Intensive Care Med

https://doi.org/10.1007/s00134-023-07266-7

NARRATIVE REVIEW

Diagnosis and management of autoimmune

diseases in the ICU
Guillaume Dumas1* , Yaseen M. Arabi2,3,4, Raquel Bartz5, Otavio Ranzani6,7, Franziska Scheibe8,9,
Michaël Darmon10 and Julie Helms11

© 2023 Springer-Verlag GmbH Germany, part of Springer Nature

Abstract
Autoimmune diseases encompass a broad spectrum of disorders characterized by disturbed immunoregulation
leading to the development of specific autoantibodies, resulting in inflammation and multiple organ involvement.
A distinction should be made between connective tissue diseases (mainly systemic lupus erythematosus, systemic
scleroderma, inflammatory muscle diseases, and rheumatoid arthritis) and vasculitides (mainly small-vessel vasculitis
such as antineutrophil cytoplasmic antibody-associated vasculitis and immune-complex mediated vasculitis). Admis-
sion of patients with autoimmune diseases to the intensive care unit (ICU) is often triggered by disease flare-ups,
infections, and organ failure and is associated with high mortality rates. Management of these patients is complex,
including prompt disease identification, immunosuppressive treatment initiation, and life-sustaining therapies, and
requires multi-disciplinary involvement. Data about autoimmune diseases in the ICU are limited and there is a need
for multicenter, international collaboration to improve patients’ diagnosis, management, and outcomes. The objec-
tive of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe
systemic autoimmune diseases.
Keywords: Autoimmunity, Lupus, Vasculitis, Corticosteroids, Intensive care unit

Introduction cytoplasmic antibody-associated vasculitis (ANCA-vas-

culitis) and immune-complex mediated vasculitis,
Autoimmune diseases are heterogeneous inflammatory
medium-vessel vasculitis such as polyarteritis nodosa
disorders ranging from organ-specific involvement to
and large vessel vasculitis such as giant-cells vasculitis or
multisystem disorders responsible for multiorgan fail-
Takayasu’s arteritis), but also sarcoidosis or unclassified
ure. Overall, their prevalence is probably 5–10% in the
pathologies (Still’s disease).
general population [1]. Among them, systemic autoim-
These disorders share common features: various
mune diseases cover a broad spectrum of conditions,
clinical symptoms with multiple organ involvement
including mainly connective tissue diseases (CTD) (sys-
(sometimes causing incorrect or delayed diagnosis),
temic lupus erythematosus (SLE), systemic scleroderma,
autoantibodies production, and frequent management
Sjögren’s syndrome, inflammatory muscle diseases,
with immunosuppressant therapy.
rheumatoid arthritis, and overlap-syndromes) and vas-
Although survival has dramatically improved over the
culitides (small-vessel vasculitides such as antineutrophil
past two decades [2, 3] thanks to a better understanding
of disease mechanisms, new diagnostic tools, and tar-
*Correspondence: Dumas.guillaume1@gmail.com geted therapies, up to 10% of patients still require admis-
1
Medical Intensive Care Unit, Service de Médecine sion to the intensive care unit (ICU) because of disease
Intensive‑Réanimation, CHU Grenoble-Alpes, Université Grenoble-Alpes,
INSERM, U1042‑HP2 Grenoble, France flare-ups, infections, and acute organ failures [4–6].
Full author information is available at the end of the article
 Intensivists, therefore, have to face several chal-
lenges: (1) to identify disease flare early in a context of
unexplained or unusual clinical presentation to avoid
end-organ failures and mortality; (2) to provide immu-
nosuppressive treatment along with life-sustaining
therapies; (3) to identify and manage severe adverse
events of immunosuppressive therapies, mainly infec-
tion, which are sometimes difficult to distinguish from
underlying disease exacerbation. However, there are
limited data regarding autoimmune diseases in the
ICU.
In this review, we summarize the most recent
achievements in diagnosing and managing critically ill
adult patients with autoimmune diseases, as well as the
future research agenda.
Five clinical situations that every intensivist should
be aware of
Scleroderma crisis
Patients with scleroderma are prone to life-threatening
complications that may require ICU admission, mainly
for non-scleroderma-related causes (71.4%) or respira-
tory complications [7].
Scleroderma renal crisis (SRC) is a rare (2.4% of the
patients) [8], but severe complication with a 5-year
survival of 50–70% [8, 9]. SRC usually presents with
malignant hypertension and oliguric acute kidney
injury. Left ventricular insufficiency and hypertensive
encephalopathy are common. SRC is more frequent
in patients receiving corticosteroids and can be trig-
gered by nephrotoxic drugs or volume depletion [9,
10]. Microangiopathic hemolytic anemia is detected in
43% of cases, and anti-RNA-polymerase III antibodies
are present in one-third of patients [8]. SRC should be
differentiated from ANCA-positive rapidly progres-
sive glomerulonephritis, as treatment regimens and
patient management are different [8]. The mainstay
of treatment is aggressive blood pressure control with
angiotensin-converting enzyme inhibitors and other
antihypertensive drugs, such as calcium channel block-
ers if needed. β-blockers should be avoided as these
might exacerbate Raynaud’s phenomenon [11]. Dialysis
is frequently indicated, and some patients require renal
transplantation [9].
Scleroderma cardiac crisis is an uncommon but life-
threatening complication occurring in patients with
recent onset and vascular phenotype (including severe
Raynaud phenomenon, digital ulceration, profuse tel-
angiectasia and arterial pulmonary hypertension). It
is characterized by acute left ventricular dysfunction,
usually reversible, but associated with poor long-term
outcomes (44% alive at 6 months) [12].
Take‑home message
Diagnosing autoimmune diseases in the intensive care unit in the
context of unexplained or unusual clinical presentation is challeng-
ing for the intensivist. The treatment to avoid end-organ failures and
mortality includes immunosuppressive treatments, life-sustaining
therapies, and prevention and treatment of severe adverse events of
immunosuppressive therapies.
Pulmonary‑renal syndrome
The pulmonary-renal syndrome is characterized by
diffuse alveolar hemorrhage and necrotizing glomer-
ulonephritis. The most underlying etiologies are ANCA-
vasculitis (∼70% of cases) and anti-glomerular basement
membrane (anti-GBM) disease (∼20% of cases) [13].
Acute respiratory failure (ARF) requiring invasive
mechanical ventilation occurs in approximately 50% of
cases [14, 15]. Pulmonary-renal syndrome should be
differentiated from other common ICU presentations
such as sepsis [16]. Bronchoscopy should be performed
to exclude infection and evaluate for evidence of diffuse
alveolar hemorrhage, which manifests on sequential
samples of bronchoalveolar lavage fluid with increas-
ing blood-staining and hemosiderin-laden macrophages
on cytology [13]. Histological diagnosis can be achieved
from percutaneous renal biopsy. Lung biopsy is associ-
ated with considerable risk and should be considered as
an alternative option [13].
Acute interstitial lung disease (connective‑tissue related
ILD)
Interstitial lung disease (ILD) is a rare parenchymal pul-
monary disorder characterized by interstitial abnor-
malities and sometimes fibrosis, complicating ∼15%
of all patients with connective tissue diseases (mainly
rheumatoid arthritis, scleroderma, myositis, Sjögren,
mixed-CTD, and SLE). Interestingly, many patients with
myositis-associated ILD present without elevated cre-
atine kinase or muscle symptoms [35, 36]. Nonspecific
interstitial pneumonia is the most common pattern,
but usual interstitial pneumonia can also be identified
(rheumatoid arthritis, scleroderma, myositis). High-
resolution computed tomography (CT), bronchoalveo-
lar lavage, and serology for autoantibodies are critical
to confirm the diagnosis and eliminate competing eti-
ologies (infection, drug toxicity) [17]. A lung biopsy is
generally not required. While carrying useful diagnos-
tic information, bronchoalveolar lavage fluid patterns
poorly correlate with prognosis or treatment response
[19]. Rapidly progressive forms with acute respiratory
distress syndrome (ARDS) are described, with poor out-
comes (> 50% of mortality), especially in patients with
scleroderma [20] and anti-synthetase or anti-melanoma
differentiation-associated gene 5 (aMDA-5) syndromes
[18, 19]. Lung fibrosis and pulmonary hypertension are
the other major prognostic factors [19, 21]. Except for
scleroderma, corticosteroids are used as the first-line
therapy, usually in combination with immunosuppres-
sive agents, mainly cyclophosphamide or mycopheno-
late mofetil [35, 39]. Tacrolimus, rituximab, and more
recently Janus kinase (JAK) inhibitors (tofacitinib) are
promising. In highly selected patients extracorpor-
eal membrane oxygenation (ECMO) may be discussed,
sometimes as a bridge to transplantation [22].
Acute severe cytopenias
Haematological abnormalities are common findings in
autoimmune diseases, mainly inflammatory anemia.
However, some emergencies should be systematically
discussed (Table 1). Autoimmune cytopenias such as
autoimmune hemolytic anemia (mainly warm-type IgG
on direct anti-globulin test) and idiopathic thrombocy-
topenic purpura are rare but sometimes life-threatening
complications, commonly encountered in SLE (∼10%
and ∼15% respectively). A peripheral blood film to look
for red blood cell fragmentation (i.e. schistocytes) is
mandatory in case of simultaneous thrombocytopenia
and hemolytic anemia to diagnose thrombotic microan-
giopathy. Potential causes in this context are thrombotic
thrombocytopenic purpura (sometimes associated with
SLE and mixed-CTD), SRC, and catastrophic antiphos-
pholipid syndrome (CAPS).
Pancytopenia should be explored by bone mar-
row aspiration. Besides infections, drug toxicity, and
malignancies, hemophagocytic lymphohistiocytosis
(HLH) and bone marrow necrosis are the most com-
mon specific findings [23, 24]. HLH is a life-threatening
hyperinflammatory state that presents with high fever,
hepatosplenomegaly, bicytopenia, and the presence of
activated macrophages in hematopoietic sites. HLH
may be triggered by infection (especially by Epstein-Barr
virus, cytomegalovirus, or human immunodeficiency
virus), lymphoid malignancy (B- or T-cell lymphoma),
connective tissue diseases (mainly Lupus and Still’s dis-
ease), or drugs. The clinical presentation should be dif-
ferentiated from common ICU diagnoses such as sepsis,
multiple organ dysfunction syndrome, and disseminated
intravascular coagulation [25]. Fardet et al. proposed a
diagnostic tool based on 9 criteria (HScore): 3 clinical
criteria (known underlying immunosuppression, high
temperature, organomegaly); 5 biological ones (cytope-
nia, elevated triglyceride, ferritin, and serum glutamic
oxaloacetic transaminase (SGOT), and low level of fibrin-
ogen); and 1 cytological one (hemophagocytosis features
on bone marrow aspirates) [26]. HScore ranges from 0 to
337. The probability of having hemophagocytic syndrome
is lesser than < 1% with an HScore of ≤ 90 while higher
than 99% with an HScore of ≥ 250. In a study of 71 HLH
cases admitted to the ICU, the hospital mortality was
68% [27].
Catastrophic antiphospholipid syndrome
CAPS is caused by antiphospholipid antibodies that
activate endothelial cells, platelets, and immune cells,
resulting in proinflammatory and prothrombotic mani-
festations, and is usually triggered by infection, surgery,
or medication. CAPS involves most often the kidneys,
lungs, heart, central nervous system, skin, liver, and gas-
trointestinal tract. Renal manifestations include hyper-
tension and acute kidney injury. Histologically, CAPS is
characterized by acute thrombotic microangiopathy and
should be differentiated from hemolytic-uremic syn-
drome, thrombotic thrombocytopenic purpura, dissemi-
nated intravascular coagulation, and heparin-induced
thrombocytopenia. Diagnostic criteria for CAPS have
been defined for definite and probable CAPS (supple-
mentary e-Table 1) [28]. However, limitations of this
definition have been recognized. A French multicenter
study (24 ICUs), studied patients with antiphospholipid
antibodies and any new thrombotic manifestation(s).
Using international criteria, patients were classified into
definite CAPS episodes (N = 11, 7.2%), probable episodes
(N = 60, 39.5%), and no-CAPS (N = 81, 53.3%). No histo-
pathological proof of microvascular thrombosis was the
most frequent reason for not being classified as definite
CAPS. Overall, 35/152 (23%) episodes were fatal, with
comparable rates for definite/probable CAPS and no
CAPS. Moreover, hematological patterns were similar
across groups, suggesting that several patients who did
not satisfy CAPS criteria, presented in fact “near CAPS”
episodes. Further studies are needed to evaluate the
adequacy of CAPS criteria for critically ill patients with
antiphospholipid syndrome and appropriate manage-
ment [29].
How to recognize an autoimmune disease
in critically ill patients
Disease flare-ups account for one-third of ICU admis-
sions [5, 6], either due to new organ failure development
in the context of established autoimmune disorder, or
the inaugural manifestations of new one (supplementary
e-Table 2) [30].
Clinical signs suggesting severe autoimmune disease
Patients with autoimmune disease flare-ups usually pre-
sent with acute respiratory failure, acute kidney injury,
neurological disorders, or cardiovascular complications
[2, 3, 5, 6, 30, 31], and a history of nonspecific symp-
toms lasting for several weeks or months (fatigue, fever,
Table 1 Important clinical investigations to consider during the evaluation of critically ill patients with suspected auto‑
immune disease
Tests
Routine laboratory tests
Complete blood count
Renal function tests
Inflammatory biomarkers
Muscle enzymes
Coagulation tests
Liver function tests
Exams guided by the clinical syndrome
Main findings
• Anaemia:
◦ Inflammation
◦ Hemolysis: frequent in SLE
  -Peripheral blood smear to look for schistocytes (TMA: TTP (sometimes associated with Lupus or mixed
connective tissue), scleroderma renal crisis, CAPS)
  -Coombs test (direct antiglobulin testing) to rule out AIHA (frequent in Lupus)
• Thrombocytopenia:
◦ Alone: ITP (frequent in SLE), CAPS (primitive or secondary)
◦ Associated with anemia: TMA, Evans’ syndrome (AIHA)
• Leukopenia: frequent in SLE (lymphopenia), RA
• Hyperleukocytosis: vasculitis, Still’s disease
• Pancytopenia: bone marrow aspiration (± biopsy):
◦ Macrophagic Activation syndrome (Lupus, Still’s disease, Juvenile chronic arthritis)
◦ Bone marrow necrosis (APS, SLE)
• First line:
◦ Blood pressure, creatinine, urea
◦ Urine dipstick test (Proteinuria, hematuria)
• If abnormalities: Kidney Syndrome diagnosis
◦ Urine sediment (microscopic hematuria, red cell casts, leukocyturia)
◦ Proteinuria
◦ Renal ultrasound (with Doppler)
• CRP: marked elevation in vasculitis and most diseases flare-up. In SLE, usually low except in infection and
serositis
• Procalcitonin: limited value, could be useful to detect infection
• Ferritin: high level in hemophagocytic syndrome, sometimes associated with low glycosylated ferritin
(Still’s disease)
• Creatine kinase, AST, LDH
• Very often marked elevation in:
◦ Inflammatory myopathies (polymyositis-dermatomyositis)
◦ Vasculitis, SLE
• Dilute Russell’s viper venom time, activated partial thromboplastin time: prolongation in the presence of
autoantibodies against clotting factors, Lupus anticoagulant, hypoprothrombinemia syndrome
◦ APS, SLE
• AST, ALT, ALP, GGT: low specificity, elevation in various disorders
◦ Autoimmune hepatitis (primitive or not)
◦ Lupus (30%), scleroderma (primary biliary cholangitis), Sjögren
◦ Vasculitis
• Lumbar puncture:
◦ Pleocytosis (lymphocytes: SLE, sarcoidosis, Sjögren, autoimmune encephalitis, multiple sclerosis,
NMOSD; neutrophils/mixed: Behçet disease)
◦ Elevated protein levels and normal white blood cell count (acute and chronic autoimmune polyneu-
ropathies, e.g. Guillain-Barré syndrome)
◦ Intrathecal immunoglobulin synthesis or oligoclonal bands (autoimmune encephalitis, multiple sclero-
sis, NMOSD, autoimmune neuropathies)
• Nerve conduction studies/electromyography (autoimmune polyneuropathies, myasthenia gravis, myosi-
tis, AAV)
• Lung bronchoscopy with bronchoalveolar lavage:
◦ DAH (macroscopic aspect, Gold score)
◦ Alveolitis:
   -Lymphocytic (> 15% lymphocytes): sarcoidosis, CTD-ILD, hypersensitivity pneumonitis
   -Neutrophilic (> 3% neutrophils): CTD-ILD, infections
   -Eosinophilic alveolitis (> 1% eosinophils): EGPA, eosinophilic pneumonia, drug-induced pneumonia
◦ Infection
• Imaging:
◦ Chest CT scan (DAH, ILD)
◦ Abdominal CT scan with angiography (gastrointestinal tract vasculitis, microaneurysms (PAN), renal
artery stenosis, occlusion or aneurysm (Takayasu disease, GCA))
◦ Brain: MRI ± angiography (vasculitis)
◦ PET-CT (paraneoplastic syndromes, vasculitis)
Table 1 (continued)
Tests Main findings
Immunological work-up
Complement tests • C3, C4, CH50:
◦ C3 N, low C4/CH50: SLE, cryoglobulinemia
◦ C3 low, low C4/CH50: SLE, RA associated vasculitis, cryoglobulinemia (type II), post-streptococcal
glomerulonephritis
◦ Low CH50, C3/C4 N: C1q deficit (SLE)
◦ Low CH50/C3, C4 N: membranoproliferative or post-infectious glomerulonephritis
Cryoglobulinemia • Cryoglobulinaemic vasculitis (sometimes associated with C-hepatitis)
Autoantibodies
Connective tissue diseases • First line (screening): Antinuclear antibodies (positivity if ≥ 1/100)
• Specificity:
◦ ds-DNA: SLE
◦ ENA:
   -Sm: SLE
   -Ro (SSA), SSB: Sjögren, SLE
   -RNP: mixed tissue connectivitis
   -Centromere: localized scleroderma
   -Scl‑70, anti-Anti‑RNA polymerase III: diffuse scleroderma
• Myositis-specific antibodies:
◦ Ro-52/SSA/SSB/Ku/U1RNP/ PM-Scl/ mitochondrial: dermato-polymyositis
◦ HMGCoA-R/anti-SAE: dermatomyositis
◦ J01, PL7, PL12, EJ, OJ, KS: antisynthetase syndrome
◦ SRP: 5% polymyositis (black women +  + , ILD, steroids resistance)
◦ TIF1γ/α/ anti-NXP2: paraneoplastic dermato-polymyositis +  +
◦ MDA5: dermatomyositis with severe ILD
◦ Mi2: dermatomyositis, high steroids sensitivity
• Tissue-specific expressed Antibodies: Type 1 diabetes (Islet antigen (IA2), Glutamic Acid Decarboxylase
Autoantibodies (GAD)), adrenal insufficiency (21-hydroxylase), Autoimmune thyroid diseases (Anti-TSH
receptor antibodies, thyroid peroxidase antibody, Thyroglobulin antibody)
• Anti-CCP: RA
Vasculitis • ANCA:
◦ c-ANCA (PR3): GPA > MPA > PAN > EGPA
◦ p-ANCA (MPO): MPA > PAN > GPA > EGPA
•anti-GBM: Goodpasture syndrome
Neurological autoimmune diseases (not as • Encephalitis-specificantibodies:
part of a systemic autoimmune disorder) ◦ Amphiphysin, PNMA2 (Ma2/Ta), Ri, Yo, Hu, CV2 (CRMP5), Tr (DNER): autoimmune encephalitis associated
with onconeuronal antibodies (mostly paraneoplastic)
◦ NMDA-R, LGI1, CASPR2, ­GABAb-R, ­GABAa-R AMPA-R1/2 (GluA1/GluA2), mGluR5, Glycin-R, Dopamin-
2-R, DPPX, Myelin, GAD65, GFAP: autoimmune encephalitis with antibodies against neuroglial surface
epitopes
◦ Aquaporin-4, MOG: NMOSD, MOGAD
• Antibodies associated with autoimmune peripheral neuropathies:
◦ GM1, GM2, GM3, GD1a, GD1b, GT1b, GQ1b, MAG, neurofascin (NF-155/NF-186), Contactin1
• Antibodies associated with dysfunction of the neuromuscular junction:
◦ AChR, Titin, MuSK, LRP4, Agrin, Ryanodin-Receptor (myasthenia gravis)
◦ VGCC (Lambert-Eaton myasthenic syndrome)
Antiphospholipid syndrome • Should be assessed by screening for:
◦ Lupus anticoagulant (prolonged Dilute Russell’s viper venom time, activated partial thromboplastin
time)
◦ Anticardiolipin and anti-β2-glycoprotein I antibodies (IgG and IgM)
Involved organs biopsy
• Kidney (if glomerulonephritis, nephrotic syndrome)
• Skin (Leukocytoclastic vasculitis, IgA vasculitis, AAV, SLE, sarcoidosis, etc.)
• Salivary gland biopsy (Sjögren, Sarcoidosis, amyloidosis)
• Muscle (dermato-polymyositis)
• Others (less common): Lung, heart, brain, sural nerve
AChR Acetylcholine Receptor, AIHA autoimmune hemolytic anemia, APS antiphospholipid syndrome, AAV ANCA-associated vasculitis, ALT alanine aminotransferase,
ALP alkaline phosphatase, AST aspartate aminotransferase, CAPS Catastrophic antiphospholipid syndrome, CRP C-reactive protein, CTD-ILD connective tissue
associated interstitial lung disease, DAH diffuse alveolar hemorrhage, ds-DNA Anti-double stranded DNA, EGPA Eosinophilic Granulomatosis with Polyangiitis, ENA
Anti-extractable nuclear antigen, ENT Ear, Nose, and Throat, GCA​ giant cell arteritis, GGT​ gamma-glutamyl transferase, GPA Granulomatosis with Polyangiitis, IgA
IgA-associated vasculitis, ILD interstitial associated disease, ITP immune thrombocytopenia, MOGAD MOG-antibody associated diseases, NMOSD neuromyelitis
optica spectrum disorder, PAN polyarteritis nodosa, PET-CT Positron Emission Tomography and Computed Tomography, RA rheumatologic arthritis, scleroderma
systemic scleroderma, Sjögren Sjogren’s syndrome, SLE systemic lupus erythematosus, SRC scleroderma renal crisis, TMA thrombotic microangiopathy, TTP thrombotic
thrombocytopenic purpura, VGCC​ Anti-Voltage Gated Calcium Channel
headache, unintended weight loss, polymyalgia, or pol-
yarthralgia) (Fig. 1). Rarely, acute cytopenia (mainly ane-
mia and thrombocytopenia) can occur [9, 10].
Systemic lupus erythematosus and other connective tissue
diseases
Some diseases, such as SLE, can virtually affect any
organ, while others have limited involvement [33]. ARF
is the leading cause of ICU admission among patients
with connective tissue diseases [2, 3]. Rapidly progres-
sive interstitial lung disease is highly suggestive of such
diseases, while diffuse alveolar hemorrhage remains rare
[34]. Respiratory muscle weakness frequently compli-
cates dermato-polymyositis and should be distinguished
from the shrinking-lung syndrome in patients with SLE
(small lung fields and elevation of the diaphragm) [35,
36]. Renal involvement is another prominent feature
(30%) with three suggestive syndromes: glomerulone-
phritis (SLE, rheumatoid arthritis), vessels thrombosis
(antiphospholipid syndrome), and thrombotic micro-
angiopathy (scleroderma, antiphospholipid syndrome,
SLE, thrombotic thrombocytopenic purpura) [37]. Other
life-threatening complications can be prominent, such as
cardiogenic shock complicating myocarditis, or various
central nervous system disorders, which occur mainly in
patients with SLE [3].
Systemic vasculitis
Systemic vasculitides encompass various diseases charac-
terized by blood-vessel inflammation. Clinical presenta-
tion varies depending on the size of the vessels involved,
including unexplained ischemia and multisystem disease
(Fig. 2). Small-vessel vasculitides are the most common
forms, divided into ANCA-associated vasculitis and
immune-complex mediated vasculitis (IgA-vasculitis,
anti-GBM disease, cryoglobulinemia). Most patients pre-
sent with ARF [6, 7, 15], often related to alveolar hem-
orrhage (sometimes combined with rapidly progressive
glomerulonephritis in the pulmonary-renal syndrome)
[13], but ILDs can occur [39]. Pulmonary nodules, exca-
vated in more than 50%, are highly suggestive of granu-
lomatosis with polyangiitis (GPA) and large airway
inflammation or stenosis. Severe asthma (associated with
transient and migratory lung infiltrates) is present in 90%
of patients with eosinophilic granulomatosis with poly-
angiitis (EGPA) [40, 41].
Renal involvement is frequent, affecting ∼80%
of patients with ANCA-vasculitis. Besides

Fig. 1 Clinical presentation suggestive of autoimmune diseases: connective tissue diseases. APS antiphospholipid syndrome, DAH diffuse
alveolar hemorrhage, ITP immune thrombocytopenia, PAN polyarteritis nodosa, RA rheumatologic arthritis, SSc systemic scleroderma, SjS Sjogren’s
syndrome, SLE systemic lupus erythematosus, SRC scleroderma renal crisis, TMA thrombotic microangiopathy, TTP thrombotic thrombocytopenic
purpura, VTE venous thromboembolism
 Fig. 2 Clinical presentation suggestive of autoimmune diseases: systemic vasculitides. AAV ANCA-associated vasculitis, Cryo. cryoglobulinemia
vasculitis, DAH diffuse alveolar hemorrhage, EGPA Eosinophilic Granulomatosis with Polyangiitis, ENT Ear, Nose, and Throat, GCA​ giant cell arteritis,
GPA Granulomatosis with Polyangiitis, IgA IgA-associated vasculitis, PAN polyarteritis nodosa, RA rheumatologic arthritis

glomerulonephritis, renovascular hypertension is com-
mon in polyarteritis nodosa and Takayasu’s arteritis,
sometimes associated with renal infarction and vascular
occlusion [42].
Due to the nature of the disease, cardiovascular com-
plications are frequent (see below). Gastrointestinal
complications (mesenteric ischemia, perforation, bloody
diarrhea, ulcers) are common in IgA-vasculitis (∼90%),
polyarteritis nodosa (∼20%), and ANCA-vasculitis
(∼30%) and should be suspected in any patient with
systemic vasculitis and abdominal pain. Neurological
involvement such as cerebral ischemia or mononeuri-
tis multiplex in polyarteritis nodosa (∼50–80% of cases)
and ANCA-vasculitis, or meningitis and parenchymal
brain lesions in Behçet disease can also occur as primary
manifestations.
Others systemic diseases
Sarcoidosis is rarely diagnosed in ICU. However, besides
exacerbation of lung disease, some extrapulmonary man-
ifestations can be life-threatening, particularly cardiac
location (2%) with atrioventricular blocks, ventricular
tachycardia, and heart failure. Neuro-sarcoidosis is a rare
feature, associated in 90% of cases with lung involvement,
affecting any part of the nervous system [43].
Adult-onset Still’s disease is a rare systemic inflamma-
tory disorder, classically presenting with high spiking
fever, evanescent skin rash, and arthralgia. It should be
considered as an alternative diagnosis in patients with
unexplained myocarditis or severe macrophage activa-
tion syndrome and uncommonly high polymorphonu-
clear neutrophil count.
Diagnosis work‑up
A detailed medical history and examination are the most
important steps for diagnosis. Epidemiological consid-
erations are important: some diseases are more prevalent
in given ethnical groups (SLE/scleroderma in non-Cau-
casian people; Behçet disease in patients from countries
referred to as “Silk Road countries”) or sex/age groups
(connective tissue diseases typically affect women before
40 years; ANCA-vasculitis occur more commonly in men
after 50 years).
Some clinical symptoms are suggestive of autoimmune
disease: severe sinusitis (GPA), myalgia (myositis), pol-
yarthritis, pleuro-pericarditis, or mononeuritis (ANCA-
vasculitis). Examination of the skin and eyes may be very
informative (Figs. 3, 4, 5). Mouth ulcers, photosensitivity,
or rash would suggest SLE. Some cutaneous lesions must
be recognized: livedo reticularis (SLE, antiphospholipid
Fig. 3 Overview of selected eye features that can help with the diagnosis of systemic autoimmune disease. GPA Granulomatosis with polyangiitis,
RA rheumatologic arthritis, SjS Sjogren’s syndrome, SLE systemic lupus erythematosus

Fig. 4 Overview of selected hands features that can help with the diagnosis of systemic autoimmune disease. APS antiphospholipid syndrome, GPA
Granulomatosis with Polyangiitis, RA rheumatologic arthritis, SjS Sjogren’s syndrome, SLE systemic lupus erythematosus
 Fig. 5 Selected clinical signs suggestive of autoimmune diseases. A Gottron’s papules (dermatopolymyositis); B Mechanical hands (antisynthetase
syndrome); C Digital necrosis (antiphospholipid syndrome); D Scleroderma hand; E Blue toe syndrome (cholesterol crystal embolization); F Livedo
racemosa (antiphospholipid syndrome, vasculitis); G Palpable purpura (vasculitis); H Erythema nodosum (sarcoidosis, Behçet’s disease); I Oral ulcer
(systemic lupus erythematosus); J Cutaneous rash in a patient with Systemic lupus erythematosus; K Skin rash in a patient with Still’s disease; L
Scleritis (granulomatosis with polyangiitis). Personal collection, A. Mirouse, JR Lavillegrand and Dumas

syndrome, vasculitis), tender nodules, or palpable pur-
pura (small vessel vasculitis).
Although usually nonspecific, routine blood tests and
urinalysis (proteinuria, hematuria, red cell casts) are
important to suspect autoimmune disease or assess the
extent (Table 1).
A detailed work-up – guided by the clinical syn-
drome—is then needed to confirm the diagnosis and
exclude competing etiologies (Table 2 and Fig. 6). For
most diseases, international societies have provided diag-
nosis criteria and classifications. Although they can be
useful, they have been developed for epidemiological and
research purposes and may fail to identify patients with
autoimmune diseases at the bedside [29]. Additionally, it
is not straightforward to apply them directly to the criti-
cally ill patient seen in the ICU.
Detection of antibodies is critical (Table 1 and supple-
mentary e-Table 3), but often not enough to confirm the
diagnosis of autoimmune diseases. Auto-antibodies can
be detected in the absence of any autoimmune disease
(rheumatoid factor in older people, antiphospholipid in
chronic infections, or antinuclear antibodies and anti-
histone antibodies in drug-induced lupus) [44], while
their absence does not rule out all systemic diseases
(e.g., large vessel or IgA-vasculitis, polyarteritis nodosa,
Behçet disease, sarcoidosis).
Obtaining histological positive samples showing auto-
immune organ involvement (immune complex depos-
its, vasculitis, granulomatous or inflammatory infiltrate)
could assist in establishing the diagnosis and/or evalu-
ating the prognosis [45, 46]. Common sites for biopsy
include skin, kidney, muscle, sural nerve, temporal artery,
or salivary gland biopsy (Table 1) [47].
Management of critically ill patients
with autoimmune diseases flare‑up
General principles
There is scarce evidence-based management of criti-
cally ill patients with autoimmune disease and practices
may vary across centers. Also, prompt ICU admission
Table 2 Commonly used immunosuppressant therapies in autoimmune diseases and their main side effects
Treatment Main indications Useful Side-effects
for severe
diseases

Steroids SLE, CAPS, CTD-ILD, vasculitis, myositis, sarcoidosis, severe + Pulse: cardiac arrhythmia, hypertension, delirium, heart failure
CTD, RA, ITP, AIHA, TTP, autoimmune encephalitis, myasthe-
nia gravis, multiple sclerosis, NMOSD, chronic autoimmune Infections:
polyneuropathies Bacterial, Tuberculosis
Fungal: Pneumocystis pneumonia, invasive aspergillosis
Indicative dose: Viral: Herpes viridae, B hepatitis
Pulse: 250 to 1000 mg IV for 2–3 days, then 0.5 to 1 mg/kg/
day Strongyloidiasis

General: Glycemic disorders, hypertension, hypokalemia, adre-

nal insufficiency, myopathy, osteoporosis, GI bleeding
Cyclophosphamide SLE, vasculitis, CTD-ILD + General: hemorrhagic cystitis, bone marrow toxicity (neutro-
penia + +)
Indicative dose:
- Eurolupus protocol: 500 mg /2 weeks, 3 months Infections:
- Vasculitis: 500 mg (Day1, Day15, Day 29) then every 3 weeks Bacterial, Tuberculosis
Fungal: Pneumocystis pneumonia, invasive aspergillosis
Viral: Herpes viridae
IV- Immunoglobulins Guillain-Barré syndrome, myasthenia gravis, chronic autoim- + General: Acute kidney injury, aseptic meningitis, hypervolemia
mune polyneuropathies, NMOSD, severe, dermato-poly-
myositis, CAPS, severe ITP/AIHA, autoimmune encephalitis,
Kawasaki disease
Plasma exchanges anti-GBM, CAPS, TTP, SLE, multiple sclerosis, NMOSD, Guillain- + Infections (bacterial)
Barré syndrome, myasthenia gravis, chronic autoimmune Bleeding disorders
polyneuropathies, autoimmune encephalitis Hypocalcemia
AAV: unclear benefits, maybe for the most severe patients
Removal of some disease markers such as autoantibodies (no
longer suitable for monitoring)
Rituximab AAV, severe ITP/AIHA, RA, TTP, SLE, autoimmune encephalitis, + Hypersensitivity reaction
NMOSD, multiple sclerosis, myasthenia gravis, chronic Hypogammaglobulinemia
autoimmune polyneuropathies
Infections:
Indicative dose: Bacterial
4 IV doses of 375 mg/m2 or 2 IV doses of 1000 mg Pneumocystis pneumonia
JC virus
Azathioprine/ Mycophenolate Mofetil SLE, AAV, RA, IBD, Myasthenia gravis, NMOSD + General: nausea, vomiting, hepatotoxicity
Lupus
Indicative dose: nephritis Infections: bacterial, Pneumocystis pneumonia
Mycophenolate Mofetil (SLE): 1.5 g BID, 3 months (induction
regimen) Cancer
AAV
(unclear)
Table 2 (continued)
Treatment Main indications Useful Side-effects
for severe
diseases

cDMARDs
Methotrexate, Leflunomide RA, vasculitis, sarcoidosis – General: nausea, bone marrow toxicity, hepatotoxicity
Infections: unclear (Herpes viridae)

Drug induced pneumonia

Antimalarial drugs (hydroxychloroquine) SLE, RA, sarcoidosis – General: nausea, ocular complications
anti-TNF biologics IBD, RA and inflammatory rheumatisms, sarcoidosis, Behçet – Infections:
Infliximab, Etanercept, disease
Adalimumab,Golimumab, Bacterial
Tuberculosis +  + (and other mycobacteria)
Opportunistic: uncommon
Other biological drugs
Anti IL-6 (Tocilizumab, Sarilumab, Satralizumab) RA, GCA, Takayasu’s disease, Still’s disease, Castleman, + Hypersensitivity reaction
NMOSD
Infections: uncommon

CRP suppression for about 14 days

Anti IL-1 (Anakinra) RA, Still’s disease + Hypersensitivity reaction

Infections: bacterial (tuberculosis?)

CRP suppression for about 14 days

Anti-IL-5 (Mepolizumab) EGPA – Hypersensitivity reaction
Anti IL-17 (Secukinumab) RA and inflammatory rheumatisms – Hypersensitivity reaction

Infections: opportunistic (IFI mainly candidosis, Herpes viridae)

B Cell Growth Factor (BlyS) SLE – Hypersensitivity reaction
(Belimumab)
Infections: bacterial
CTLA-4/CD28 (Abatactept) Inflammatory rheumatisms – Hypersensitivity reaction

Infections: bacterial (uncommon)

Complement inhibitors (Eculizumab, Ravulizumab) Myasthenia gravis, NMOSD + Infections: bacterial (meningococcus meningitis)

General: headaches, flu-like symptoms

 and close collaboration with specialists are warranted.

IFI invasive fungal infection, IL interleukin, ITP immune thrombocytopenia, IV intravenous route, JC virus John Cunningham virus, NMOSD Neuromyelitis optica spectrum disorders, RA rheumatologic arthritis, Scleroderma
Immunosuppressive therapy is the cornerstone of treat-

connective tissue disease, CTD-ILD connective tissue associated interstitial lung disease, EGPA Eosinophilic Granulomatosis with Polyangiitis, GCA​giant cell arteritis, GI gastrointestinal, IBD inflammatory bowel disease,
ment, with some disease specificities (Table 2). Remis-

AIHA autoimmune hemolytic anemia, AAV ANCA-associated vasculitis, anti-GBM anti glomerular basement membrane, BID twice a day, CAPS Catastrophic antiphospholipid syndrome, CRP C-reactive protein, CTD
sion-induction regimens of life-threatening connective
tissue diseases or vasculitides, commonly associate
high-dose glucocorticoids (pulse methylprednisolone
of 250–500 mg/day followed by a taper over time)
with cytotoxic agents. Importantly, reducing the time
to treatment initiation is key to improving functional
status and reducing mortality [30, 38]. Diagnostic
Hypogammaglobulinemia

Hypogammaglobulinemia

errancy and inability to distinguish between infection

Hypersensitivity reaction

Peripheral neuropathy

and flare are the main sources of delayed therapy [48].

Infections: bacterial

Infections: bacterial

Because no reliable markers are available to differenti-

systemic scleroderma, Sjögren Sjogren’s syndrome Lupus: systemic lupus erythematosus, SLE systemic lupus herythematosus, TTP thrombotic thrombocytopenic purpura
ate between the two, most patients are treated for both
Side-effects

conditions while awaiting the results of investigations

Cytopenia

[49].
In ANCA-vasculitis, the Five Factor Score (e-Table 4) is
an easy-to-use tool that can help to guide urgent treat-
for severe

ment decision [50]. In that setting, cyclophosphamide

diseases
Useful

is the most used cytotoxic agent. Intravenous immuno-

globulin may be discussed in critically ill patients with
+

concurrent severe infection, and plasmapheresis as an

Plasma cell depleting agents (bortezomib, daratumumab) Treatment-refractory courses of antibody-mediated autoim-

adjunctive therapy to immunosuppression in patients

with rapidly progressive glomerulonephritis or fulminant
pulmonary hemorrhage, although its benefit in terms of
Please note that the dose of immunosuppressive therapy may need to be adjusted in case of kidney injury or liver failure

mortality is uncertain [51]. In giant cell arteritis, gluco-

corticoids should be initiated as soon as the diagnosis is
suspected, especially if neurologic or ophthalmologic
symptoms are present [52].
For SLE with life-threatening organ involvement, cor-
mune encephalitis, SLE, AAV

ticosteroids with other agents such as cyclophospha-

mide or mycophenolate mofetil should be considered.
Although hydroxychloroquine is the mainstay of lupus
Main indications

Myasthenia gravis

treatment, its usefulness in the acute setting is unclear

[53]. In severe myositis, intravenous immunoglobu-
lin should be started in addition to steroids. Treatment
of autoimmune cytopenia usually requires in addition
to corticosteroids, intravenous immunoglobulin for
2–5 days, and/or anti-CD20 antibodies (a B-cell surface
antigen) such as rituximab. In refractory cases, urgent
splenectomy may be considered [53]. CAPS requires
Neonatal Fc receptor antagonist (Efgartigimod)

treatment with anticoagulation to reduce associated

morbidity and mortality, whatever platelet counts [54].
Additionally, high-dose methylprednisolone along with
plasmapheresis should also be initiated with or without
intravenous immunoglobulin. Rituximab or eculizumab
could be of interest [55].
Table 2 (continued)

Maintenance therapy is usually required in patients to

avoid relapse and spare steroids, mainly methotrexate,
azathioprine, and mycophenolate [57]. However, these
treatments are an important source of morbidity and
Treatment

mortality. Also, targeting key mechanisms involved in the

pathogenesis of connective tissue diseases or vasculitides
 Fig. 6 Proposed diagnosis workup for suspected autoimmune disease in the ICU AID Auto-immune disease, ANA antinuclear antibodies, anti-GBM
Anti-glomerular basement membrane, ANCA Anti-neutrophil cytoplasmic for antibodies, AKI acute kidney injury, BAL bronchoalveolar lavage, CK
creatine kinase, C3-C4 complement C3 and C4 protein, anti-CCP cyclic citrullinated peptide antibodies, ENA Anti-extractable nuclear antigen, Hb
hemoglobin, HBV Hepatitis B virus, HCV Hepatitis C virus, HIV Human immunodeficiency virus, IHA intraalveolar hemorrhage, LDH lactate dehydroge-
nase, RF rheumatoid factor, WBC white blood cells count

is now a major field of research with important therapeu-
tic advances (Table 2), but their right place in critically ill
patients is not defined.
Treatment‑related complications
Intensivists should be aware of the treatment-related
complications, which range from complications of old
drugs, such as pulmonary toxicity of methotrexate and
adrenal crisis following the sudden suspension of ster-
oids, to complications of new drugs (Table 2) [56].
Patients are at risk of specific infections (Table 2). Bac-
terial infections (especially pneumonia or bloodstream
infections including Listeria) are the most encountered
complications, mainly during the first year after the
diagnosis or relapse [65, 66]. Tuberculosis reactivation
and nontuberculous mycobacteria infection are frequent,
especially in patients who received anti-TNF drugs [58].
Steroids (> 15 mg/day), cyclophosphamide, or rituxi-
mab increased the risk of Pneumocystis pneumonia (in
particular in ANCA-vasculitis and myositis) [59] while
eculizumab is associated with invasive meningococcal
infection [60, 61]. Patients treated with steroids, cyto-
toxic or immunomodulatory drugs have also an increased
risk of varicella-zoster virus reactivation, including her-
pes zoster (∼1.5 fold higher than healthy subjects) or dis-
seminated infection (pneumonia, encephalitis, hepatitis,
and retinitis), with high mortality rate (> 10%) [62]. Hep-
atitis B virus reactivation may occur as early as 2 weeks
from immunosuppressive therapy initiation, causing ful-
minant hepatitis and should be screened systematically
before treatment initiation. Prophylaxis is recommended
in high-risk patients [63].
Strongyloidiasis is a rare intestinal parasitic infection,
with increasing importance even in patients from non-
endemic regions (tropical and subtropical areas) [64].
Two severe presentations can occur: hyperinfection syn-
drome (i.e. accelerated autoinfection process affecting the
gastrointestinal tract, lungs, and skin) and disseminated
strongyloidiasis (spread of larvae to organs and tissues
beyond the autoinfection cycle) [65]. Due to high case
fatality, it is advisable to offer prophylaxis empirically,
even without laboratory-confirmed previous contact [66,
67]. Ivermectin is the drug of choice for prophylaxis and
treatment of severe forms. Other opportunistic infec-
tions (Nocardia sp., Histoplasmosis, Aspergillosis, cyto-
megalovirus (CMV) reactivation) are less common than
in solid organ or bone marrow recipients but can occur,
especially in patients exposed to long-term steroids or
multiple immunosuppressive regimens [68, 69].
Particular conditions
Neurological autoimmune emergencies in patients
with autoimmune diseases
Neurological autoimmune disorders within the ICU
setting require a high degree of neurological expertise
regarding their time-consuming diagnostics and complex
treatment strategies. The clinical spectrum is variable and
depends on the location and extent of the lesions. Defi-
cits can evolve very quickly, resulting in life-threatening
emergencies. The most common symptoms are altered
level of consciousness (e.g., delirium, coma), seizures/
status epilepticus, tetraparesis involving the respiratory
muscles with respiratory failure, dysphagia and rarely
autonomic dysregulation or raised intracranial pressure
[70].
Importantly, we should distinguish between primary
neurological autoimmune diseases (mainly myasthenia
gravis, autoimmune neuritis or encephalitis) and sys-
temic autoimmune diseases involving the nervous system
(Fig. 7) [71]. Three diseases frequently involve periph-
eral nervous system: Sjögren’s syndrome (∼2–60%,
distal sensory or chronic inflammatory demyelinating
polyneuropathy, axonal sensorimotor neuropathy), sys-
temic vasculitis (multiple mononeuropathy, ∼20–70% in
ANCA-vasculitis and ∼70% in polyarteritis nodosa) and
sarcoidosis (∼2–6%, including multiple mononeuropa-
thies, radiculoplexus /polyradiculoneuropathies, cranial
neuropathies) [72].
All central nervous system structures may be affected
in SLE (∼40% of patients), manifesting as demyelinating
disease (mimicking multiple sclerosis or neuromyelitis
optica), pachymeningitis, seizures but also psychosis or
encephalopathy. Sjögren’s syndrome could also manifest
in ∼6% of patients with multiple sclerosis-like lesions in
the brain, transverse myelitis, or meningitis, sometimes
associated with concurrent neuromyelitis optica spec-
trum disorder [73, 74].
In ANCA-vasculitis, inflammation of small and
medium-sized cerebral vessels and granuloma formation
may cause brain injury, responsible for pachymeningi-
tis, parenchymal mass lesions, ischemic or hemorrhagic
stroke. Neurobehcet occurs in 5–10% of cases with
parenchymal (meningoencephalitis) and non-parenchy-
mal (vascular, mainly central venous sinus thrombosis)
subtypes. Although less frequent than peripheral neu-
ropathy, sarcoidosis may present with meningoencephali-
tis, seizures or transverse myelitis, as well as IgG4-related
disease.
Most of the patients respond to corticosteroids, usually
associated with immunosuppressive agents in severe dis-
eases such as cyclophosphamide (ANCA-vasculitis, SLE,
sarcoidosis), rituximab (ANCA-vasculitis) or methotrex-
ate (sarcoidosis). TNFalpha antagonists might be useful
in Neurobehcet and sarcoidosis. Last, plasmapheresis or
immunoglobulins should be considered in severe presen-
tation [75].
Careful exclusion of other differential diagnoses is
mandatory (e.g., vascular or infectious diseases, met-
abolic/hereditary or neurodegenerative disorders,
tumors). The respective diagnostic work-up is depend-
ent on the affected anatomical structures: central nerv-
ous system involvement requires a cerebral and/or spinal
magnetic resonance imaging (MRI), suspected vasculi-
tis a digital subtraction angiography [76]. For peripheral
nervous system disorders, electromyography detects
inflammatory neuropathies, dysfunction of the neuro-
muscular junction, or myopathies. An additional plexus
MRI can be useful for some types of autoimmune neu-
ritis [71]. Further diagnostics involve a lumbar puncture
with cerebrospinal fluid analysis and an extensive panel
 Fig. 7 Overview of main autoimmune neurological disorders
testing of different autoantibodies, rarely an organ biopsy
of the involved tissue (Table 2) [76].
Cardiovascular emergencies in patients with systemic
diseases
Cardiovascular manifestations are the hallmark of sev-
eral autoimmune diseases (Fig. 1). Usually, two patterns
should be recognized: vascular occlusions leading to
infarcts and ischemia, or cardiac failure manifesting as
myocarditis, coronary aneurysms, valvulitis, conduction
disorders, pericarditis, and tamponade.
In connective tissue diseases, pericardial and myo-
cardial involvement is common (∼50%). Pericar-
ditis is the most common cardiac manifestation of
SLE (∼25%) [77]. Myocarditis prevalence (∼9%) var-
ies across diseases, mainly seen in SLE and myositis
(6–75%), sometimes leading to cardiogenic shock [78].
In scleroderma, myocardial fibrosis can occur, result-
ing in cardiac failure (with or without preserved ejec-
tion fraction), conduction defects, or arrhythmias.
Severe valvular diseases remain rare. Libman-Sacks
endocarditis (verrucous growth occurring on the valve
leaflets, papillary muscles, and endocardium) has been
reported in 10% of patients with SLE, commonly on
the mitral valve [77]. Antiphospholipid syndrome can
affect any part of the vascular system due to throm-
bosis and immune-mediated injury. In particular,
thrombosis in unusual sites (renal vein, Budd Chiari
syndrome) and non-atherosclerotic thrombosis (acute
coronary syndrome or stroke) are highly suggestive of
the diagnosis. Pulmonary hypertension is usually seen
in scleroderma and APS [3] with poor prognosis sig-
nificance [79].
In patients with vasculitides, cardiac failure is a major
source of death, linked to myocarditis (∼2%, EGPA,
GPA) or coronary diseases (giant-cell arteritis, Kawa-
saki disease, polyarteritis nodosa). Severe aortitis can be
encountered in Takayasu disease and giant-cell arteritis,
responsible for aortic dissection, severe aortic valvular
regurgitation, and end-organ ischemia including stroke.
As in antiphospholipid syndrome, venous pathology
and thrombotic complications are hallmarks of Behçet
disease. Cardiac involvement (including pericarditis,
endocarditis with aortic valve involvement, intracardiac
thrombosis, endocardial fibroelastosis, and myocardial
aneurysm) has been reported in up to 6% of patients with
Behçet disease, with one-third of these patients having it
at baseline [80].
 Importantly, cardiovascular diseases are the main cause
of morbidity and mortality in patients with autoimmune
diseases. In a cohort of 446, 449 individuals with autoim-
mune diseases and 2,102,830 matched controls, the inci-
dence rate of cardiovascular disease was 23.3 events per
1000 patient-years, significantly higher than in controls
(hazard ratio:1.56 [95% confidence interval (CI) 1.52–
1.59]) [81]. Patients with scleroderma and SLE had the
highest cardiovascular risk. Vascular abnormalities with
endothelial dysfunction, chronic inflammation as well
as medications (glucocorticoids) could explain acceler-
ated atherosclerosis and such increased risk. Also, clini-
cians should have a high index of suspicion when seeing a
patient with known autoimmune disease and cardiovas-
cular manifestations.
Prognosis of critically ill patients with autoimmune
diseases
Data regarding the prognosis factors of critically ill
patients with autoimmune diseases are scarce and mostly
based on retrospective studies (supplementary e-Table 2).
Patients usually suffer from multiple organ dysfunctions
and require invasive mechanical ventilation in ∼60%,
renal replacement therapy in ∼30%, and vasopressor in
∼50%, with variation according to reasons for admission
and underlying disease. Outcomes remain unclear, with
ICU mortality rates ranging from 5% to 60%. Reported
prognosis factors are mainly severity scores, number
of organ failures, and patient frailty (supplementary
e-Fig. 1). Infections are also commonly associated with
higher mortality as well as delayed initiation of specific
treatment in case of flare-ups [6, 14, 31, 32]. Myositis and
scleroderma are often associated with poor outcomes, in
particular in the case of advanced lung diseases and pul-
monary arterial hypertension [18, 20, 82].
Unanswered questions and research agenda
Only a few studies, mostly retrospective, aimed at assess-
ing the prevalence of autoimmune disorders and manifes-
tations in ICU patients. Hence, to detect these relatively
rare diseases, there is a need to describe the true clinical
picture in critically ill patients to help guide decisions in
the diagnostic work-up. For example, ARDS lacking com-
mon risk factors of Berlin Consensus (so-called ARDS-
mimickers) may represent up to 10% of ARDS, of whom
up to one-third are related to connective tissue disease or
vasculitis [83, 84]. The only multicenter study in this field
is an ancillary study, lacking a standardized diagnostic
work-up which may have underestimated the prevalence
of autoimmune diseases [83]. Similarly, data regarding
the prevalence of renal involvement by auto-immune
diseases and vasculitis among an unselected popula-
tion of critically ill patients with acute kidney injury are
surprisingly scarce [85, 86], which might reflect the rar-
ity of these syndromes [87]. Nonetheless, large, prospec-
tive, multicenter studies, aiming to identify patients with
a high probability of having autoimmune diseases are
needed to assess more precisely the prevalence of these
disorders, but also to allow identification of red-flag
symptoms and decrease heterogeneity among centers in
both diagnosis and management.
Despite major advancements in autoimmune diseases
treatment, data dedicated to critically ill patients are lim-
ited. Recent changes in ANCA-vasculitis management
may illustrate this point. The recent PEXIVAS trial raised
much attention suggesting that plasma exchange had
little benefit in both overall and renal survival and that
a reduced-dose regimen of glucocorticoids had similar
efficacy with fewer side effects than a standard-dose regi-
men [51]. Although interesting, conclusions which may
be drawn are limited by the relative lack of severity of
included patients which may not match the population of
patients with vasculitis usually admitted to the ICU [51].
This has led to ongoing controversy regarding the exter-
nal validity of these results in the subgroup of the more
severe patients [88, 89]. Similarly, the optimal treatment
of CTD-ILD remains uncertain [90–92]. Addressing such
issues raises several challenges. First, the rarity of these
disorders along with the need for a disease-by-disease
assessment precludes any individual randomization.
Nevertheless, optimal management can be approached
with multicenter and multi-national registers, to assess
temporal change in outcome with evolving treatment
options [93]. In selected diseases, multi-arm phase II ran-
domized controlled trials might be feasible and required.
Understanding the side effects of treatments, in par-
ticular in the era of targeted therapies, is another field
of research and concern. Nearly ten years were needed
between the Food and Drug Administration approval of
rituximab (1997) and the first reported cases of pneu-
mocystis infection [94] and John Cunningham virus (JC
virus, or human polyomavirus 2) infection [95]. Multi-
plication of new therapeutic options along with multi-
ple sequential lines in specific diseases raise numerous
concerns regarding the rapid change in exposure to
risk landscape and as a consequence ability of intensiv-
ists to identify these later. There is an urgent need for a
dedicated register to allow both identification and docu-
mentation of these consequences [96]. The first step to
address these issues might be a multicenter, multinational
effort to develop long-time needed registered and, ide-
ally adjudicate on a real-time basis, potential side effects
which may be detected in patients’ management.
In conclusion, although autoimmune diseases are
rare, many conditions could lead these patients to the
ICU, with high morbidity and mortality, in particular
infections complicating immunosuppressive therapies
and diseases flare-up. Intensivists should keep a high
index of suspicion in patients admitted with several
and not fully explained organ dysfunctions. Treatment
is complex, requiring multi-disciplinary collaboration,
and includes both immunosuppressive treatment man-
agement and life-sustaining therapies.
Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1007/​s00134-​023-​07266-7.
Author details
1
Medical Intensive Care Unit, Service de Médecine Intensive‑Réanimation,
CHU Grenoble-Alpes, Université Grenoble-Alpes, INSERM, U1042‑HP2 Greno-
ble, France. 2 Intensive Care Department, Ministry of the National Guard-
Health Affairs, Riyadh, Kingdom of Saudi Arabia. 3 King Abdullah International
Medical Research Center, Riyadh, Kingdom of Saudi Arabia. 4 King Saud Bin
Abdulaziz University for Health Sciences Riyadh, Riyadh, Kingdom of Saudi
Arabia. 5 Department of Anesthesia, Perioperative, and Pain Medicine, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 6 Barcelona
Institute for Global Health, ISGlobal, Hospital Clínic, Universitat de Barce-
lona, Barcelona, Spain. 7 Pulmonary Division, Faculdade de Medicina, Heart
Institute, InCor, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo,
Sao Paulo, Brazil. 8 Department of Neurology and Experimental Neurology,
Charité– Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
9
NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin,
Charitéplatz 1, 10117 Berlin, Germany. 10 Medical Intensive Care Unit, APHP,
Hôpital Saint‑Louis, Famirea Study Group, ECSTRA Team, and Clinical Epide-
miologyUMR 1153, Center of Epidemiology and Biostatistics, Sorbonne Paris
Cité, CRESS, INSERM, Université Paris Cité, Paris, France. 11 Faculté de Médecine,
Service de Médecine Intensive‑Réanimation, Université de Strasbourg (UNIS-
TRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, 1 Place de
L’Hôpital, Strasbourg, France.
Acknowledgements
We are grateful to Chantal Dumestre-Perard, Adrien Mirouse, and Jean-Rémi
Lavillegrand for sharing their personal collection of pictures. Figures have
been designed using Biorender.
Funding
FS reports obtained funding by NeuroCure Clinical Research Center (NCRC),
funded by the Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation) under Germany´s Excellence Strategy EXC 2049-89829218.
Declarations
Conflicts of interest
GD has no conflict of interest to disclose. YA has no conflict of interest to
disclose. RB has received honararium from the Difficulty Airway Course. OR
has no conflict of interest to disclose. MD reports having received consult-
ing fees from Gilead-Kite, research support from MSD, and speaker fees from
MSD, Gilead-Kite and Astellas. JH has received honoraria for lectures from
Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, Inotrem, MSD and
Shionogi, all unrelated to this work and paid to her institution.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive
rights to this article under a publishing agreement with the author(s) or other
rightsholder(s); author self-archiving of the accepted manuscript version of
this article is solely governed by the terms of such publishing agreement and
applicable law.
Received: 23 June 2023 Accepted: 1 November 2023
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