|Ahead of print publication
Peripheral ulcerative keratitis in a patient with granulomatous rosacea
Fang-Chi Hsiao1, Yaa-Jyuhn James Meir2, Ching-Hsi Hsiao3, Kuan-Jen Chen4, David Hui-Kang Ma5, Wei-Chi Wu4, Hung-Chi Chen6
1 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan
2 Department of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan
3 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou; Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
4 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou; Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan, Taiwan
5 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou; Department of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
6 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou; Department of Medicine, Chang Gung University College of Medicine, Taoyuan; Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan
|Date of Submission||18-Jun-2022|
|Date of Acceptance||03-Sep-2022|
|Date of Web Publication||05-Jan-2023|
5 Fuxing Street, Guishan District, Taoyuan 333423
Source of Support: None, Conflict of Interest: None
A 24-year-old woman visited our emergency department due to intermittent dull pain in the right eye, blurred vision, foreign body sensation for 3 weeks, and progressive facial rash with pustules for 3 months. She had a history of recurring skin rash on her face and extremities since early adolescence. Peripheral ulcerative keratitis (PUK) was diagnosed based on slit-lamp examination and corneal topography and then granulomatous rosacea (GR) based on clinical manifestations and skin pathology. Topical prednisolone, artificial tears, oral doxycycline, oral prednisolone, and topical clindamycin were administered. After 1 month, PUK progressed to corneal perforation probably due to eye rubbing. The corneal lesion was repaired with a glycerol-preserved corneal graft. A dermatologist prescribed oral isotretinoin for 2 months in conjunction with topical betamethasone gradually tapered for 14 months. After 34 months of follow-up, no signs of skin and ocular recurrence were noted, and the cornea graft was intact. In conclusion, PUK may present with GR, and oral isotretinoin may be an effective therapy for PUK in the setting of GR.
Keywords: Granulomatous rosacea, isotretinoin, peripheral ulcerative keratitis
|How to cite this URL:|
Hsiao FC, Meir YJJ, Hsiao CH, Chen KJ, Ma DH, Wu WC, Chen HC. Peripheral ulcerative keratitis in a patient with granulomatous rosacea. Taiwan J Ophthalmol [Epub ahead of print] [cited 2023 Jan 28]. Available from: https://www.e-tjo.org/preprintarticle.asp?id=367071
| Introduction|| |
Granulomatous rosacea (GR) is a variant of rosacea characterized by yellow–brown or pink papules around the cheeks, mouth, and eyes similar to skin disorders such as seborrheic dermatitis, demodicidosis, sarcoidosis, granuloma faciale, and perioral dermatitis. However, the etiology of GR is not fully understood. Chronic inflammation and T-helper 17 (Th17) activation are found to be associated with GR.
Peripheral ulcerative keratitis (PUK) is a disease presenting with crescent-shaped destructive inflammation at the juxtalimbal corneal stroma. It may cause vision-threatening corneal perforation. PUK is highly associated with autoimmune disorders. Interleukin (IL)-17 from Th17 can degrade the corneal stroma due to the production of matrix metalloproteinases (MMPs). Suppression of Th17 leads to less PUK ocular morbidity.
While antibiotics, anti-inflammatories, or retinoid drugs are administered, there remains no consensus on the management of GR. Meanwhile, PUK is treated on a case-by-case basis depending on the patient's condition. Topical treatment, systemic glucocorticoids, and conventional immunosuppressive drugs are adopted.
Herein, we report a case of PUK presenting in a patient with GR and oral isotretinoin might be effective for PUK and GR.
| Case Report|| |
A 24-year-old woman with recurring facial rash and pustules presented to our emergency department with intermittent dull pain in the right eye, blurred vision, and foreign body sensation persisting for 3 weeks.
The patient denied any history of underlying disease or operation, except for social alcohol consumption, occasional smoking, and, since early adolescence, recurring skin rash on the extremities and face. Three months before consultation, her facial rash with pustules progressed and developed more severely than ever [Figure 1]a, [Figure 1]b, [Figure 1]c. At the local dermatology clinic, acne was suspected and treated with intermittent topical agents, but the response was poor. At the local ophthalmology clinic, itchy and foreign body sensations in the right eye were caused by compulsive eye rubbing; topical sulfamethoxazole eye drops and tetracycline ointment were administered for 2 weeks. As the symptoms became more progressive, the patient was referred to our hospital.
|Figure 1: Clinical appearance of skin rash. (a) Facial rash with firm pustules over the periocular, perinasal, and perioral areas (b) Brown papules left on the bilateral skin of the arms after rash (c) Erythematous papules present at bilateral legs and feet (d) Face skin biopsy showed one granuloma with central microabscess (circle), and one necrosis with empty vacuoles surrounded by histiocytes (10×)|
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At the emergency room, the patient was tested for visual acuity: 20/200 in the right eye and 20/100 in the left eye without correction. Slit-lamp examination revealed major abnormalities in the right eye: diffuse hyperemia in the conjunctiva and episclera, perilimbal 3 to 6 o'clock circumferential stromal thinning in the cornea without infiltrate, lipid deposit or vessel ingrowth, and 2+ cells (moderate) in the anterior chamber with flare and iris pigments [Figure 2]a. Later, in the outpatient follow-up, corneal topography revealed a thin cornea with an irregular surface and epithelium defect at peripheral 3 to 6 o'clock in the right eye, which was consistent with PUK. A survey for the autoimmune disease only revealed slightly decreased C3 of 89.5 mg/dL and C4 of 7.37 mg/dL and elevated erythrocyte sedimentation rate of 36 mm/h (normal range, 0-15). As for C-reactive protein, rheumatoid factor, antinuclear antibody, perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA), cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA), anti-ribonucleoprotein (anti-RNP), anti-Smith (anti-Sm) antibody, anti-SSA antibody, anti-SSB antibody, anti-double stranded DNA anti-body (anti-dsDNA), syphilis rapid plasma reagin (PRP), herpes simplex virus-IgM (HSV-IgM), HSV-1 IgG, and HSV-2 IgG were negative. At the dermatology clinic for consultation, acne skin biopsy revealed a granuloma with central microabscess, and small and large empty vacuoles in the dermis with traced granular IgG, IgA, and C3 immunocomplex at dermoepidermal junction, which was consistent with GR [Figure 1]d. Chest X-ray showed increased perihilar infiltration on both lungs. Accordingly, prednisolone acetate ophthalmic suspension 1% QID, tetracycline HCl 1% eye ointment, artificial tears, oral doxycycline 100 mg BID, oral prednisolone 10 mg TID, oral mefenamic acid 250 mg QID, and 1% topical clindamycin for facial rash were prescribed.
|Figure 2: Clinical appearance of the right cornea before and after treatment (a) Initial slit-lamp examination of the right eye presenting PUK at the 36 o'clock area with stromal thinning and cells in the anterior chamber with flare and iris pigments (b) Primary repair of perforated peripheral ulcerative keratitis with glycerol cornea (c) One month after glycerol cornea repair. The corneal graft was in situ with negative Seidel test (d) Inferonasal corneal graft with 1 stitch before removal of 9 months after repair. The anterior chamber was shallow and clear. No perforation, neovascularization, or inflammation was noted|
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However, after 1 month of treatment, PUK progressed to corneal perforation due to eye rubbing. The emergent repair was performed with a glycerol-preserved corneal graft [Figure 2]b. After surgery, the wound was clear and intraocular pressure was within normal limits. Topical betamethasone eye drops 0.1% after corneal suture was administered and gradually shifted to dexamethasone 0.1% + tobramycin 0.3% suspension and then prednisolone acetate ophthalmic suspension 1%. The topical steroid was gradually tapered 14 months after keratoplasty. In terms of her skin lesions, the dermatologist suggested oral isotretinoin 20 mg QD for 2 months and then switched to 0.1% adapalene cream. On the last visit, after 34 months of follow-up postoperatively, no sign of skin and ocular recurrence was reported, and the cornea graft was intact. Her final visual acuity of the right eye was 0.08.
| Discussion|| |
GR, a variant of rosacea, is diagnosed based on characteristic history and physical findings, and a biopsy may be necessary. Differential diagnosis includes periorificial dermatitis, childhood granulomatous periorificial dermatitis, lupus miliaris disseminatus faciei, sarcoidosis, facial Afro-Caribbean eruption, and cutaneous tuberculosis.
The etiology of GR is not fully understood. Steroids, ultraviolet radiation, heat, spicy food, alcohol, Demodex mites, GI bacteria, and immune dysfunction have been reported as triggers. GR has been associated with inflammation, altered immunity, and dysregulation of the vessel., The epidermis of a patient with rosacea releases IL-37, which activates mast cells releasing proteases such as chymase, tryptase, and MMPs. The MMPs damage the dermal matrix, thereby causing leakage and accumulation of inflammatory cells, leading to granuloma formation., Patients with ocular rosacea have elevated levels of IL-1a, IL-1b, MMP-8, MMP-9,,, elevated serum tumor necrosis factor-alpha (TNF-α), and overexpression of intercellular adhesion molecule 1 (ICAM-1) and human leukocyte antigen-DR (HLA-DR) in the epithelium of the conjunctiva., In such an inflammation microenvironment, Th17 polarization is supported and activates the T-cell response.
PUK is associated with rheumatoid arthritis, granulomatosis with polyangiitis, polyarteritis, systemic lupus erythematosus, rosacea, and other autoimmune disorders. It presents with crescent-shaped destructive inflammation at the juxtalimbal corneal stroma, causing vision-threatening corneal perforation. The pathogenesis of PUK is a combination of humoral immunity and cell-mediated immunity. The supposed mechanisms are autoimmune reactions to the corneal antigens, circulating immune complex deposition, and hypersensitivity reactions to exogenous antigens., The classic pathway of the complement system is activated by circulating immune complexes, which are deposited in the limbal vessels and later cause chemotaxis of inflammatory cells primarily macrophages and mast cells, leading to elevation of local collagenases, MMPs, and inflammatory cytokines such as TNF-α and IL-6., MMPs would hydrolyze the collagens at the peripheral cornea which correlated to PUK progression., Th17 secretes IL-17 and can be activated by cytokines such as TGF-β1, IL-6, and IL-21, whereas IL-1 stimulates Th17 differentiation.,, IL-17 could enhance MMP production and further causes corneal stroma degradation. Suppression of Th17 leads to less PUK ocular morbidity.
Despite the lack of standardized management for GR, antibiotics, anti-inflammatories, or retinoid drugs are administered. PUK is treated on a case-by-case basis depending on the patient's condition, commonly including the use of topical treatment, systemic glucocorticoids, and conventional immunosuppressive drugs. In our case, topical steroid plus topical tetracycline and topical steroid plus topical clindamycin with oral doxycycline were used initially. However, the patient's corneal condition did not improve quickly [Figure 2]c and [Figure 2]d. Although we performed therapeutic keratoplasty with a patch graft for temporal sealing of the corneal perforation, oral isotretinoin, or topical adapalene might be responsible for the long-term maintenance of ocular surface integrity. Isotretinoin inhibits sebum production by affecting cell cycle and differentiation, and it can induce apoptosis of sebocytes and keratinocytes, which subsides the acne. In addition, isotretinoin has anti-inflammatory properties, inhibits the activity of Th17, and promotes the activity of regulatory T-cells, which helps in the relief of PUK in this case., Presumably, medications targeting Th17 may be helpful for GR or PUK although systemic isotretinoin could cause meibomian gland dysfunction and decrease corneal epithelium cell density.,
| Conclusion|| |
To our knowledge, this is the first case of GR presenting with PUK and corneal perforation. Although there is no direct evidence that systemic isotretinoin can cure PUK, the clinical response shed light on isotretinoin to be the drug of choice for PUK in the setting of GR.
This work was approved by the Institutional Review Board of Chang Gung Medical Foundation (IRB no. 202101828B0).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
His study was supported by grants from Chang Gung Memorial Hospital (CRRPG3M0071) and the Ministry of Science and Technology (MOST-111-2314-B-182A-067-MY3) to Chen HC.
Conflicts of interest
Prof. Ching-Hsi Hsiao and Prof. David Hui-Kang Ma, an editorial board members at Taiwan Journal of Ophthalmology, had no roles in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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