Accelerated corneal endothelial cell loss in two patients with granulomatosis with polyangiitis following phacoemulsification

Granulomatosis with polyangiitis (GPA) is a systematic autoimmune disease with prevalence of 0.003% in America [1, 2], with 50–60% patients presenting with ocular manifestation lifetime [3]. The suspected etiology is activated dendritic cells that present autoantigen and prime type 1 T helper cells inducing macrophage migration, maturation and causing granuloma and tissue destruction. Chronic T cells activation promotes B cells secretion of antineutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) or myeloperoxidase (MPO) which trigger neutrophil activation and lead to vasculitis [4]. The clinical manifestations include flu-like symptoms, hearing loss, otitis media, bloody rhinorrhea, sinusitis, pulmonary disease, renal, cutaneous, neurologic problems and also conjunctivitis, scleritis, corneal ulceration, or uveitis [5, 6]. Importantly, most patients with GPA and ocular comorbidity are visually or systemically impaired [3].

Physiologically, the corneal endothelium consists of a monolayer of human corneal endothelial cells (HCEC), which remain contact-inhibited or non-proliferative, and endothelial cell density (ECD) diminishes gradually since birth until death [7]. The average ECD is around 2500 cells/mm² in older adults [8]. When the ECD falls below 400–700 cells/mm², the HCEC fail to pump the water out the cornea which ends up with corneal edema [9]. Pathologically, the loss rate of HCEC in routine cataract surgery is 8.5% [10], while that in patients with low ECD ranges from 5.1% to 12.1% [11, 12]. By contrast in the diabetic population, phacoemulsification-induced HCEC loss ranges from 6.2% up to 29.7% [13].

Here, we report a 69-year-old man with GPA suffering from significantly declined ECD up to 45% after phacoemulsification in the following-up of 49 months. Additionally, we report a 54-year-old woman with GPA suffering from declined ECD to 36.1% four months after cataract surgery, whose ECD recovered to 69.6% of the original level with ascorbate drops for 11 months.

Previously known as Wegener's granulomatosis, GPA is an ANCA-associated autoimmune disease involving multi-organ damage and is fatal without treatment. In this report, the patients had most classic manifestations of GPA and gradually developed to hypertension, and even cataract due to long-term use of steroid. Besides, PUK was also presented concurrently in one patient [17].

For a patient with GPA, long-term use of corticosteroid may accelerate the formation of posterior subcapsular cataract, with several theories [18]. Thorough systemic review, close follow-up, and control of local inflammation are mandatory before intraocular surgery because autoimmune-related corneal melting can occur spontaneously or after cataract extraction [19, 20]. There is also research aiming to discover specific antibodies in patients with autoimmune diseases that are responsible for corneal melting [21]. When the auto antibodies bind to specific corneal antigen forming immune complex, the classical pathway of complement was activated. Inflammatory cells are driven to peripheral cornea and produce cytokines inducing stromal keratocytes to release matrix metalloproteinases which subsequently dissolve the cornea [22‐24].

In this case, we observed an abnormal pattern of corneal endothelial cell loss after cataract surgery, even though that one patient had concomitant diabetes under stable metformin therapy and a long-term serum HbA1c level of 6.0 to 6.5%. In addition, his inflammatory status was relatively stable based on preoperative examinations of serum C reactive protein (CRP) quantity and erythrocyte sedimentation rate (ESR) which were controlled around 10 mg/L and 25 mm/hour one month after the right cataract surgery.

Though this is only a case report, the patient’s binocular ECD decreased approximately 40% four months postoperatively and ended up around 44% in the forty months follow-up and another patient’s ECD decline 38.3% nine months after surgery which was apparently higher than that of 1.4% to 18.4% in non-diabetic and 6.2% to 29.7% in diabetic patients three months postoperatively shown in a meta-analysis study [13]. We speculate that the patient’s corneal endothelial cells were more susceptible to intraocular surgery than those in the normal population and even the diabetic patients owing to underlining GPA. In other word, the marked ECD decline was less likely related to autoimmune reaction aroused by cataract surgery per se since there was no severe postoperative local inflammation and no significant ECD decline in the left eye after the right cataract surgery. Also, no right eye ECD decreased in the second patient after left cataract surgery for 15 months. In the second case, tropical ascorbate sodium was given since the 4^th month after phacoemulsification which showed gradually increasing ECD to the last follow up at the 15^th month. Perioperative topical ascorbic acid (AA) has been shown preventive effects of corneal endothelial dysfunction in high-risk patients undergoing phacoemulsification [16]. AA has shown promoting proliferation effects in other human cells [25, 26]. In vitro evidence also shed light on the proliferative effects of AA on corneal endothelial cells [27]. Besides, there is clinical evidence of protective effect of AA on HCEC recently [16].

We have illustrated two rare cases of an old-aged male patient with GPA and PUK and a middle-aged female with GPA undergoing uneventful phacoemulsification but with marked loss of corneal endothelial cells. In the long-term follow-up, ECD decline was even more the that in the general population and diabetic group [13]. Collectively, we advocate extensive preoperative ophthalmic evaluation and meticulous postoperative inflammatory control to prevent severe corneal endothelial cell loss in such patients.