uoa.gr

.www.bioacademy.gr

Funding source (s): This work was funded in part by the Hellenic Society of Rheumatology; the

Foundation for Research in Rheumatology (FOREUM); the Greek General Secretariat for

Research and Technology 'Aristeia' action of the Operational Programme 'Education and

Lifelong Learning' (co-funded by the European Social Fund and National Resources, Aristeia I

2344 to DTB); the European Research Council (ERC) under the European Union‟s Horizon 2020

research and innovation programme (grant agreement no 742390); and the SYSCID (A Systems

Medicine Approach to Chronic Inflammatory Diseases) under the European Union‟s Horizon

2020 research and innovation programme (grant agreement no 733100).

Declarations of interest: none

All authors had access to the data and a role in writing the manuscript

Article type: clinical research study

Key words: systemic lupus erythematosus, new onset, diagnosis, hospitalization, criteria,

SLERPI

2
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Abstract

Background: Prompt recognition of systemic lupus erythematosus (SLE) in hospitalized patients

presenting with severe disease is essential to initiate treatment. We sought to characterize the

phenotype of hospitalized patients with new-onset SLE and estimate potential diagnostic delays.

Methods: Observational study of 855 patients (“Attikon” SLE cohort). Clinical phenotype was

categorized according to the leading manifestation that led to hospitalization. Disease features,

time to diagnosis, classification criteria and the SLE Risk Probability Index (SLERPI) were

recorded for each patient.

Results: 191 patients (22.3% of the total cohort) were hospitalized due to manifestations

eventually attributed to SLE. Main causes of admission were neuropsychiatric syndromes

(21.4%), cytopenias (17.8%), nephritis (17.2%) and thrombotic events (16.2%). Although 79.5%

of patients were diagnosed within 3 months from hospitalization, in 39 patients diagnosis was

delayed, particularly in those with hematological manifestations. At hospitalization, a SLERPI

>7 (indicating high probability for SLE) was found in 87.4% of patients. Patients missed by the

SLERPI had fever, thrombotic or neuropsychiatric manifestations not included in the algorithm.

Lowering the SLERPI threshold to 5 in patients with fever or thrombotic events increased the

diagnostic rate from 88.8% to 97.9% in this subgroup, while inclusion of all neuropsychiatric

events yielded no additional diagnostic value.

Conclusion: One in five patients with new-onset SLE manifest disease presentations

necessitating hospitalization. Although early diagnosis was achieved in the majority of cases, in

3
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

approximately 20% diagnosis was delayed. A lower SLERPI cut-off (≥5) in patients with fever

or thrombosis could enhance early diagnosis.

Clinical significance

 One in five new-onset lupus patients presents with disease necessitating hospitalization.

 Although early diagnosis was achieved in the majority of these patients, in approximately

20% the diagnosis was missed or delayed, especially in cases of cytopenias.

 A modification of the SLE Risk Probability Index (SLERPI) in hospitalized patients with

suspected systemic lupus erythematosus (SLE) may assist in earlier SLE diagnosis.

Introduction

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with a broad spectrum

of clinical manifestations and variable severity1. Clinical presentation ranges from mild to severe

organ- and life-threatening disease, and the clinical course frequently follows a relapsing-

remitting pattern2,3. SLE can occasionally first present with severe or critical disease

necessitating hospitalization4,5. Previous studies have reported significant variations in rates of

hospitalization and reasons of admission. About 10-20% of SLE patients are hospitalized

annually, the most common causes of admission being active disease, infections and

4
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

cardiovascular events6-18. Notably, among hospitalized SLE patients, 20-30% are new cases

diagnosed during hospitalization10,12,14-15.

The diagnosis of SLE can be challenging especially at early stages, when the disease is often

insidious with only a few features present. In the hospital setting, these features can resemble

lupus-mimicking conditions, such as other autoimmune, infectious or hematological diseases,

which may lead to diagnostic delays5,19-20. Such a delay in diagnosis and prompt treatment

initiation has been associated with increased flares and organ dysfunction20-24. To this end,

application of existing classification criteria may assist the diagnosis of SLE, with the

combination of all three sets (ACR-1997, SLICC-2012, EULAR/ACR-2019) showing the

highest sensitivity4,25-29. However, criteria still fail to classify up to 20% of cases at diagnosis,

and thus some patients with potentially severe disease may be “missed”20,25-29. To facilitate early

diagnosis, we have recently developed a clinician-friendly algorithm for SLE diagnosis, by the

use of machine learning. The SLE Risk Probability Index (SLERPI) consists of 14 variably

weighted clinical and serological SLE features, that can produce individualized risk probabilities

for clinical SLE against competing rheumatologic diseases (i.e., “definite”, “likely/probable”,

“possible”, “unlikely”), alike clinical diagnostic reasoning30. A threshold >7 can be used as a

dichotomous algorithm (i.e., SLE or not) with high accuracy (94.2%) for SLE diagnosis,

including early and severe disease30.

The aim of the present study was i) to determine the clinical phenotype of new-onset SLE

patients requiring hospitalization, ii) calculate the delay between hospitalization and SLE

diagnosis, and iii) assess the diagnostic performance of the SLERPI in hospitalized patients with

suspected SLE.

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Methods

Study design

This was an observational study from the “Attikon” lupus cohort, which was established in the

Rheumatology Unit of the “Attikon” University Hospital, serving as a lupus referral center, as

previously described4,31. All specialist departments are represented in “Attikon” Hospital,

assuring an unbiased referral base. As of February 2021, the cohort includes 855 SLE Caucasians

patients. Chart review was undertaken to identify patients diagnosed during hospitalization.

Additionally, new SLE cases in hospitalized patients were prospectively recorded from

November 2018 to February 2021. SLE diagnosis was based on expert physician assessment

(AF,DB), taking into account the three existing classification criteria27-29. All patients had

received appropriate work-up based on the presenting symptoms, to exclude competing

diagnoses. Patients <15 years of age, those with inadequate data or lost-to-follow up were

excluded. The study was approved by the local Ethics Committee.

Data collection and definition

For patients hospitalized prior to SLE diagnosis, a review of hospital discharge records was

performed to capture demographic characteristics, chief symptom/complaint leading to hospital

admission, clinical manifestations attributed to SLE at admission and during hospitalization,

length of hospitalization, admission to intensive care unit (ICU), and information on treatment

and outcome at discharge (i.e., improved/stable/death). Prolonged hospitalization was defined as

>7 days of hospitalization.

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Data on disease manifestations were collected using a standardized form, which included

classification criteria27-29, and additional non-criteria features (e.g. Raynaud‟s phenomenon, sicca

symptoms, fatigue)19,21,26. To characterize the clinical phenotype at the time of hospital

admission, we defined 10 domains of organ system involvement (neuropsychiatric, thrombosis,

nephritis, serosal, hematologic, pulmonary, cardiovascular, gastrointestinal, skin-joint, fever-

lymphadenopathy). The respective items of clinical domains are shown in Supplemental Table

S1. Clinical phenotype was categorized based on the predominant organ manifestation at the

time of admission. Moreover, disease was categorized as multisystem or organ-dominant. The

revised Sydney classification criteria were used for definite diagnosis of antiphospholipid

syndrome (APS)32. Neuropsychiatric manifestations were assessed through a multidisciplinary

approach and ascertained by expert physician assessment combined with attribution models33-36.

Lupus nephritis (LN) was defined as biopsy-proved nephritis37 and/or fulfilment of the renal

component of SLE classification criteria, following exclusion of other causes27-28.

Chart review and patient interview was performed to assess the time interval between

hospitalization and definite SLE diagnosis; the latter was defined as early (up to 3 months from

hospitalization) or delayed (> 3 months from hospitalization). The cut-off of 3 months was

chosen arbitrarily, to ensure adequate time for completion of the essential laboratory work-up

(including immunological tests).

Disease activity [according to the SLE Activity Index-2K (SLEDAI-2K)]38, irreversible organ

damage [according to the Systemic Lupus International Collaborating Clinics (SLICC) Damage

Index (SDI)]39 and the SLERPI30 were recorded for each patient at hospitalization.

7
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Statistical analysis

Descriptive statistics were undertaken for continuous variables and mean (SD) or median (IQR)

values were calculated for normally and non-normally distributed variables, respectively. The

Chi-squared test was used to compare categorical variables, and Student‟s t-test or non-

parametric Mann-Whitney U test was used to compare continuous variables, as appropriate.

Time from hospitalization to SLE diagnosis was evaluated with Kaplan-Meier analysis, and log

rank test was implemented to compare SLE patients with and without hematological

involvement. For all comparisons, a p-value of <0.05 was considered statistically significant. All

analyses were performed using SPSS V.24.0.

Results

Study population

Among the 855 SLE patients, 229 were hospitalized prior to SLE diagnosis. Of these, 17 were

younger than 15 years and 6 with inadequate data, were excluded. In 15 patients diagnosed

during hospitalization, admission to the hospital was due to manifestations unrelated to lupus

(incidental diagnosis). Since our focus was on lupus-related manifestations leading to

hospitalization, we also excluded these patients from further analysis (Supplemental Table S2

summarizes the causes of admission and SLE-related features of these patients). Our final study

sample included 191 patients (22.3% of the total cohort). Female to male ratio was 5:1 (83.7%

females), with mean ±SD age at diagnosis 45.3 ± 16.3 years; 71 patients (37.1%) were diagnosed

with late-onset SLE (i.e., older than 50 years).

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Chief symptom/complaint leading to admission and clinical phenotypes

Most common symptoms leading to hospital admission were fever (32.9%), shortness of breath

(20.4%), chest or pleuritic pain (16.7%), prolonged intense arthralgias (14.6%) and profound

debilitating fatigue (10.4%). Forty-three patients (22.5%) were referred for hospitalization by

primary care physicians due to abnormal laboratory findings from blood, urine or liver function

tests.

The number of patients per clinical domain at admission are shown in Table 1 and Figure 1. The

most common predominant features were neuropsychiatric (21.4%), especially cerebrovascular

events (n=10/41). Cytopenias (17.8%), nephritis (17.2%) and thrombotic events (16.2%) were

also common as dominant manifestations; pulmonary embolism was the leading thromboembolic

event (n=20/31). Of 33 patients presenting with nephritis, 26 patients underwent a kidney biopsy,

with proliferative LN being the most common histological type (69.2%). On admission, 12.5%

of patients (n=24) had dominant manifestations from at least 2 clinical domains, with the most

frequent combination being cytopenias with LN (n=5/24) (Supplemental Table S3,

Supplemental Figure S1).

Clinical features and immunologic profile following rheumatologic evaluation

A detailed review of organ system involvement revealed that most patients had multisystem

disease (94.2%), with only 5.8% of cases manifesting organ-dominant disease (mostly

neuropsychiatric, n=5/11). Most common SLE-related features were arthritis (n=169, 88.4%),

followed by acute cutaneous lupus (cumulatively n=148, 77.4%). Among non-criteria features,

fatigue and Raynaud‟s phenomenon were reported by 37.7% and 31.9% of patients, respectively.

9
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

At the time of hospitalization, 89% of patients were ANA-positive, while anti-dsDNA and low

complement were recorded in 35.6% and 37.6%, respectively. Detailed clinical features and

serological items are summarized in Table 2.

Delay in diagnosis

Early diagnosis (up to 3 months from hospitalization) was established in 79.5% of patients, with

approximately 2/3 (64.9%) being diagnosed within the first month. Thirty-nine patients were

diagnosed >3 months from hospitalization (delayed diagnosis), with a median (IQR) lag time

between hospitalization and definite diagnosis of 8 (8) months. Seventy-one patients (37.1%)

were discharged and re-admitted at least once for the same reason; the median (IQR) time

between first and last hospitalization was 1 (3) months. The mean time from hospitalization to

established diagnosis for each clinical domain is shown in Figure 2A. Approximately one fourth

of patients with delayed diagnosis were hospitalized due to hematological manifestations

(Figure 2B). Patients with cytopenias had longer diagnostic delay after hospitalization compared

with patients hospitalized due to non-hematologic lupus (p=0.03) (Figure 3).

Outcome of hospitalization

The mean ±SD length of hospital stay was 13.3±11.4 days. Twelve patients (6.2%) were

admitted to ICU, leading to significant increase in mean (SD) hospitalization stay to 20 (11.3)

days. The main reason for ICU admission was thrombotic events. Although no deaths were

recorded, irreversible organ damage (i.e., SDI≥1; attributed to manifestations present during

hospitalization) was recorded in 39.7% of patients, mostly attributed to neuropsychiatric

10
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

manifestations and thrombotic events. Prolonged hospitalization was associated with an

increased SDI (mean SDI 0.7 ±0.9 vs. 0.4 ±0.7, p=0.001).

Classification Criteria and the role of SLERPI for SLE diagnosis

Next, we assessed the performance of the three classification criteria and SLERPI in our study

population. At hospitalization, the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria

were fulfilled in 82.1%, 84.8% and 85.3% of cases, respectively, while the combination of three

criteria sets missed the classification only in 12 patients (6.2%). A SLERPI>7, indicating high

probability risk for SLE, was present in 167 patients (87.4%) (Figure 4). Of these, 147 patients

had a diagnostic certainty level of “definite” diagnosis (risk probability 87%-100%), while the

remaining 20 were categorized as “likely” SLE (risk probability 44%-86%). Twenty-four

patients did not exceed the threshold of 7; half of them were labelled as “unlikely” SLE (i.e.,

other CTD more likely than SLE) according to the algorithm (score ranges 4.5-5.5, probability

ranges 1.46%-8.50%). For this latter group, approximately 60% (n=7) had a dominant clinical

manifestation on admission not included in the SLERPI algorithm, mainly from neuropsychiatric

or thrombotic domains (i.e., demyelination syndrome, cerebrovascular event, pulmonary

embolism), combined with positive serology and/or a few more clinical features (Supplemental

Table S4). To this end, we examined the performance of SLERPI if we extended its

neuropsychiatric items to include demyelination and strokes (n=16). Although there was no

difference in the proportion of patients exceeding the threshold of 7, using the full probabilistic

model there was an increase in risk probabilities. Specifically, 13/16 patients achieved >93%

SLE risk probability after the SLERPI modification, while the risk probability was increased by

~50% in the remaining 3 (Figure 4D). We also tested if the combination of fever and/or

11
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

thrombotic events with a lower cut-off of SLERPI could improve its diagnostic rates. When we

chose a score ≥5 as threshold, 7/9 patients with fever and both patients (n=2/2) with thrombotic

events who did not exceed the threshold of 7, would then be classified as SLE, thus increasing

the diagnostic rate from 88.8% to 97.9% (Figure 4E).

Discussion

In this single-center study, we described the phenotype of new-onset SLE patients admitted to

the hospital prior to disease diagnosis for reasons ultimately attributed to lupus. Previous studies

suggest that nearly 20-30% of hospitalized SLE patients represent new cases diagnosed during

hospitalization and the leading causes of admission are infections, active disease, mainly LN or

hematological disorders, and cardiovascular events, with frequencies varying among different

studies6-18.

Although the majority of patients from the “Attikon” lupus cohort were diagnosed on an

ambulatory basis, one fifth were hospitalized for SLE-related features prior to establishment of a

lupus diagnosis. The most common clinical phenotype leading to hospital admission was

neuropsychiatric lupus (NPSLE, 21.4%), with cerebrovascular events constituting the main

manifestation. NPSLE as the dominant clinical syndrome for admission was generally higher in

our study compared with previous literature, wherein 1.6-24.8% of SLE admissions because of

active disease are due to neuropsychiatric manifestations6-12,14-16. This may reflect that our Unit

represents one of the largest referral centers, but also has a specific research interest for

NPSLE40-41. In addition, the Neurology Department has formed a distinct unit which focuses on

neuropsychiatric manifestations attributed to systemic autoimmune diseases40-41 (potential

referral bias).

12
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

The second most common clinical phenotype at admission was hematological lupus (17.8%),

especially thrombocytopenia, consistent with earlier reports suggesting that hematological

abnormalities are leading manifestations of active lupus requiring hospitalization6-17. LN and

thromboembolic events were also recorded as dominant clinical syndromes leading to hospital

admission (17.2% and 16.2%, respectively). Compared to other studies, in which LN represented

common flares on admission (10.5%-65%)6-17, LN seems to be a less common cause of

hospitalization in our experience. This could be due to a higher threshold for admission or the

fact that LN prevalence among Caucasians is known to be lower than other ethnicities (~25%),

often manifesting during the course, rather than at disease onset42-44. Thromboembolic events

were slightly higher compared to respective rates in previous studies6-17, possibly implying a

lower threshold for admission in our practice, since deep venous thrombosis and minor

pulmonary embolisms may also be treated on an outpatient basis. Of note, although we excluded

from further analysis patients with incidental diagnosis, the majority of these cases were initially

hospitalized due to an infectious disease.

Importantly, the majority of patients (79.5%) were diagnosed during or soon after

hospitalization. The reasons for diagnostic delay in a subset of patients are the objective of a

separate manuscript, however our initial analyses show that the majority (31/39, 79.5%) of

patients with diagnostic delay were initially hospitalized in hospitals lacking inpatient

rheumatology service, and delayed specialist assessment constituted the principal reason for late

diagnosis and subsequent treatment initiation. Regarding disease-related factors, time to

diagnosis varies among clinical phenotypes, with the bigger lag in patients with hematologic

manifestations. Cytopenias may be the first clinical manifestation of SLE, present months or

years prior to diagnosis45. Zhu et al demonstrated that patients with idiopathic immune

13
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

thrombocytopenia have a 26-fold higher risk of new-onset SLE compared to control

population46. Of note, severe organ involvement in lupus has been associated with hematological

abnormalities45-46, with thrombocytopenia representing an independent risk factor of death and

being associated with higher disease activity and greater damage in different SLE cohorts45-49.

Thus, patients who present with hematologic abnormalities should routinely be evaluated for the

identification of additional features suggestive of a connective tissue disease.

Early diagnosis of SLE is essential to ensure early intervention and improve short and long-term

outcomes23. Although the combination of all three classification sets enables the earlier

classification of increased number of patients, a significant proportion (7-17%)20,26-29 with

potentially severe or life-threatening disease is still missed or experiences diagnostic delays. In

our study population, 6.2% of patients fulfilled none of the three sets of criteria, while a

SLERPI>7 was recorded in 87.4%. Although the SLERPI showed a modest improvement in

diagnostic accuracy for SLE compared with each one of the three sets of criteria, the rates were

lower than we expected, owing to non-inclusion in this scoring system of clinical manifestations,

like thrombosis and fever. A modification Of SLERPI to a lower cut-off (threshold of 5) in

hospitalized patients presenting with fever and thrombotic events led to increased possibility for

a correct diagnosis in our study.

Certain limitations of our study need to be acknowledged. First, it is limited by the retrospective

data extraction in a significant part of the study population. Nevertheless, “Attikon” cohort is a

well-established and comprehensive registry for lupus patients, wherein data collection derives

from detailed structured forms and medical records, which help to reduce possible data

completeness bias. Despite being a single-center study, our Rheumatology Unit covers

14
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

approximately 1.7 million citizens, is the largest tertiary center in Western Attica and serves as a

referral center for SLE. Regarding the value of SLERPI, one should keep in mind that the latter

was designed to evaluate the accuracy of SLE diagnosis against other rheumatic diseases.

Although there was no control population in our cohort, the true accuracy of SLERPI may be

even higher among hospitalized patients with suspected SLE, given the expected lower SLERPI

scores among patients with non-rheumatic diseases. Finally, SLERPI represents a recently

proposed tool which requires validation in additional cohorts with diverse ethnic/racial

characteristics, to further establish its clinical utility and diagnostic value.

In conclusion, our data suggest that up to 22% of SLE patients are first diagnosed with severe

disease during hospitalization. The mean time from hospitalization to definite SLE diagnosis

differs among clinical phenotypes, being higher for hematological lupus, and this indicates the

need for increased physician awareness in such manifestations. A modification of the SLERPI in

hospitalized patients with suspected SLE against non-rheumatic diseases could assist in earlier

SLE diagnosis.

Figures, Tables and Supplemental material

Figures (Figure 1, Figure 2, Figure 3, and Figure 4) included in 4 separate files respectively.

Tables (Table 1 and Table 2) included in a single file.

15
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Supplemental material (Supplemental Table S1, Supplemental Table S2, Supplemental Table

S3, Supplemental Table S4 and Supplemental Figure S1) included in a single file.

Figure legends

Figure 1: Clinical domains in hospitalized lupus patients. Most common clinical domain was

neuropsychiatric lupus, followed by cytopenias, lupus nephritis and thrombotic events.

Pulmonary disease, cardiovascular disease and gastrointestinal disease were uncommon

phenotypes. SLE: systemic lupus erythematosus; n=191

Figure 2: A) Mean interval (months) from hospitalization to definite diagnosis per clinical

domain. Patients hospitalized with fever-lymphadenopathy were diagnosed earlier after

hospitalization (mean 1.6 months). Patients hospitalized due to hematological disorders had the

greatest diagnostic delay (mean lag time 8.5 months). B) Distribution of clinical phenotypes in

early (within 3 months from hospitalization, black bars) and delayed (after 3 months from

hospitalization, grey bars) diagnosis groups. Neuropsychiatric lupus was the most common

phenotype among patients with early diagnosis. One fourth of patients with delayed diagnosis

were hospitalized due to cytopenias.

Figure 3: Kaplan-Meier curve for time between hospitalization and definitive SLE diagnosis in

patients with hematologic (n=34) and non-hematologic SLE (n=157). Log-rank (Mantel-Cox)

test was used to compare two groups. Patients hospitalized due to cytopenias had a greater

diagnostic delay after hospitalization compared with patients hospitalized due to non-

hematological lupus (p-value=0.03).

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Figure 4: A) Sensitivity of ACR 1997, SLICC 2012, EULAR/ACR 2019 SLE classification

criteria and SLERPI index >7 at time of hospitalization in the study population (n=191). A

SLERPI score >7 was recorded in 167 patients indicating a modest improvement in diagnostic

accuracy for SLE compared with each one of the three sets of classification criteria. B) SLERPI

score for each patient within the subgroups of early and delayed diagnosed patients (n=152 and

39, respectively) at the time of hospitalization. SLERPI> 7 was recorded in 135 out of 152 and

32 out of 39 patients with early and delayed diagnosis, respectively. C) Risk probabilities and

correlation of diagnostic certainty levels for the presence of SLE for each patient at the time of

hospitalization. Approximately 80% and 70% of patients with SLERPI>7 among the group of

early and delayed diagnosis, respectively, had definite diagnosis. Blue and red dots represent

SLE subjects with a score >7 and ≤7 in each group, respectively. D) SLERPI performance before

and after the modification to include strokes and demyelination on its items in patients

presenting with neuropsychiatric manifestations (n=16). There was no difference in the

proportion of patients exceeding the threshold of 7. Using the full probabilistic model, an

increase in risk probability scores was recorded for all patients. Thirteen patients achieved >93%

SLE risk probability after the SLERPI modification, while the risk probability was increased by

~50% in the remaining 3. E) SLERPI score before and after the modification for each patient

among those presenting with thrombotic events (n=31) or fever (n=68). When a lower cut-off

(score ≥5 as threshold) of SLERPI was set, 7/9 patients with fever and both patients (n=2/2) with

thrombotic events who did not exceed the threshold of 7, would then be classified as SLE, thus

increasing the diagnostic rate from 88.8% to 97.9% in this subgroup.

17
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Acknowledgments:

We thank the staff physicians (Drs T Karageorgas, D Kassara, K Thomas, GS Moysidou, M

Kosmetatou, E Atsali, L Fotis) and nurses (G Rapsomaniki, A Ntourou, K Togia, T Gerogianni)

of the Rheumatology Unit of the 'Attikon' University Hospital of Athens for their referral and

care to the patients with SLE. We are also indebted to Dr M Kostopoulou for her insightful

comments.

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Fig. 1

Fig. 2

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First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Fig. 3

Fig. 4
27
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Clinical phenotype Subtype Frequency n (%)

Neuropsychiatric 41 (21.4)

Cerebrovascular events 10 (24.3)

Seizures 6 (14.6)

Myelopathy 4 (9.7)

Psychosis 4 (9.7)

Demyelination syndrome 3 (7.3)

Optic neuritis 3 (7.3)

Cranial neuropathy 3 (7.3)

Cognitive disorder 2 (4.8)

Mood disorder 2 (4.8)

Headache 2 (4.8)

Aseptic meningitis 1 (2.4)

Peripheral neuropathy 1 (2.4)

Hematological 34 (17.8)

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Thrombocytopenia 21 (61.7)

Hemolytic anemia 9 (26.4)

Pancytopenia 5 (14.7)

Leukopenia 3 (8.8)

Multiple 4 (11.7)

Nephritis 33 (17.2)

Biopsy-proven 26 (78.8)

IV 7 (26.9)

IV/V 7 (26.9)

V 5 (19.2)

II 4 (15.3)

III 2 (7.7)

III/V 1 (3.8)

No biopsy 7 (21.2)

Thrombotic events 31 (16.2)

Pulmonary embolism 20 (64.5)

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

DVT 8 (25.8)

Other vein thrombosis 3 (9.6)

Valvular 3 (9.6)

Arterial thrombosis* 1 (3.2)

Multiple 6 (19.3)

Serosal 28 (14.6)

Pleuropericarditis 16 (57.1)

Pleuritic/pleurisy 8 (28.5)

Pericarditis/pericardial effusion 4 (14.2)

Skin-joint 21 (10.9)

Pulmonary 17 (8.9)

DAH 4 (23.5)

ILD 3 (17.6)

Pneumonitis 3 (17.6)

PAH 2 (11.7)

Combination 5 (29.4)

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Cardiovascular 4 (2)

Myocarditis 3 (75)

Large/medium vessel vasculitis 1 (25)

Fever-lymphadenopathy 3 (1.5)

Gastrointestinal 2 (1)

Mesenteric vasculitis 2 (100)

Table 1: Clinical phenotypes at the time of admission with the respective subtypes. N=191

*excluding cerebrovascular disease

DVT: deep vein thrombosis; ILD: interstitial lung disease; DAH: diffuse alveolar hemorrhage; PAH: pulmonary arterial

hypertension

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 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Table 2: Clinical features and immunologic profile of SLE patients following rheumatologic

consultation. Ν=191

Clinical features n (%)

Synovitis 169 (88.4)

Photosensitivity 135 (70.6)

Malar rash 103 (53.9)

Photosensitive rash 112 (58.6)

Subacute rash 15 (7.8)

Discoid rash 5 (2.6)

Non-scarring alopecia 58 (30.3)

Oral/nasal ulcers 41 (21.4)

Pleuritis 43 (22.5)

Pericarditis 34 (17.8)

Lupus nephritis 35 (18.3)

32
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Neuropsychiatric lupus 27 (14.1)

Autoimmune hemolytic anemia 17 (8.9)

Leukopenia 41 (21.4)

Thrombocytopenia 40 (20.9)

Raynaud‟s phenomenon 61 (31.9)

Livedo reticularis 25 (13)

Lymphadenopathy 27 (14.1)

Secondary antiphospholipid syndrome 40 (20.9)

Immunologic profile

ANA 170 (89)

Anti-dsDNA 68 (35.6)

Anti-Sm 13 (6.8)

Anti-SSA 42 (21.9)

Anti-SSB 13 (6.8)

33
 First diagnosis of SLE in hospitalized patients | Noemin Kapsala et al.

Anti-RNP 11 (5.7)

aPL 57 (29.8)

Anti-CL 44 (23)

Anti-b2GP1 28 (14.6)

LA 26 (13.6)

Low complement 72 (37.6)

SLE: systemic lupus erythematosus; ANA: antinuclear antibodies; anti-dsDNA: anti-double stranded DNA antibodies; anti-Sm:

anti-Smith antibodies; anti-SSA: anti–Sjögren's-syndrome-related antigen A antibodies; anti-SSB: anti–Sjögren's-syndrome-

related antigen B antibodies; anti-RNP: anti-ribonucleoproteins antibodies; aPL: antiphospholipid antibodies; anti-CL: anti-

cardiolipin antibodies; antib2GP1: anti-beta-2 glycoprotein antibodies; LA: lupus anticoagulant

34