Variability in the efficacy of interferon-α in Erdheim-Chester disease by patient and site of involvement: Results in eight patients

Abstract

Objective

Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin, characterized by infiltration of tissues by spumous histiocytes. ECD features heterogeneous systemic manifestations, and the general prognosis remains poor despite various treatment options.

Methods

We treated 8 patients with multisystemic ECD with subcutaneous interferon-α (IFNα) at a dosage of 3–9 × 10⁶ units 3 times weekly, for a median duration of 23 months (range 1–46 months).

Results

Treatment was generally well tolerated, and side effects remained limited to fever following injections. Treatment was discontinued in 1 patient, because of severe depression. During treatment, some manifestations of ECD disappeared (i.e., xanthelasma, exophthalmos, papilledema, and intracranial hypertension). The efficacy of IFNα on cardiovascular ECD was variable, however. Treatment resulted in partial regression of “coated aorta” in some cases and clear failure in others; 2 patients died. The level of C-reactive protein diminished sharply in 5 patients.

Conclusion

IFNα might be a valuable first-line therapy for prolonged treatment of ECD. However, the efficacy of IFNα varies among patients and according to the sites of disease involvement, and symptoms may fail to respond to treatment, especially in patients with severe multisystemic forms of ECD with central nervous system and cardiovascular involvement.

First described in 1930, Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis characterized by tissue xanthomatous infiltration by spumous histiocytes. Immunohistochemical staining results are positive for CD68 and negative for CD1a, whereas those for S-100 protein may be negative or positive. By May 2006, ∼240 cases of ECD were reported in the literature (1, 2).

Treatment for ECD includes steroids, cytotoxic agents (3–11), and double autologous hematopoietic stem cell transplantation (12). The efficacy of these treatments is difficult to determine, because many of them have been used in few patients or in combination with other drugs and/or with a short followup period.

Interferon-α 2a (IFNα) has been effective therapy for other forms of histiocytosis (Langerhans cell histiocytosis [13] and Rosai-Dorfman disease [14]) and in 3 patients with ECD (15). The report of the 3 patients with ECD described rapid, substantial, and durable regression of retroorbital infiltration (n = 2 patients) and gradual improvement over many months in bone lesions (n = 1), pain (n = 1), and diabetes insipidus (n = 1).

Our group previously described a patient with ECD treated with high doses of IFNα (18 × 10⁶ units given subcutaneously 3 times weekly) in whom mediastinal and retroorbital infiltration showed 50% regression (1). Heart failure developed, however, and the patient died after receiving a 2-year course of IFNα. Necropsy revealed a massive histiocytic infiltration of the mediastinum, the pericardium, and large vessels. Disease in this patient may have been too advanced for IFNα to affect the cardiovascular manifestations.

We used IFNα to treat 8 other patients with ECD and now report the effects of this treatment, focusing especially on cardiovascular involvement.

PATIENTS AND METHODS

Here, we retrospectively describe our clinical experience with 8 patients (6 men and 2 women; mean age at diagnosis 47.4 years), all of whom were referred to the Internal Medicine Department of Pitié-Salpêtrière Hospital, Paris. All patients had a histologic diagnosis of ECD, based on tissue biopsy specimens displaying CD68+ spumous histiocytes but negativity for CD1a (Table 1). In all patients, bone scintigraphy with ^99mTc-labeled hydroxymethylene diphosphonate disclosed symmetric and abnormally increased labeling of the distal ends of the long bones of the lower limbs and sometimes the upper limbs. The clinical and morphologic characteristics of patients are shown in Table 1. In patient 8, who was described previously (12), double autologous hematopoietic stem cell transplantation was successful. Patients 2, 3, 4, and 5 were recently described elsewhere (2).

Table 1. Characteristics of the 8 patients with Erdheim-Chester disease*

Patient	Sex	Age, years	Duration of IFNα therapy, months	Site(s) of biopsy	Clinical involvement	IFNα efficacy on clinical and radiologic findings†	Time to response	IFNα failure
* IFNα = interferon-α; E = exophthalmos; X = xanthelasma; BP = bone pain; HT = hypertension; “coated aorta” = extensive periaortic fibrosis involving the whole aorta; ICHT = intracranial hypertension; HF = heart failure; RPF = retroperitoneal fibrosis; MF = mediastinal fibrosis; CNS = central nervous system. † Indicates efficacy of IFNα.
1	M	37	46	Orbital, patella	E, X, patella tumefaction	Disappearance of E, X	E, X: ∼6 months
2	M	46	43	Parirenal, bone	BP, X, renovascular HT, “coated aorta”, bilateral hydronephrosis	Disappearance of X, 50% regression of “coated aorta”, withdrawal of bilateral ureteral stents	X: several months “Coated aorta”: 43 months Ureteral stents: 12 months
3	M	54	23 (stopped due to depression)	Perirenal	Renovascular HT, “coated aorta”, pericardium, left coronary artery, bilateral hydronephrosis, papilledema, ICHT	Disappearance of papilledema, ICHT regression	Papilledema: 6 months ICHT: 6 months	Development of severe and fatal ischemic cardiomyopathy (death)
4	W	57	18	Perirenal, pericardium	“Coated aorta”, mitral regurgitation, right atrial tumor, pericardium, left and right coronary artery, superior vena cava, HF, RPF, MF	Initial regression of HF	HF: 1 year	Worsening of mitral regurgitation (death)
5	W	72	23	Periaortic tissue	BP, “coated aorta”, paravertebral mass	Disappearance of BP, 40–50% regression of periaortic fibrosis	BP: few months “Coated aorta”: 18 months
6	M	53	35	Periureteral	Bilateral hydronephrosis, nephrolithiasis	Disappearance of nephrolithiasis, withdrawal of bilateral ureteral stents	Ureteral stents: 3 months
7	M	41	3	Bone	BP, periaortic fibrosis (thoracic), renovascular HT, severe CNS involvement, ataxia, hypophysitis			Progression of ataxia
8	M	18	1	Sinus, bone	Massive E, voluminous facial mass involving both orbits and the facial sinuses			Absence of efficacy

Except where indicated otherwise, INFα was administered subcutaneously 3 times weekly.

RESULTS

Patient 1.

Patient 1 was a 37-year-old man with biopsy-proven ECD who had right exophthalmos and eyelid xanthelasma. IFNα (9 × 10⁶ units) was administered between November 1995 and June 1996, resulting in elimination of the exophthalmos and xanthelasma. The dose of IFNα was tapered to 6 × 10⁶ units between June 1996 and July 1997, and to 3 × 10⁶ units thereafter. Exophthalmos recurred, and the dose of IFNα was increased to 6 × 10⁶ units. Exophthalmos disappeared, and the dosage of IFNα was tapered to 6 × 10⁶ units twice weekly in July 1998 and to 6 × 10⁶ units once weekly in January 1999. IFNα was discontinued, and in September 1999, the patient was lost to followup, after 46 months of treatment. In October 2001, the patient presented because of a recurrence of xanthelasma and tumefaction of the left patella developed in July 2002. A biopsy performed in December 2003 disclosed CD68+ spumous histiocytes. IFNα therapy was resumed at a dose of 3 × 10⁶ units. One year later, the size of the patella tumefaction had decreased by 30%. The C-reactive protein (CRP) level was normal before treatment and remained within normal limits throughout IFNα treatment.

Patient 2.

In February 2000 patient 2, a 46-year-old man with renal failure (serum creatinine level 182 μmoles/liter) and severe renovascular hypertension (2), underwent abdominal computed tomography (CT) scanning and was diagnosed as having retroperitoneal and periaortic fibrosis with bilateral hydronephrosis. He had had hypertension for 3 years, with a recent increase (blood pressure 220/120 mm Hg [normal 140/90 mm Hg]). His CRP level was 57 mg/liter. Ureteral stents were inserted on both sides, with subsequent normalization of the serum creatinine level. Steroid therapy at a dosage of 1 mg/kg/day was initiated in April 2000 and was progressively tapered to a dosage of 20 mg/day in September. In November, xanthelasma of the left eyelid developed. Thoracoabdominal CT scanning disclosed a “coated aorta” aspect (6) and ostial stenosis of the right renal artery. Both kidneys were surrounded by circumferential infiltration. A diagnosis of ECD was made by perirenal biopsy.

The right renal artery was dilated and stented, resulting in improvement in the patient's blood pressure. In June 2001, the patient's CRP level was 202 mg/liter, and treatment with IFNα (3 × 10⁶ units) was initiated. Ureteral stents were removed in July 2002. In February 2005, after 43 months of IFNα therapy, the patient's condition was stable, his blood pressure normalized during treatment with calcium channel inhibitors and beta blockers, and xanthelasma had disappeared. CT scanning of the area of periaortic fibrosis showed a 50% decrease in the maximum diameter at 2 levels (Figure 1). The CRP and creatinine levels were within normal limits.

Figure 1. Computed tomography scans of patient 2, showing sustained regression (50%) of “coated aorta” at the thoracic level (A and B) and at the abdominal level (C and D) after 43 months of treatment with interferon-α. Note the diminution of the perirenal infiltration.

Patient 3.

Patient 3, a 54-year-old man, was referred to our hospital in November 2001, with malaise attributable to tight ostial stenosis of the right renal artery (2). His CRP level was 80 mg/liter, and his serum creatinine level was within normal limits. A thoracoabdominal CT scan disclosed bilateral hydronephrosis with perirenal infiltration and a “coated aorta.” Fibrosis involved the pericardium, left coronary artery, and right pulmonary artery. Physical examination revealed papilledema. A lumbar puncture was performed, and the opening pressure was 47 cm of water, which is consistent with intracranial hypertension. The results of encephalic magnetic resonance imaging were normal. A diagnosis of ECD was made by perirenal biopsy.

The right renal artery stenosis was stented, with subsequent normalization of blood pressure and resolution of malaise. Prednisone (initially at a dosage of 1 mg/kg/day) was started in January 2002 but did not result in reduced periaortic fibrosis. IFNα (3 × 10⁶ units) treatment was started, followed by a subsequent decrease in the CRP level to 35 mg/liter and improvement in the patient's general condition. The steroid dosage was tapered to 5 mg/day. Papilledema disappeared, and the opening pressure of lumbar puncture decreased to 22 cm of water.

Seventeen months after initiation of therapy, perivascular infiltration had not progressed. Severe multivessel ischemic cardiomyopathy developed over 21 months (the results of cardiac catheterization in December 2002 were normal). In September 2004, 3 coronary stents were placed. At that time, IFNα was discontinued (after 23 months of therapy) because of severe depression. During the next 6 months, the patient had several thrombotic complications involving the stents, with myocardial infarction leading to death in March 2005.

Patient 4.

Patient 4, a 57-year-old woman, was referred to our hospital in August 2002 because of a 2-year history of mediastinal and retroperitoneal corticosteroid-resistant fibrosis (2). Congestive heart failure developed because of frank mitral regurgitation. Steroid therapy was progressively tapered until discontinuation. The CRP level was 78 mg/liter. Re-reading of a previous CT scan disclosed “coated aorta” and “hairy perirenal infiltration” aspects. A diagnosis of ECD was based on results of perirenal tissue biopsy and typical bone scintigraphy.

Treatment with IFNα (3 × 10⁶ units) was started in October 2002. The CRP level returned to within the normal range, the patient's general status improved significantly, and dyspnea diminished, enabling the patient to ride a bicycle for the first time in years. In April 2004, perivascular involvement was stable, but mitral insufficiency worsened. A mitral valve replacement that was attempted in May 2004 was unsuccessful due to extensive pericardial and myocardial fibrosis. A few days later, the patient experienced a tamponade. She was transferred to the intensive care unit, where multiple complications developed, including respiratory distress because of severe pulmonary infection (which required mechanical ventilation), vasogenic shock, renal failure requiring hemodialysis for several weeks, and severe critical-illness myopathy. During the next 5 months, the patient had recurrent pulmonary infections, without withdrawal of mechanical ventilation. She died in October 2004 because of pulmonary infection.

Patient 5.

Patient 5, a 72-year-old woman, was referred to our hospital in February 2003. Her CRP level was high (120 mg/liter). The patient had bone pain and periaortitis (2). A thoracoabdominal CT scan disclosed a right paravertebral mass and a “coated aorta.” A diagnosis of ECD was made by a CT scan–guided biopsy of retroperitoneal periaortic tissue. Steroid therapy was initiated at a dosage of 0.5 mg/kg/day but was ineffective for alleviating bone pain and lowering the CRP level. Treatment with IFNα (3 × 10⁶ units) was started in August 2003, which improved both the patient's general status and her CRP level. In February 2005, CT scanning showed a 40–50% decrease in the maximum diameter of the periaortic fibrosis, and IFNα therapy was continued. When she was last seen in July 2005, the patient was well, and her CRP level remained within normal limits.

Patient 6.

Patient 6, a 53-year-old man with a history of hypertension, had recurrent episodes of nephrolithiasis since October 2000. Intravenous urography disclosed a nonfunctioning right kidney and a tight left ureteral stenosis with dilatation of the pyelocaliceal system. Echocardiography showed bilateral hydronephrosis. Ureteral stents were inserted on both sides. In May 2002, ureterolysis via a right posterolumbar incision enabled a pathologic diagnosis of ECD. Treatment with IFNα (3 × 10⁶ units) was initiated in July 2002. Bilateral stents were removed in September without further recurrence of hydronephrosis and nephrolithiasis. When he was last seen in June 2005, the patient's condition was stable. His CRP level, which was 17 mg/liter before treatment, was <5 mg/liter after treatment.

Patient 7.

In 2000 patient 7, a 41-year-old man was given a diagnosis of ECD, based on the results of a bone biopsy. He had bone pain, and during 2003, major ataxia developed due to a cerebellar mass. Although no biopsy specimen was obtained, this mass was thought to be attributable to ECD, because brain stem cell localization is classically described in ECD (1). Other manifestations of ECD involvement were thoracic periaortic fibrosis, renovascular hypertension, and asymptomatic pulmonary infiltration. The left renal artery stenosis was treated with stenting, with subsequent normalization of blood pressure. IFNα (3 × 10⁶ units) was given over a period of 3 months. Because of worsening ataxia (the patient was confined to a wheelchair), we performed autologous hematopoietic stem cell transplantation (based on results of our previous experience [12]). After 18 months of followup, the patient was unresponsive to this therapy, and ataxia remained severe.

Patient 8.

We previously reported this case of an 18-year-old man with massive bilateral exophthalmos refractory to steroids, 2-chloro-2′-deoxyadenosine, and etoposide (12). Despite therapy with high-dose IFNα (9 × 10⁶ units), massive exophthalmos remained unchanged after 1 month. He was then successfully treated with double autologous hematopoietic stem cell transplantation.

DISCUSSION

We report a series of 8 patients with histologically proven ECD (Table 1) treated with IFNα. These patients exhibited multisystemic histiocyte infiltration with periaortic fibrosis (n = 5), hypertension due to renal artery stenosis by ECD infiltration (n = 3), exophthalmos (n = 2), bilateral hydronephrosis (n = 2), xanthelasma (n = 2), pericardial involvement (n = 2), coronary artery involvement (n = 2), mitral regurgitation (n = 1), heart failure (n = 1), and papilledema with intracranial hypertension (n = 1). The median duration of treatment was 23 months (range 1–46 months). Treatment was generally well tolerated, and side effects remained limited to fever following injections (n = 2). In 1 patient (patient 3), severe depression developed, most likely because of IFNα, which required treatment discontinuation. The first 2 patients (patients 1 and 8) were initially treated with high doses of IFNα (9 × 10⁶ units), whereas the other 6 patients received lower doses (3 × 10⁶ units).

Similar to the findings in a recent report by Braiteh et al (15), IFNα was efficacious in 6 patients. Xanthelasma disappeared in 2 patients (patients 1 and 2), and hydronephrosis regressed in 2 patients (patients 2 and 6), allowing withdrawal of ureteral stents in both. In 1 patient (patient 3), papilledema disappeared, and intracranial hypertension improved. Exophthalmos disappeared in 1 patient (patient 1), and this clearly illustrates the efficacy of IFNα in ECD. Indeed, following treatment with high-dose IFNα, both exophthalmos and xanthelasma disappeared in patient 1, but 25 months and 34 months after IFNα discontinuation, respectively, xanthelasma relapsed and patella tumefaction developed. In 1 patient (patient 5), bone pain disappeared during IFNα therapy. Five patients (patients 2, 3, 4, 5, and 6) showed improvement of their general status, particularly patient 4, who demonstrated marked improvement of dyspnea (a reduction in the New York Heart Association Classification from class III–-IV to class II). Before IFNα therapy, 6 patients showed evidence of high CRP levels (median 69.5 mg/liter; range 17–202 mg/liter) (Figure 2), which diminished sharply with treatment in 5 patients (median 9 mg/liter; range 4–35 mg/liter) (Figure 2). In 5 patients (patients 2, 3, 4, 5, and 7), disease was refractory to steroids (Figure 2).

Figure 2. Time course of the C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESRs) in patients 2, 3, 4, and 5 during therapy with interferon-α (IFNα) and corticosteroids (CT).

Because cardiovascular involvement is a major and underdiagnosed cause of death in ECD (2), we focused on the efficacy of IFNα in 5 patients with such involvement. CT scanning revealed a frank and sustained regression, close to 50%, of the diameter of periaortic fibrosis in 2 patients (patients 2 and 5) after 43 and 18 months, respectively, of treatment with IFNα (Figure 1). However, in the 3 other patients with “coated aorta” (patients 3, 4, and 7), periaortic fibrosis remained unchanged, which suggested that the efficacy of IFNα in the setting of cardiovascular involvement was inconsistent. In patient 4, mitral regurgitation became massive after 18 months of IFNα therapy, and an attempt at surgical treatment was required. ECD-related cardiovascular involvement was the cause of death in 2 patients. Patient 3 died of ischemic cardiomyopathy, and patient 4 died of complications after failure of mitral valve replacement. Interestingly, in these 2 cases, IFNα was efficacious for other features of ECD (general status, papilledema, intracranial hypertension, elevated CRP levels). Thus, cardiovascular ECD could have been unresponsive to IFNα either because the course of disease was too far advanced or because of the site of involvement. Massive exophthalmos in patient 8 and major central nervous system involvement in patient 7 were also refractory to IFNα therapy, despite the administration of high doses in the former patient. Thus, IFNα might not be effective for some ECD features, especially cardiovascular involvement, which could even worsen despite treatment. We recently reported cardiovascular involvement as the major and underdiagnosed cause of death in patients with ECD (2).

To our knowledge, this is currently the largest reported series of patients with ECD treated with IFNα. Our results confirm, in part, previous results reported by Braiteh et al (15). Those investigators proposed that IFNα could have several mechanisms of action, such as maturation and activation of dendritic cells, immune-mediated (e.g., via natural killer cells) destruction of histiocytes, or direct antiproliferative effects. However, those mechanisms remain largely unknown. IFNα appears to be effective for moderate forms of exophthalmos, bilateral hydronephrosis, and xanthelasma, and for improving general status of the patient and CRP levels. The efficacy of IFNα on cardiovascular ECD is, however, variable, with partial regression of “coated aorta” in some cases and clear failure in others. In our series, 2 of the 5 patients with ECD cardiovascular involvement died (40% mortality after a mean ± SD followup of 41 ± 14 months). Given the 60% mortality observed in our recent series of 72 patients with ECD and cardiovascular involvement after a mean followup of 28.9 months (2), IFNα should be considered as a first-line therapeutic option for ECD on a long-term basis. Failure of IFNα therapy should lead to more aggressive or experimental alternative therapeutic regimens.