From the 2nd Ophthalmology Department (MP, TK, PT), Attikon University Hospital; and the Internal Medicine Department (EZ), Spiliopoulio Hospital, Athens, Greece.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Miltiadis Papathanassiou, MD, 2nd Ophthalmology Department, Attikon University Hospital, Athens, Greece. E-mail: firstname.lastname@example.org
Juvenile idiopathic arthritis (JIA) is the most common form of childhood arthritis and one of the more common chronic childhood illnesses, but its cause is still poorly understood. In fact, JIA is an umbrella term that refers to a group of disorders that have in common chronic arthritis with an onset before the 16th birthday and are divided into seven categories. These subtypes demonstrate unique clinical presentations, immunogenic associations, and clinical courses.1 Approximately 10% of children with JIA have systemic-onset JIA.2 Daily fever of at least 2 weeks’ duration, documented to be continuous for at least 3 days, as well as evanescent, nonfixed erythematous rash, hepatomegaly and/or splenomegaly, generalized lymph node enlargement, and serositis are characteristic of systemic-onset JIA.1,2 Positive rheumatoid factor is rare. Extra-articular features are usually mild to moderate in severity, whereas uveitis is less common than in other subtypes of JIA.2
Peripheral corneal ulceration is a potentially devastating disorder consisting of a crescent-shaped destructive inflammation at the corneal periphery that is associated with an epithelial defect, presence of stromal inflammatory cells, and progressive stromal degradation and thinning. Peripheral ulcerative keratitis can quickly produce progressive necrosis of the corneal stroma, leading to perforation.3 Peripheral ulcerative keratitis may be associated with several systemic conditions, with several studies denoting rheumatoid arthritis as the most common associated disease. Corneal melt usually occurs in a patient with longstanding rheumatoid arthritis, in whom rheumatoid vasculitis is frequent and rheumatoid factor is usually positive.4
In contrast, corneal involvement has not yet been reported in pediatric patients with systemic-onset JIA. We present a patient with systemic JIA who presented with unilateral peripheral ulcerative keratitis during arthritis exacerbation.
A 10-year-old girl presented with a painful inflamed left eye, photophobia, and reduced visual acuity for the past 2 weeks. Her medical history revealed systemic-onset JIA diagnosed at the age of 7 years. She did not report having any episode of uveitis in the past or any other ocular involvement. She gave a history of an exacerbation of the disease 2 months ago, after discontinuing treatment with anti-tumor necrosis factor agents (etanercept and adalimumab) due to allergic reaction. At presentation, the patient was receiving 16 mg of methylprednisolone per day and 15 mg of methotrexate per week.
On examination, uncorrected visual acuity in the left eye was 6/36 and best spectacle-corrected visual acuity was 6/9 with a refraction of −1.0 sphere −3.0 cylinder at 180°. Slit-lamp examination revealed a temporal crescent-shaped melting lesion of the juxtalimbal corneal stroma from the 2- to 5-o’clock positions (Figure). It was associated with an overlying epithelial defect and severe corneal stromal thinning. The anterior chamber was deep with a moderate amount (grade 3) of inflammatory cells. The lens was clear and vitreous did not reveal any inflammatory cells. Fundus examination was unremarkable and intraocular pressure was 20 mm Hg. No pathology was revealed from the contralateral eye, which had an intraocular pressure of 17 mm Hg. No blepharitis was found in either eye. Corneal sensation measured with a cotton tip was equally normal in both eyes. There was no evidence of dry eyes and Schirmer’s test without anesthetic was 12 mm in the right eye and 14 mm in the left eye.
Figure. Slit-Lamp Examination at Presentation. The Area Between the Arrows Shows a Temporal Crescent-Shaped Melting Lesion of the Juxtalimbal Corneal Stroma Between the 2- and 5-o’clock Postions.
Laboratory tests showed normal complete blood cell count, urinalysis, blood urea nitrogen, and creatinine. Erythrocyte sedimentation rate and C-reactive protein were within normal ranges, whereas ferritin, an acute phase protein indicative of inflammation, was elevated. Rheumatoid factor, commonly found in patients with rheumatoid arthritis and anti-cyclic citrullinated peptide antibodies, highly specific for rheumatoid arthritis, were negative. Serum angiotensin-converting enzyme, a marker mainly of sarcoidosis but also antinuclear antibodies, antibodies to double-stranded DNA, and anti-extractable nuclear antigen found in patients with collagen vascular diseases such as systemic lupus erythematosus, were also negative. Antibodies associated with Wegener’s granulomatosis, such as cytoplasmic anti-neutrophil cytoplasmic antibodies and complement (C3, C4), were also negative. Antibodies for herpes simplex virus I and II, hepatitis B surface antigen, varicella zoster virus, human immunodeficiency virus, and fluorescent treponemal antibody-absorption were negative, apart from positive IgG for herpes simplex virus I. Chest x-ray and Mantoux test were also negative. Scrapings were taken from the affected area, but culture did not reveal any pathogen.
Treatment was initiated immediately with hourly topical steroids, topical ofloxacin four times a day, lubricating drops, and gel at night. Methylprednisolone was increased to 32 mg per day and methotrexate remained at the current dose (15 mg per week). By the third week of follow-up, more than half of the ulcer had been healed. Topical and oral steroids were tapered during the next months while methotrexate was continued in the same dose. Three months after diagnosis, the ulcer was completely healed, without any significant corneal scarring or neovascularization remaining. The patient continued to receive 8 mg per day of oral methylprednisolone and 15 mg per week of methotrexate for her systemic disease.
The pathogenesis of peripheral ulcerative keratitis has not been elucidated completely. Both T cell and antibody-mediated pathways have been implicated in the disease process.5 Abnormal T cell responses have been found in several studies on peripheral ulcerative keratitis.5–7 It is hypothesized that T cells lead to antibody production and the formation of immune complexes that deposit in the peripheral cornea.3 The complement pathway is activated with resulting recruitment of inflammatory cells to the cornea. Collagenases and other proteases are secreted by those inflammatory cells, mainly neutrophils and macrophages, which lead to destruction of the peripheral corneal stroma. Histopathologic examinations of cornea and conjunctiva from patients with peripheral ulcerative keratitis reveal a multitude of inflammatory cells including plasma cells, neutrophils, mast cells, and eosinophils.5
The list of differential diagnosis of peripheral ulcerative keratitis is long. Systemic diseases that may cause immune complex deposition at the peripheral cornea and peripheral ulcerative keratitis include collagen vascular diseases such as rheumatoid arthritis, Wegener granulomatosis, polyarteritis nodosa, relapsing polychondritis, and systemic lupus erythematosus.4 Rheumatoid arthritis has been reported as the most common collagen vascular disorder associated with peripheral ulcerative keratitis, found in 34% of patients with peripheral ulcerative keratitis in one study and 42% in another.8,9 Ocular and systemic infections may also cause or be associated with peripheral ulcerative keratitis. Microbial pathogens implicated include bacteria (Staphylococcus and Streptococcus species), spirochetes (Treponema pallidum), Mycobacteria (tuberculosis), viruses (hepatitis C, herpes simplex virus, and varicella zoster virus), Acanthamoeba, and fungi.5 Differential diagnosis should also include topical factors and ocular pathologies, such as blepharitis, contact lens use, keratoconjunctivitis sicca, pellucid marginal degeneration, and Terrien marginal degeneration.4 Masquerade of malignancy (leukemia) can also be included in the differential diagnosis.10
In the case we are presenting, peripheral ulcerative keratitis was attributed to the underlying systemic-onset JIA because no other pathology could be found to explain it. To the best of our knowledge, this is the first report of peripheral ulcerative keratitis in a young patient with systemic-onset JIA with only a few years of disease duration and negative rheumatoid factor. Topical and systemic steroids are the cornerstone of therapy for arthritis-associated–peripheral ulcerative keratitis in the acute phase, combined with vigorous systemic long-term immunosuppression, which is also recommended.11 Inflammation suppression is the critical factor in the management of peripheral ulcerative keratitis because it could stop the cascade of neutrophil migration, complement activation, and release of cytokines and degradative enzymes. Peripheral ulcerative keratitis management may necessitate using cyanoacrylate glue in small perforations, or even tectonic crescentic lamellar grafts or penetrating keratoplasty and corneoscleral patch graft in large perforations.11
Peripheral ulcerative keratitis is a rare condition, which can be associated with many systemic autoimmune and infectious disorders. If not diagnosed and treated properly, it is potentially devastating not only for the vision but also for the patient’s life, because it can be associated with life-threatening underlying conditions. Systemic-onset JIA should also be included in the list of differential diagnosis of underlying disorders in children presenting with peripheral ulcerative keratitis.
- Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–392.
- Hofer M, Southwood TR. Classification of childhood arthritis. Best Pract Res Clin Rheumatol. 2002;16:379–396.
- Mondino BJ. Inflammatory diseases of the peripheral cornea. Ophthalmology. 1988;95:463–472.
- Galor A, Thorne JE. Scleritis and peripheral ulcerative keratitis. Rheum Dis Clin North Am. 2007;33:835–854. doi:10.1016/j.rdc.2007.08.002 [CrossRef]
- Dana M, Qian Y, Hamrah P. Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea. 2000;19:625–643. doi:10.1097/00003226-200009000-00008 [CrossRef]
- Foster C, Kenyon K, Greiner J, et al. The immunopathology of Mooren’s ulcer. Am J Ophthalmol. 1979;88:149–159.
- Mondino B, Brown S, Rabin B. Cellular immunity in Mooren’s ulcer. Am J Ophthalmol. 1978;85:788–791.
- Tauber J, Sainz de la Maza M, Hoang-Xuan T, Foster CS. An analysis of therapeutic decision making regarding immunosuppressive chemotherapy for peripheral ulcerative keratitis. Cornea. 1990;9:66–73. doi:10.1097/00003226-199001000-00013 [CrossRef]
- Sainz de la Maza M, Foster CS, Jabbur NS, Baltatzis S. Ocular characteristics and disease associations in scleritis-associated peripheral keratopathy. Arch Ophthalmol. 2002;120:15–19.
- Chawla B, Agarwal P, Tandon R, Titiyal JS. Peripheral ulcerative keratitis with bilateral optic nerve involvement as an initial presentation of acute lymphocytic leukemia in an adult. Int Ophthalmol. 2009;29:53–55. doi:10.1007/s10792-007-9167-1 [CrossRef]
- Messmer EM, Foster CS. Destructive corneal and scleral disease associated with rheumatoid arthritis: medical and surgical management. Cornea. 1995;14:408–417. doi:10.1097/00003226-199507000-00010 [CrossRef]