
==== Front
Ophthalmic Plast Reconstr Surg
Ophthalmic Plast Reconstr Surg
IOP
Ophthalmic Plastic and Reconstructive Surgery
0740-9303
1537-2677
Lippincott Williams & Wilkins Hagerstown, MD

38427815
OPRS-D-23-00620
00003
10.1097/IOP.0000000000002619
3
Original Investigations
Erdheim–Chester Disease With Eyelid and Orbital Involvement: A Review of Treatment Modalities at One Institution From 2014 to 2022
Sharma Meghan B.A. mxs2621@med.miami.edu
*
Stevens Shanlee M. M.D. Shanlee.Stevens@nyulangone.org
†
Maeng Michelle M. M.D. michelle.maeng@yale.edu
‡
Nagornaya Natalya M.D. nnagornaya@med.miami.edu
*
Bhatia Rita G. M.D. rbhatia@med.miami.edu
*
Wester Sara T. M.D. *
* Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, U.S.A.
† Department of Ophthalmology, New York University Grossman School of Medicine, New York City, New York, U.S.A.
‡ Department of Ophthalmology & Visual Science, Yale School of Medicine, New Haven, Connecticut, U.S.A.
Address correspondence and reprint requests to Sara T. Wester, M.D., Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136. E-mail: swester2@med.miami.edu
05 9 2024
Sep-Oct 2024
40 5 497503
05 1 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Purpose:

To review all cases of Erdheim–Chester disease (ECD) with orbital involvement treated at Bascom Palmer Eye Institute in Miami, Florida from 2014 to 2022 and compare presentations, treatment modalities, and outcomes.

Methods:

A retrospective chart review of all patients diagnosed with ECD who presented to Bascom Palmer Eye Institute from 2014 to 2022 was performed. Data collected included demographics, pretreatment history and ophthalmic examination, pathology report, treatment, subsequent examination, and relevant laboratory results. Histopathology, treatments, and outcomes were reviewed and compared between patients.

Results:

Four cases were included. Primary treatments included vemurafenib (n = 2), cobimetinib (n = 1), and prednisone (n = 1). All patients demonstrated improvement of ophthalmic symptoms. Vemurafenib was the only medical treatment that was tolerated well and resulted in significant improvement in proptosis despite some reported dry eye; all other medications were discontinued due to intolerable side effects.

Conclusions:

BRAF inhibitors such as vemurafenib have been used as novel therapy in the treatment of ECD. Vemurafenib demonstrated its utility in reducing proptosis in ECD patients at one ophthalmic institution. Vemurafenib may be a favorable treatment option for BRAF-positive ECD patients presenting with orbital disease.

A retrospective chart review of Erdheim–Chester disease patients with eyelid and orbital manifestations at one institution was performed. Vemurafenib was the only medical treatment that was well tolerated; other medications were discontinued due to side effects.

OPEN-ACCESSTRUE
==== Body
pmcAdult orbital xanthogranulomatous diseases are classified by infiltration of xanthoma cells and Touton giant cells into systemic and ocular tissues and include 4 distinct subcategories: Erdheim–Chester disease (ECD), adult-onset xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, and necrobiotic xanthogranuloma. While all 4 subtypes are classified by xanthogranulomatous infiltration, each is differentiated by its systemic presentation.

Erdheim–Chester disease is a rare disease that presents in the fourth to seventh decades of life with less than 1,200 reported cases.1 It is seen more commonly in males with systemic symptoms including bone pain, neurologic involvement, or diabetes insipidus.2,3 With an overall 5-year survival rate of 68%, ECD can be fatal secondary to systemic xanthogranulomatous infiltration causing cardiomyopathy, restrictive lung disease, or renal failure.1,2 Biopsy is required for definitive diagnosis of ECD, even in circumstances of highly suggestive clinical and imaging features.2,4 Lesional tissue typically demonstrates diagnostic lipid-laden histiocytes with admixed or surrounding fibrosis and Touton giant cells with positive CD68, CD163, and factor XIIIa and negative CD1a, S100, and Langerin (CD207) on immunohistochemical staining.1,4–7

Orbital involvement is seen in 25% of ECD and portends a worse overall prognosis.1,5 Periocular symptoms have variable presentations; however, a common sign is bilateral painless proptosis with progressive vision loss over months to years.5 Other symptoms may include proptosis, diplopia, orbital pressure, or conjunctival lesions.2,8 Retro-orbital masses may occur in 20% to 37% of patients and are commonly bilateral. Expansion of the intraconal masses can cause optic disc edema and peripapillary hemorrhage due to compressive ischemic changes. Intraocular manifestations are rare but may include subretinal and choroidal infiltrative lesions accompanied by subretinal fluid, retinal detachments, and choroidal neovascular membranes leading to vision loss.5

Due to the rare nature of the disease and diverse symptomatology, it is difficult to perform randomized controlled trials to establish clear management guidelines. Furthermore, the course of ECD often remains aggressive despite treatment.3 Conventional treatment methods for ECD include surgical debulking or treatment with corticosteroids, cladribine, anakinra, and radiotherapy, although limitations have been observed with each. Novel therapy options inhibiting the BRAF pathway have been shown to be efficacious in the treatment of ECD.9,10 In 2017, vemurafenib, a target inhibitor of mutated BRAF-V600E, was approved by the Food and Drug Administration for the treatment of ECD and has been shown to provide rapid radiologic, clinical, and laboratory marker improvements in multisystemic and refractory patients.5 Cobimetinib, an orally bioavailable, potent, and selective mitogen-activated protein kinase-ERK kinase inhibitor, has been used in combination with vemurafenib in other disease processes such as melanoma. Patients with advanced BRAF V600-mutated melanoma received cobimetinib in addition to vemurafenib in a 2014 study and experienced significant improvement in progression-free survival despite some increase in toxicity.11 Cobimetinib received Food and Drug Administration approval for the treatment of ECD regardless of mutation status in 2022. In patients who do not respond to these agents and have no other known targetable mutation, treatments such as cladribine or methotrexate may be used.12 The purpose of this study is to review all ECD cases with orbital involvement treated at Bascom Palmer Eye Institute (BPEI) in Miami, Florida from 2014 to 2022 and compare presentations, treatment modalities, and outcomes.

METHODS

All methods were approved by the University of Miami Institutional Review Board. Research methods are Health Insurance Portability and Accountability Act compliant and adhere to the ethical principles outlined in the Declaration of Helsinki. A retrospective chart review of all patients diagnosed with ECD who presented to BPEI was performed. Charts from the BPEI pathology database with inclusion of the term “Erdheim Chester disease” were selected for initial review. Eight patients were included. After further chart review, 4 patients were excluded. One patient was excluded because the final diagnosis was IgG sclerosing disease, one was excluded for adult-onset asthma with periocular xanthogranuloma as the final diagnosis, one was excluded for loss to follow up after treatment, and the final patient was excluded for having no definitive diagnosis of ECD and no characteristic symptoms. Data collected on the remaining 4 patients included demographics, pretreatment history and ophthalmic examination, pathology report, treatment, subsequent examination, and relevant laboratory results. Histopathology, treatments, and outcomes were reviewed and compared between patients.

Patients were classified based on orbital and systemic outcomes using the following measures: “worsening,” “stabilization,” “improvement,” and “resolution” (Table). For orbital outcomes, disease classification was based on comparison of pre- and posttreatment reported ocular symptoms, ocular exam, and Hertel measurements. Worsening was characterized by subjective worsening of symptoms such as orbital pain, increased conjunctival lesion size, or at least 1 mm increase in Hertel measurements from baseline measurements in either eye. Stabilization referred to no changes in stated symptoms, ocular exam, or Hertel measurements. Improvement was defined as stated improvement in symptoms, decreased conjunctival lesion size, or at least 1 mm improvement in Hertel measurements in either eye. Resolution was defined as no remaining symptoms or clinical signs. Systemic outcomes were based on reports from the patients’ interdisciplinary team, including hematology–oncology, rheumatology, and pulmonology. Four patients who presented to BPEI with signs of ECD with orbital involvement were included (Table).

Four cases presenting with Erdheim–Chester disease (ECD) at Bascom Palmer Eye Institute from 2014 to 2022

Case	Age at initial visit to BPEI	Sex	Pretreatment ocular symptoms	OD/OS	Primary treatment method	Duration of primary treatment	Posttreatment ocular symptoms	Hertel value before primary treatment (mm)	Hertel value after primary treatment (mm)	Ocular exam before treatment	Ocular exam after treatment	Orbital outcome	Systemic outcome	
1	35	M	Conjunctival lesion	OS > OD	Cobimetinib 40 mg	7 months	No stated symptoms	Not obtained	Not obtained	OS conjunctiva/sclera shows temporal to caruncle elevated vascular, fleshy granulomatous lesion approx. 10 × 7, resolved subconjunctival hemorrhage superiorly. OD has diffuse melanosis.	OU complexion-associated melanosis.	Resolution	Improvement	
2	57	F	Orbital pain	OD	Prednisone 30 mg for 5 days	1 month	No stated symptoms	18 OD, 18 OS	17 OD, 17 OS	OS and OD normal.	OS and OD normal.	Improvement	Not obtained	
3	45	F	Bilateral periorbital rash, OD proptosis	OD > OS	Vemurafenib 240 mg 2× daily	6 years	Dry eye	30 OD, 27 OS	25 OD, 25 OS	OD conjunctiva has trace injection inferiorly and trace punctate epithelial erosions following medial orbitotomy OD. OS normal.	OD puncta patent. OS normal.	Improvement	Not obtained	
4	67	M	Proptosis, redness, swelling	OS > OD	Vemurafenib 240 mg 2× daily	1 year+	Dry eye and discharge	20 OD, 22 OS	Not obtained	OS showing ptosis with 3+ injection inferiorly > superiorly with chemosis. OD normal.	OS with inferior chemosis, early keratinization of conjunctiva inferiorly. OD normal.	Improvement	Improvement	
Orbital outcome and systemic outcome classifications: Worsening: subjective worsening of symptoms such as orbital pain, increased conjunctival lesion size, or at least 1 mm increase in Hertel measurements from baseline measurements in either eye. Stabilization: no changes in stated symptoms, ocular exam, or Hertel measurements. Orbital improvement: stated improvement in symptoms, decreased conjunctival lesion size, or at least 1 mm improvement in Hertel measurements in either eye. Systemic improvement: determination based on reports from the patients’ interdisciplinary team, including hematology–oncology, rheumatology, and pulmonology. Resolution: no remaining symptoms.

Not obtained: data were not found from chart review.

BPEI, Bascom Palmer Eye Institute; F, female; M, male.

CASE REPORTS

Case 1

A 35-year-old Black male with no relevant past medical history presented to BPEI with a left, inferonasal, raised, pink conjunctival lesion. The patient had been evaluated by hematology–oncology 2 years prior to noticing ocular involvement for evaluation of sternal and low back pain. CT of the spine identified lytic lesions of the vertebral bodies. A bone marrow biopsy was performed, which showed 90% maturing trilineage hematopoiesis and granulocytic hyperplasia. Two years later, he noticed a conjunctival lesion, which was biopsied at an outside institution and found to be CD-30+, a finding raising suspicion for a more threatening condition such as lymphoma. He was transferred to BPEI for further evaluation.

Upon presentation, he described symptoms of fever, chills, weight loss, skin lesions on his face and legs, and lymphadenopathy. Initial exam revealed visual acuity of 20/20 OU and full extraocular motility (EOM). Mild left-sided chemosis was noted. Slit-lamp exam showed diffuse melanosis with a mobile conjunctival lesion in the inferior bulbar conjunctiva OD, and an elevated, vascular, fleshy granulomatous lesion approximately 11 mm × 7 mm, mild chemosis, and a resolving subconjunctival hemorrhage OS. Anterior segment optical coherence tomography showed subconjunctival lesions with cellular but somewhat heterogeneous infiltration bilaterally. A BRAF immunohistochemical stain of a conjunctival biopsy was negative; however, CD68 and S100 positivity with CD1a and CD207 negative histiocytes suggested ECD.

The patient was started on high-dose oral prednisone, resulting in resolution of the right conjunctival lesion. There was no change in the left conjunctival lesion with stable findings on posttreatment anterior segment optical coherence tomography. He was transitioned to peg interferon while continuing a prednisone taper. After 1 month of interferon therapy, the patient discontinued use due to intolerable side effects, including gastrointestinal upset, diarrhea, malaise, fever, additional weight loss, and postnasal drip with cough. He was switched to dexamethasone 20 mg daily.

Within a month, he developed steroid-induced hyperglycemia and was transitioned to cladribine, which lead to the development of additional skin lesions on his face. Cladribine was discontinued due to intolerable side effects, and he was switched to oral methotrexate/6-mercaptopurine. After 4 months on methotrexate, he developed malaise and weakness, and this also had to be discontinued. He began cobimetinib therapy, which resulted in significant improvement in the left conjunctival lesion over the next 5 months. Despite initial ocular improvement on cobimetinib, it also caused severe facial and ankle swelling, leading to hospitalization and a steroid taper. He resumed cobimetinib 40 mg after the steroid taper and noted some weight gain but no other systemic symptoms. Four months after resuming cobimetinib for the second time, the patient demonstrated visual acuity of 20/20 OD and 20/20 OS with full EOMs OU and resolution of the chemosis. Three months after this visit, his conjunctival lesion had resolved and no other ocular lesions were noted; however, he developed some facial swelling and stopped cobimetinib. He has currently been stable off therapy for over a year.

Case 2

A 57-year-old Hispanic female with a past medical history of type 2 diabetes, hypertension, iron deficiency anemia, and trigeminal neuralgia presented with 9/10 right orbital pain, worse with eye movement. Initial ocular exam demonstrated visual acuity 20/20 OU with full EOMs. Hertel ophthalmometry measured 18 OU. She was started on prednisone 30 mg for 5 days, with improvement of the right orbital pain, although the patient noted fluctuation of her blood sugar. CT of orbits was obtained, which showed enhancing lesions in both intraconal spaces around the optic nerves favored to represent optic nerve sheath meningiomas.

One month later, she complained of persistent OD pain and blurry vision. She deferred oral steroids to avoid hyperglycemia, so she was managed with oral non-steroidal antiinflammatory drugs. Two months later, the patient claimed significant reduction of pain with eye movements, rating it 2/10 OD. She underwent right anterior orbitotomy with a biopsy that showed xanthogranulomatous tissue consisting of foam-filled histiocytes and rare Teuton giant cells. The CD68 stain was positive within histiocytes, pointing to ECD as a likely diagnosis. Three months postoperatively, visual acuity was 20/25 OD and 20/20 OS with full EOMs. Hertel measurements were 17 mm OD and 17 mm OS. She was maintained on NSAIDs as needed but was no longer on prednisone. The patient did not report any other systemic symptoms and did not undergo further treatment. She was then lost to follow up.

Case 3

A 45-year-old Black female with a past medical history of chronic heart failure, pericardial effusions requiring pericardiocentesis, chronic kidney disease, panniculitis, bilateral angiomyolipomas, and diabetes insipidus presented with bilateral orbital inflammation. She had been previously treated with high-dose oral prednisone and desmopressin despite a clear diagnosis; however, she developed skin lesions on the bilateral medial thighs after 5 months, prompting a transition to oral methotrexate 20 mg weekly. The skin lesions improved on methotrexate; however, after 1 year, she noted worsening of her panniculitis and stopped the medication. Four months following cessation of methotrexate, she presented to the emergency room for severe bilateral lower extremity edema and ascites and was found to have a pituitary mass on MRI. She was admitted to the intensive care unit where she underwent a pericardial window for a large pericardial effusion. At that time, her systemic symptoms began improving, and she was discharged in stable condition.

One year later, the patient presented to BPEI with right orbital pressure and intermittent proptosis. Visual acuity was OD 20/25 and OS 20/20 with full EOMs. She had significant proptosis, with Hertel measurements of OD 31 and OS 25 as well as bilateral lacrimal gland enlargement. MRI showed heterogeneously enhancing bilateral lacrimal gland and intraconal masses exerting mass effect on the orbital content and associated with mild proptosis, findings consistent with ECD (Fig. A,B). The lesions also demonstrated slightly heterogeneous, isointense T2 signal with areas of low signal intensity, which may indicate a fibrotic component (Fig. C). Right lacrimal gland biopsy was obtained and inconclusive, so a medial right orbitotomy with biopsy was performed. Histopathological examination showed diffuse orbital inflammation and fatty infiltration positive for CD68 and negative for S100. The lesion consisted of xanthogranulomatous inflammation with reactive fibrosis. The patient was placed on a prednisone 60 mg taper over 3 weeks, which improved the swelling and pressure. Hertel measurements significantly improved after treatment with prednisone to 27.5 mm OD and 24.5 mm OS. However, she did not experience systemic improvement on prednisone so a switch to a steroid-sparing agent was recommended. In collaboration with rheumatology, she was transitioned to mycophenolate mofetil 500 mg 4 times daily. Despite some clinical improvement, the medication was discontinued after 4 months due to fever and severe knee and hip pain. Proptosis worsened after discontinuation, with Hertel measurements of 30 mm OD and 27 mm OS.

After 9 months on mycophenolate mofetil, she was transitioned to vemurafenib 240 mg twice daily following a positive test result for the BRAF V600E mutation. She noted subjective improvement in proptosis and bone pain with improvement in her ascites and other systemic symptoms. She denied other constitutional symptoms following initiation of treatment but did develop epiphora of the OS. Examination disclosed worsening bilateral dry eye and blepharitis, and this was managed conservatively with lubrication. Three years following vemurafenib initiation, visual acuity was 20/20 OU with full EOMs. Her right proptosis improved by 5 mm, left proptosis improved by 2 mm, and bilateral lacrimal gland enlargement stabilized. The patient remained stable on vemurafenib through 3 additional years of follow up with orbital and systemic improvement.

Case 4

A 67-year-old Hispanic male with a past medical history of type 2 diabetes, hypertension, atrial fibrillation, dementia, and hypothyroidism presented with OS proptosis, redness, and swelling. On review of systems, he also endorsed progressive shortness of breath and cognitive decline over the past 3 years. CT chest 3 years prior showed marked periaortic soft tissue thickening and a large pericardial effusion, resulting in a pericardiocentesis. During workup of cognitive impairment, CT showed homogenously enhancing bilateral intraconal masses surrounding the optic nerve sheath complexes with proptosis and mild tenting of the posterior aspect of the left globe, which prompted his referral to BPEI (Fig. D). At presentation, visual acuity was OD 20/50, OS 20/100, and EOMs in the left were restricted in upgaze (−1), downgaze (−3), adduction (−2), and abduction (−2). Hertel measurements were 20 OD and 22 OS. Fundus exam showed OS optic disc elevation 360 with no hemorrhage. He underwent left orbitotomy with biopsy, which disclosed fibrovascular tissue that contained a lymphoid infiltrate composed of small lymphocytes with positive CD68 and IgG staining and negative cytokeratin, CD1a, and S100 stains, consistent with ECD. He was started on prednisone 50 mg daily, which was discontinued after 4 months due to hyperglycemia, pretibial skin changes, and ulcers.

The patient began vemurafenib 240 mg twice daily, and 2 months after initiation, he reported reduction in OS inflammation and proptosis but some dryness and discharge. His EOMs demonstrated residual horizontal restriction but normal vertical motility, and he reported subjective improvement in inflammation. Visual acuity was OD 20/100 and OS 20/70, which was attributed to concurrent mixed mechanism optic neuropathy, primarily of the OS, and intraocular pressure readings suspicious of open angle glaucoma. Vemurafenib resulted in significant improvement of proptosis, mentation, and cardiac function with no evidence of toxicity. Three months later, he developed hypertrophic skin lesions, so therapy was switched to dabrafenib, a BRAF inhibitor with better central nervous system penetration, in combination with trametinib. However, the new regimen resulted in recurrence of proptosis, so he was transitioned back to vemurafenib. His proptosis reduced despite some skin lesions and ocular surface dryness. Following treatment with BRAF inhibitors, CT scans at 12 and 18 months after initial presentation demonstrate interval reduction in size of the lesions with improved proptosis and decreased mass effect (Fig. E,F). He has remained stable for 1 year on treatment.

DISCUSSION

Erdheim–Chester disease is a clonal neoplastic disorder that manifests as infiltration of tissues by foamy xanthomatous histiocytes, which has been shown to be associated with recurrent activating kinase mutations and fusions involving the mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway.2 BRAF is a serine/threonine kinase that functions in the MAPK pathway which consists of (rat sarcoma/rapidly accelerated fibrosarcoma/MEK/extracellular-signal-regulated kinase).13 In recent years, ECD has also been linked to a BRAF/V600E mutation with estimations of mutation frequencies ranging from 38% to 68% in most reports, portending a poor prognosis.2,7 V600E–mutant BRAF results in RAS-independent monomeric signaling, increased kinase activity, and MEK and ERK activation.13 BRAF inhibitors such as vemurafenib have been shown to be safe and effective and are recommended as first-line management for patients with multisystem BRAF–V600E–mutant ECD with life-threatening cardiac or neurologic involvement.2,14 As of August 2023, vemurafenib has been Food and Drug Administration approved for the treatment of ECD and metastatic and unresectable melanoma with V600 mutation.15 Vemurafenib has particularly proven effective in targeting orbital involvement of ECD, with one preliminary case report in 2017 detailing a dramatic response after 6 months of vemurafenib therapy in a patient with bilateral orbital involvement of ECD.8,16 In a literature review performed by Park et al. of 47 patients with ophthalmic presentations, 12.8% were on vemurafenib. The vision improved by 79.1% in the vemurafenib group as compared with a 24.4% decrease in the final visual acuity in group on historical therapy, such as oral or intravenous steroids. Moreover, overall mortality was significantly higher in patients on historical therapy (29.3%) as compared with those on vemurafenib (16.7%).5 The standard dosage of vemurafenib is 960 mg twice daily; however, lower doses have been associated with improvement of ECD symptoms as well.17

This is a single-institution case series detailing the course of ECD in 4 patients treated at BPEI. All patients also experienced improvement in either systemic or ophthalmic findings. Case 3 and case 4 were treated on vemurafenib after lack of response to other medical therapy. These findings were compared to one patient on cobimetinib for 7 months who experienced resolution of a conjunctival lesion (case 1) and one patient on prednisone for 1 month who experienced improvement in ocular pain (case 2). Both patients on vemurafenib achieved reduction in proptosis and were maintained on the medication regimen long-term, notable differences from the outcomes of the patients not treated with vemurafenib.

Vemurafenib was the only medical treatment that was tolerated well for an extended period; all other medications were discontinued due to intolerable side effects. In case 1, prednisone therapy had to be discontinued due to unfavorable effects of the medication on her blood sugar. Case 2 had to discontinue steroid use, peg interferon, cladribine, and methotrexate/6-mercaptopurine due to adverse systemic effects. Cobimetinib was the most well-tolerated medication used in this patient and achieved remission of ocular disease; however, this medication was also discontinued due to intolerable swelling leading to hospitalization. Reported side effects of cobimetinib in literature include nonacneiform rash, ocular disorders, creatine phosphokinase elevation, and cardiomyopathy.18 On the contrary, the 2 patients on vemurafenib were able to maintain the vemurafenib regimen long term. Case 3 was treated with vemurafenib for 6 years while case 4 is continuing to use vemurafenib after initiation 1 year ago.

Vemurafenib use in these 2 ECD patients was associated with substantial improvement in proptosis. Case 3 experienced the greatest reduction in proptosis following vemurafenib initiation as compared to prednisone, which slightly decreased proptosis but did not lead to systemic improvement, and mycophenolate mofetil, which increased proptosis. Despite experiencing bilateral dry eye from the chemotherapy, she noted improvement in the bulging of her eyes and bone pain that significantly impacted her quality of life; as such, she has continued the medication regimen for 6 years. Recent case studies have reported similar improvement in proptosis on vemurafenib, with one case showing a reduction in bilateral posterior eyeball muscle cones on vemurafenib 960 mg twice daily for 2 months.19 Case 4 also experienced substantial proptosis control on vemurafenib that was not seen with other medications, including prednisone and dabrafenib, despite some worsening of visual acuity and development of dry eye on vemurafenib. He also experienced improved mentation and cardiovascular function on vemurafenib. In both patients, the main ocular complaint following vemurafenib use was dry eye. According to one study of 901 patients treated with vemurafenib for systemic malignancy, dry eye was the second most common ocular side effect. Fourteen had ophthalmic side effects with uveitis occurring in 7 of those 14 (50%) followed by dry eye in 4 (29%) and central serous chorioretinopathy in 2 (14%) of patients.20 In a similar study examining 568 patients with cutaneous melanoma, dry eye was the third most common ocular side effect (2.0%) after uveitis (4.0%) and conjunctivitis (2.8%).21

Despite its efficacy in treating many disease sites effectively and rapidly, vemurafenib has been shown to be associated with cutaneous complications (rash, squamous cell carcinoma), arthralgia, heart-rate corrected QT interval prolongation, and fatigue. In one study from China of 12 patients with ECD, the most cited adverse effect was a skin rash (58.3%).14 Cutaneous complications were also seen in case 4 of the present study when the patient developing hypertrophic skin lesions following vemurafenib initiation. BRAF inhibitors may also increase the risk of secondary neoplasia, sarcoidosis, and pancreatitis by activation of RAS signaling in BRAF-wild-type cells. Nevertheless, vemurafenib has been shown to be critical to the reversal of the ECD disease state in several cases.2 One study by Cohen Aubart et al.22 showed that 75% of patients who discontinued vemurafenib relapsed within 6 months and required rescue treatment to recapture response. Similarly, case 4 discontinued treatment after experiencing cutaneous complications and required retreatment with vemurafenib in order to maintain improvement in proptosis.

While vemurafenib targets the MAP kinase pathway of ECD pathogenesis, management of ECD may also utilize drug therapy that targets other involved pathways such as mammalian target of rapamycin. The mammalian target of rapamycin pathway is involved in 11% to 17% of ECD patients, particularly through phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutations.2,23,24 Sirolimus with prednisone has been used as a target of this pathway. In a prospective cohort study of 10 ECD patients, 8 had objective responses of disease stabilization while 2 had disease progression.24 However, mammalian target of rapamycin inhibitors such as sirolimus have only been indicated as a therapeutic option in refractory ECD patients and are not classified as first-line therapy.2 Additionally, a treatment regimen with a significant amount of supporting evidence for its use in ECD is IFN-α and pegylated IFN-α. In a study of 53 ECD patients, 46 had significantly improved overall survival on this regimen. Nevertheless, IFN-α and pegylated IFN-α are associated with several potential toxicities, including constitutional symptoms, neuropsychiatric symptoms, gastrointestinal symptoms, alopecia and pruritus, transaminitis, and myelosuppression. Similarly, gastrointestinal upset, diarrhea, malaise, fever, additional weight loss, and postnasal drip with cough were observed in case 1 of the present study.7

This case series is limited by its small sample size. Only 4 patients with ECD with orbital involvement were identified at BPEI. Moreover, some patients were lost to follow up. To account for this, clinical notes from other treating physicians, such as those in rheumatology or pulmonology, were examined and any details of ophthalmic symptoms after the last visit to BPEI were reported. The study is also a retrospective observational study. Because of this, some data, such as consistent Hertel measurements, were not found for all patients. This limited the quantitative analysis of some patients even though subjective details on proptosis and other ophthalmic manifestations were often noted. A future prospective interventional study of patients on vemurafenib may help reduce these limitations.

CONCLUSIONS

Management of ECD is challenging and often requires multimodal treatment. We reviewed outcomes of all treatment methods used for ECD and found that vemurafenib demonstrated its utility in reducing proptosis in ECD patients at one ophthalmic institution. Vemurafenib was the only medication that was well tolerated long term and resulted in significant improvement in proptosis despite some reported dry eye. Vemurafenib may be a favorable treatment option for BRAF-positive ECD patients presenting with orbital disease. Future studies may prospectively compare treatment modalities to help guide management.

Radiographic images for 2 cases of Erdheim–Chester disease. Case 3: pre- and postcontrast T1-weighted images (A, B) demonstrate heterogeneously enhancing bilateral intraconal masses exerting mass effect on the orbital content and associated with mild proptosis. The lesions demonstrate slightly heterogeneous, isointense T2 signal (C) with areas of low signal intensity, which may indicate fibrotic component. Case 4: initial axial CT (D) shows homogeneously enhancing bilateral intraconal masses surrounding the optic nerve sheath complexes with proptosis and mild tenting of the posterior aspect of the left globe. Follow-up CTs obtained at 12 (E) and 18 (F) months following initial orbital symptoms demonstrate interval reduction in size of the lesions with improved proptosis and decreased mass effect.

STW is a consultant for Lassen Therapeutics and Immunovant, an advisor for Horizon Therapeutics, and participates in funded research with Horizon Therapeutics, Immunovant, and Sling Therapeutics. The remaining authors have no financial or conflicts of interest to disclose.
==== Refs
REFERENCES

1. Kanakis M Petrou P Lourida G . Erdheim-Chester disease: a comprehensive review from the ophthalmologic perspective. Surv Ophthalmol. 2022;67 :388–410.34081930
2. Goyal G Heaney ML Collin M . Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood. 2020;135 :1929–1945.32187362
3. Guo J Wang J . Adult orbital xanthogranulomatous disease: review of the literature. Arch Pathol Lab Med. 2009;133 :1994–1997.19961259
4. Campochiaro C Tomelleri A Cavalli G . Erdheim-Chester disease. Eur J Intern Med. 2015;26 :223–229.25865950
5. Park JK Huang LC Kossler AL . Erdheim-Chester disease and vemurafenib: a review of ophthalmic presentations and clinical outcomes. Orbit. 2023;42 :233–244.35702885
6. Hammond MD Niemi EW Ward TP . Adult orbital xanthogranuloma with associated adult-onset asthma. Ophthalmic Plast Reconstr Surg. 2004;20 :329–332.15266154
7. Diamond EL Dagna L Hyman DM . Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood. 2014;124 :483–492.24850756
8. Gupta A Yeganeh A Rootman D . Vemurafenib (BRAF inhibitor) therapy for orbital Erdheim-Chester disease. Ophthalmic Plast Reconstr Surg. 2017;33 :e138–e139.28099231
9. McKelvie P McNab AA Hardy T . Comparative study of clinical, pathological, radiological, and genetic features of patients with adult ocular adnexal xanthogranulomatous disease, Erdheim-Chester disease, and IgG4-related disease of the orbit/ocular adnexa. Ophthalmic Plast Reconstr Surg. 2017;33 :112–119.26882062
10. Emile JF Diamond EL Hélias-Rodzewicz Z . Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease. Blood. 2014;124 :3016–3019.25150293
11. Larkin J Ascierto PA Dréno B . Combined vemurafenib and cobimetinib in BRAF- mutated melanoma. N Engl J Med. 2014;371 :1867–1876.25265494
12. Benson JC Vaubel R Ebne BA . Erdheim-Chester disease. AJNR Am J Neuroradiol. 2023;44 :505–510.36997288
13. Halle BR Johnson DB . Defining and targeting BRAF mutations in solid tumors. Curr Treat Options Oncol. 2021;22 :30.33641072
14. Liu T He TH Niu N . Efficacy and safety of vemurafenib in the treatment of BRAF(V600E)-mutated Erdheim-Chester disease. Zhonghua Xue Ye Xue Za Zhi. 2021;42 :752–756.34753230
15. Khaddour K Kurn H Zito PM . Vemurafenib. Treasure Island, FL: StatPearls, 2023.
16. Allen RC . Molecularly targeted agents in oculoplastic surgery. Curr Opin Ophthalmol. 2017;28 :485–492.28598870
17. Qiao J Ma R Peng X . Erdheim-Chester disease with bilateral orbital masses and multi-systemic symptoms: two case reports. World J Surg Oncol. 2023;21 :233.37525276
18. King AC Diamond EL Orozco JS . Cobimetinib-induced “dropped head syndrome” and subsequent disease management in an Erdheim-Chester patient. Clin Case Rep. 2019;7 :1989–1993.31624624
19. Wang X Cao J Du W . Vemurafenib for BRAF V600-mutant Erdheim-Chester disease presenting with bilateral orbital involvement. Clin Case Rep. 2023;11 :e7780.37609641
20. Castillejo Becerra CM Smith WM Dalvin LA . Ophthalmic adverse effects of BRAF inhibitors [Epub ahead of print October 11, 2022]. Eur J Ophthalmol. 2022. doi: 10.1177/11206721221132872.
21. Choe CH McArthur GA Caro I . Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. Am J Ophthalmol. 2014;158 :831–837.e2.25036880
22. Cohen Aubart F Emile JF Carrat F . Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study). Blood. 2017;130 :1377–1380.28667012
23. Gianfreda D Musetti C Nicastro M . Erdheim-Chester disease as a mimic of IgG4-related disease: a case report and a review of a single-center cohort. Medicine (Baltim). 2016;95 :e3625.
24. Gianfreda D Nicastro M Galetti M . Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. Blood. 2015;126 :1163–1171.26041743
