To the editor:

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by foamy histiocytes, sometimes associated with central nervous system (CNS) and cardiac infiltration.1  Several reports have suggested that an interleukin (IL)1 receptor antagonist, anakinra, is effective in treating ECD.2-8 

Twelve patients (7 men and 5 women; median age, 70 years; range, 22-80 years) with biopsy-proven ECD9  and previous failure (cases 2, 3, 4, 9, and 11), poor tolerance, or contraindication (cases 1, 2, 5, 6, 7, 8, 10, and 12) to interferon-α (IFN-α) therapy received alternative treatment with daily subcutaneous injection of 100 mg anakinra. Data collection and analysis were performed retrospectively. Three patients rapidly stopped the treatment (2 for failure and 1 for pain at the injection site). Table 1 shows the characteristics of the 12 initial and the 9 remaining patients at baseline. Eight patients had long bone involvement, 8 had cardiac disease (4 with a pericardial effusion or thickening and 8 with a pseudomass in the right atrium), 3 had retro-orbital infiltration, 1 had a pseudo-meningioma of the spine, and 1 had pachymeningitis. The median duration of ECD disease when anakinra was started was 5 years (range, 1-12 years). Ten of the 12 patients were treated prior to inclusion with IFN-α (pegylated or not). For 5 of them, anakinra was given just after IFN-α treatment.

Table 1

Demographic and clinical characteristics of the 12 patients at baseline and of the 9 (1-9) patients included in the analysis of long-term outcome

Sex, age at anakinra treatment (years)Age at ECD diagnosis (years) and BRAF statusECD localizationsPrevious treatmentsBiopsy siteTreatment durationAnakinra failure, progression of diseaseAnakinra efficacy
M, 64 52 WT Retroperitoneal, bones, aorta, pericardium, atrial pseudomass, sinus, spine SteroidsIFN, PEG-IFN Pericardium, perirenal 22 mo Heart, pleura Spine 
M, 68 60 ND Retroperitoneal, bones, aorta, atrial pseudomass Steroids, IFN, PEG-IFN, imatinib Perirenal 31 mo Pleura, lung, spine  
M, 76 72 V600E Retroperitoneal, Bones, aorta, pericardium, atrial pseudomass IFN, PEG-IFN Perirenal 26 mo Aorta, heart Pleura 
F, 80 72 V600E Retroperitoneal, bones, aorta, pericardium, atrial pseudomass, lung Steroids, IFN Perirenal 7 mo Stable  
F, 58 52 ND Bones IFN, PEG-IFN Bone 28 mo  Bones 
M, 75 72 ND Bones None Bone 11 mo CNS  
F, 22 16 ND DI, lung, sinus, retroperitoneal Steroids, IFN, PEG-IFN, vinblastine Sinus 3 mo Stable  
M, 71 65 V600E Retroperitoneal, bones, lung, aorta, atrial pseudomass, CNS IFN, PEG-IFN Perirenal 5 mo Bones, pleura, CNS  
M, 70 69 V600E Aorta, bones, retroperitoneal, atrial pseudomass, retroorbital, xanthelasma Steroids, PEG-IFN Perirenal 34 mo Heart  
10 M, 72 71 ND Aorta, bones, pericardium, atrial pseudomass, hydronephrosis, retroorbital PEG-IFN Perirenal 3 wk NA NA 
11 F60 59 V600E Aorta, bones, atrial pseudomass, skin, bones, retroorbital, DI Steroids, PEG-IFN Perirenal 3 wk NA NA 
12 F70 69 ND Aorta, DI, bones None Bones 1 wk NA NA 
Sex, age at anakinra treatment (years)Age at ECD diagnosis (years) and BRAF statusECD localizationsPrevious treatmentsBiopsy siteTreatment durationAnakinra failure, progression of diseaseAnakinra efficacy
M, 64 52 WT Retroperitoneal, bones, aorta, pericardium, atrial pseudomass, sinus, spine SteroidsIFN, PEG-IFN Pericardium, perirenal 22 mo Heart, pleura Spine 
M, 68 60 ND Retroperitoneal, bones, aorta, atrial pseudomass Steroids, IFN, PEG-IFN, imatinib Perirenal 31 mo Pleura, lung, spine  
M, 76 72 V600E Retroperitoneal, Bones, aorta, pericardium, atrial pseudomass IFN, PEG-IFN Perirenal 26 mo Aorta, heart Pleura 
F, 80 72 V600E Retroperitoneal, bones, aorta, pericardium, atrial pseudomass, lung Steroids, IFN Perirenal 7 mo Stable  
F, 58 52 ND Bones IFN, PEG-IFN Bone 28 mo  Bones 
M, 75 72 ND Bones None Bone 11 mo CNS  
F, 22 16 ND DI, lung, sinus, retroperitoneal Steroids, IFN, PEG-IFN, vinblastine Sinus 3 mo Stable  
M, 71 65 V600E Retroperitoneal, bones, lung, aorta, atrial pseudomass, CNS IFN, PEG-IFN Perirenal 5 mo Bones, pleura, CNS  
M, 70 69 V600E Aorta, bones, retroperitoneal, atrial pseudomass, retroorbital, xanthelasma Steroids, PEG-IFN Perirenal 34 mo Heart  
10 M, 72 71 ND Aorta, bones, pericardium, atrial pseudomass, hydronephrosis, retroorbital PEG-IFN Perirenal 3 wk NA NA 
11 F60 59 V600E Aorta, bones, atrial pseudomass, skin, bones, retroorbital, DI Steroids, PEG-IFN Perirenal 3 wk NA NA 
12 F70 69 ND Aorta, DI, bones None Bones 1 wk NA NA 

DI, diabetes insipidus; NA, not available; ND, not determined; PEG, pegylated; V600E, presence of mutation BRAF V600E; WT, wild type.

The median duration of anakinra treatment (always given as a monotherapy) among the 9 patients was 22 months (range, 3-34 months). Clinical symptoms improved in 50% of the patients (3 of 7 for fatigue, among them 2 stopped IFN-α just before, 1 of 1 for fever, 2 of 6 for bone pain, 1 of 2 for sinus disturbance). The median C-reactive protein (CRP) value at baseline was 10 mg/L (range, 4-30 mg/L) and at the end of the treatment was 10 mg/L (range, 4-43 mg/L), which was not significantly different. All patients had a positron emission tomography (PET) evaluation at baseline and at the end of follow-up. Five had progression of the disease, 2 had stable disease, 1 had a partial response, and 1 had a complete metabolic response. Among the 6 patients who had cardiac involvement, 5 underwent baseline and final cardiac magnetic resonance imaging (MRI), which displayed stability in 3 and progression in 2 (among them, 1 had tamponade). Retro-orbital infiltration evaluated by cerebral MRI was stable in 1 of 1 patients and CNS infiltration appeared in 1 patient free of CNS involvement at the beginning of the treatment.

Tolerance was variable. Four of the 9 patients included in the long-term analysis had side effects, including pain at the injection site (n = 4), edema (n = 1), severe sepsis (n = 1), and headache (n = 1). Overall, anakinra was stopped in 11 of 12 patients because of poor tolerance (n = 4) or progression of disease (n = 7).

Proinflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor-α, are strongly increased in ECD lesions. Whether IL-1 blood levels are increased is still controversial; this finding has been reported in isolated cases but not in a larger series of 37 patients.10  Altogether, these findings suggested that inhibition of the IL-1 pathway could be a promising therapeutic area for ECD treatment.

Here, we report a series of 12 patients with ECD exhibiting multisystem histiocyte infiltration treated with anakinra. Tolerance was variable and led to discontinuation of the treatment in 33% of patients. In contrast with 6 of 8 previous case reports, we did not observe an improvement in CRP levels. This may be due to IFN-α therapy, which may have lowered basal CRP levels in 4 patients who received this treatment just before receiving anakinra. The efficacy of anakinra assessed by fluorodeoxyglucose (FDG)-PET was variable. The extent of the disease evaluated by computed tomography or MRI imaging was not improved in our patients receiving anakinra, regardless of the site (retro-orbital, cardiac, spine, brain, pleura, or retroperitoneal). Conversely, CNS infiltration and tamponade occurred during treatment in 1 patient each.

Aouba et al2  first reported the dramatic efficacy of anakinra in 2 ECD patients with a dramatic improvement in retroperitoneal infiltration and regression of hydronephrosis. Since then, the use of IL-1 blockade in ECD has been reported in 6 additional reports3-8  (Table 2), which did not mention any changes in bone lesions or retroperitoneal infiltration. Killu et al5  described a patient with a right atrial mass in which FDG uptake decreased under anakinra treatment, although there was no MRI evaluation of the cardiac infiltration. Some of our patients, conversely to several previous reports including the one by Aouba et al, were refractory to IFN-α therapy, which could be the hallmark of more severe disease and can explain the different responses to treatment.

Table 2

Previous reported cases of anakinra treatment of ECD

Sex, age (years)ECD localizations and previous treatmentsECD duration (years)Anakinra duration (months)CRPToleranceEfficacy
Aouba 113 F, 46 Bones, retroperitoneal, hydronephrosis, xanthelasma 25 Normalized Pruritus Disappearance of bone pain and fever 
Steroids Regression of hydronephrosis and retroperitoneal infiltration 
Zoledronic acid Normalization of bone scintigraphy 
Cladribine  
Aouba 213 M, 55 Bones, coated aorta and renal artery stenosis, retroperitoneal, hydronephrosis 26 Normalized Pain at injection sites Disappearance of bone pain and fever 
Steroids Regression of hydronephrosis 
IFN-α No improvement of scintigraphic bone uptake 
Tran14 F, 10 Bones, retroperitoneal 10 Normalized Pain at injection sites Disappearance of bone pain and fever 
Vinblastine No changes in bone lesions nor retroperitoneal infiltration 
Steroids  
IFN-α  
Aubert20 F, 32 Bones, retroperitoneal, adrenal infiltration 10 12 Normalized Slight injection sites reaction Disappearance of bone pain and fever 
Steroids Improvement of bone hypermetabolism in PET 
Vesanoid No change in retroperitoneal infiltration 
Killu22 M, 71 Right atrial mass, bilateral pleura infiltration, temporal artery infiltration Improvement of 18 FDG uptake in right atrial mass 
No prior treatment Heart MRI evaluation not done 
Courcoul23 M, 57 Bones 12 Normalized No side effects Disappearance of bone pain 
Steroids No changes in 18 FDG uptake, bone scan and bone MRI 
Pamidronate  
IFN-α  
Darstein24 M, 48 Bones, retroperitoneal, hydronephrosis, CNS Rapid decrease Gram-negative urosepsis controlled under antibiotics Improvement of neurological symptoms (not assessed by MRI) 
No prior treatment 
Cohen25 F, 43 Bones, pituitary involvement, sinuses, lichen planus NA Injection site reaction Cutaneous lesions, desmopressin need and bone pain improvement 
Sex, age (years)ECD localizations and previous treatmentsECD duration (years)Anakinra duration (months)CRPToleranceEfficacy
Aouba 113 F, 46 Bones, retroperitoneal, hydronephrosis, xanthelasma 25 Normalized Pruritus Disappearance of bone pain and fever 
Steroids Regression of hydronephrosis and retroperitoneal infiltration 
Zoledronic acid Normalization of bone scintigraphy 
Cladribine  
Aouba 213 M, 55 Bones, coated aorta and renal artery stenosis, retroperitoneal, hydronephrosis 26 Normalized Pain at injection sites Disappearance of bone pain and fever 
Steroids Regression of hydronephrosis 
IFN-α No improvement of scintigraphic bone uptake 
Tran14 F, 10 Bones, retroperitoneal 10 Normalized Pain at injection sites Disappearance of bone pain and fever 
Vinblastine No changes in bone lesions nor retroperitoneal infiltration 
Steroids  
IFN-α  
Aubert20 F, 32 Bones, retroperitoneal, adrenal infiltration 10 12 Normalized Slight injection sites reaction Disappearance of bone pain and fever 
Steroids Improvement of bone hypermetabolism in PET 
Vesanoid No change in retroperitoneal infiltration 
Killu22 M, 71 Right atrial mass, bilateral pleura infiltration, temporal artery infiltration Improvement of 18 FDG uptake in right atrial mass 
No prior treatment Heart MRI evaluation not done 
Courcoul23 M, 57 Bones 12 Normalized No side effects Disappearance of bone pain 
Steroids No changes in 18 FDG uptake, bone scan and bone MRI 
Pamidronate  
IFN-α  
Darstein24 M, 48 Bones, retroperitoneal, hydronephrosis, CNS Rapid decrease Gram-negative urosepsis controlled under antibiotics Improvement of neurological symptoms (not assessed by MRI) 
No prior treatment 
Cohen25 F, 43 Bones, pituitary involvement, sinuses, lichen planus NA Injection site reaction Cutaneous lesions, desmopressin need and bone pain improvement 

Altogether, these results show that anakinra displays a variable efficacy in ECD sometimes, with progression of cardiac or CNS involvement.

In conclusion, anakinra is possibly effective for treating constitutional symptoms, has variable efficacy in organs as measured by FDG-PET scan, and did not lead to measurable regression of tumors. For ECD patients with cardiac or CNS infiltration, other treatments, such as IFN-α or B-Raf inhibitors, should be considered first. Increasing the anakinra dose should also be considered in the future, as has been proposed in other inflammatory conditions.

Authorship

Contribution: F.C.-A., J.H., and Z.A. designed the study and analyzed the data; F.C.-A., D.S., F.C., Z.A., and J.H. wrote the manuscript; P.M. reviewed and analyzed the PET imaging; A.D. and P.C. reviewed the cerebral and cardiac imaging; and all authors approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Fleur Cohen-Aubart, Service de Médecine Interne 2, Institut E3M, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France; e-mail: fleur.cohen@psl.aphp.fr.

References

References
1
Haroche
 
J
Arnaud
 
L
Cohen-Aubart
 
F
, et al. 
Erdheim-Chester disease.
Curr Rheumatol Rep
2014
, vol. 
16
 
4
pg. 
412
 
2
Aouba
 
A
Georgin-Lavialle
 
S
Pagnoux
 
C
, et al. 
Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
Blood
2010
, vol. 
116
 
20
(pg. 
4070
-
4076
)
3
Tran
 
TA
Pariente
 
D
Lecron
 
JC
Delwail
 
A
Taoufik
 
Y
Meinzer
 
U
Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
Arthritis Rheum
2011
, vol. 
63
 
12
(pg. 
4031
-
4032
)
4
Aubert
 
O
Aouba
 
A
Deshayes
 
S
Georgin-Lavialle
 
S
Rieu
 
P
Hermine
 
O
Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra.
Joint Bone Spine
2013
, vol. 
80
 
2
(pg. 
206
-
207
)
5
Killu
 
AM
Liang
 
JJ
Jaffe
 
AS
Erdheim-Chester disease with cardiac involvement successfully treated with anakinra.
Int J Cardiol
2013
, vol. 
167
 
5
(pg. 
e115
-
e117
)
6
Courcoul
 
A
Vignot
 
E
Chapurlat
 
R
Successful treatment of Erdheim-Chester disease by interleukin-1 receptor antagonist protein.
Joint Bone Spine
2014
, vol. 
81
 
2
(pg. 
175
-
177
)
7
Darstein
 
F
Kirschey
 
S
Heckl
 
S
, et al. 
Successful treatment of Erdheim-Chester disease with combination of interleukin-1-targeting drugs and high-dose glucocorticoids.
Intern Med J
2014
, vol. 
44
 
1
(pg. 
90
-
92
)
8
Cohen
 
PR
Kurzrock
 
R
Anakinra-responsive lichen planus in a woman with Erdheim-Chester disease: a therapeutic enigma.
Dermatol Online J
2014
, vol. 
20
 
1
pg. 
21241
 
9
Diamond
 
EL
Dagna
 
L
Hyman
 
DM
, et al. 
Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease.
Blood
2014
, vol. 
124
 
4
(pg. 
483
-
492
)
10
Arnaud
 
L
Gorochov
 
G
Charlotte
 
F
, et al. 
Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
Blood
2011
, vol. 
117
 
10
(pg. 
2783
-
2790
)

Author notes

*

Z.A. and J.H. contributed equally to this work.