Conjunctivitis, episcleritis and anterior uveitis as the first presenting features of granulomatosis with polyangiitis

Abstract

Granulomatosis with polyangiitis (GPA) is a rare disorder characterised by inflammation of small-sized and medium-sized blood vessels that result in damage to various organ systems, but it most commonly affects the respiratory tract and kidneys. It is one of the few entities that can present with ocular inflammation as well as renal impairment at the same time. We describe a case of a 38-year-old man with conjunctivitis, episcleritis, anterior uveitis as a first manifestation of GPA. His presentation with red eye and anterior uveitis prompted further workup, which revealed acute renal failure (creatinine 442 mmol/L), elevated inflammatory markers (erythrocyte sedimentation rate of 85 mmol/hour and C reactive protein of 72 mg/L), and a c-antineutrophil cytoplasmic antibody titre >8. An urgent renal biopsy was performed demonstrating necrotising crescentic glomerulonephritis, which led to the final diagnosis of GPA. Treatment induction with intravenous methylprednisolone and plasmapheresis followed by an oral prednisone taper and intravenous rituximab infusions leading to resolution of all symptoms and normalisation of kidney function. This report highlights conditions that can present with both ocular inflammation and renal dysfunction with a focus on GPA and its ocular manifestations.

Background

Granulomatosis with polyangiitis (GPA) is a rare small-vessel vasculitis, which can become life threatening if not treated promptly. The 1-year mortality rate associated with GPA is as high as 80% in untreated populations but can be reduced to 10% with the use of immunosuppressive treatment regimens.¹ GPA has the capability to affect nearly any organ system, although the most commonly affected are the sinuses, respiratory tracts and kidneys. Common presenting signs and symptoms include otitis, gromerulonephritis, sinusitis, pulmonary infiltrates, arthralgias and ocular inflammation.²

Ocular and orbital manifestations are present in half of the patients with GPA and can also present as the dominant initial features of the disease.² Associated eye findings can include proptosis, lid oedema, conjunctivitis, episcleritis/scleritis, uveitis, optic neuropathy and retinal vasculitis.³ In severe cases, or when the diagnosis is delayed, vision loss may result. Patients who present with predominantly ocular symptoms (such as red eye in this case) are often misdiagnosed as these findings are neither sensitive nor specific for GPA. However, when considered in the context of other systemic manifestations of the disease, ocular findings can be critical to making the diagnosis of GPA.

Ophthalmologists are frequently involved in the care of patients with GPA and can serve a critical role in preventing disease progression, organ failure or even death in some cases. To our knowledge, there have been few, if any, cases documenting the initial clinical features of GPA from an ophthalmologic perspective. This case highlights a unique clinical presentation of GPA and can add to the growing body of literature as it pertains to ocular inflammation in GPA. In a broader context, it can also provide insight into the diagnostic and clinical challenges that ophthalmologists may encounter when patients presenting with ocular inflammation in the presence of acute kidney injury.

Case presentation

A 38-year-old man with no significant previous medical or ocular history presented to the emergency department (ED) with a 3-week history of red left eye (LE). He did not notice changes in vision. There was no discharge or eye pain, and he denied experiencing influenza-like symptoms. His symptoms did not improve with tobramycin ointment prescribed by his family physician. On examination in the ED, he was noticed to have diffuse hyperemia and engorgement of conjunctival vessels in LE. Initial testing was performed, and the patient was discharged with urgent ophthalmology follow-up.

On ophthalmologic examination 4 days later, visual acuity was found to be 20/20 in each eye. There was no relative afferent pupillary defect. Intraocular pressure was 15 mm Hg bilaterally. Anterior segment examination demonstrated mild conjunctival injection in the right eye with a clear cornea and quiet anterior chamber. The conjuctiva in LE was diffusely injected with slightly enlarged episcleral vessels and 1+ cells in the anterior chamber (figure 1). The conjunctival and superficial episcleral blood vessels blanched on administration of 10% phenylephrine. Dilated fundus examination was normal in each eye. The diagnosis of bilateral conjunctivitis, episcleritis and left mild acute anterior uveitis was made. Additional investigations were conducted, and the patient was discharged with ophthalmology follow-up 1 week later. Before the results of these investigations were reported, patient was represented to the ED 4 days later with new onset of left leg swelling.

Figure 1.

External photograph of manually retracted left eye demonstrating diffuse hyperemia of the conjunctiva and episclera.

Investigations

During the patient’s initial presentation to the ED, the patient was suspected to have a carotid cavernous fistula. CT and angiography of the brain were performed, but the results were unremarkable. Screening bloodwork was also conducted and demonstrated elevated creatinine at 110 mmol/L (age-corrected normal less than 103), elevated erythrocyte sedimentation rate (ESR) at 75 mm/hour (age-corrected normal 19 or less) and elevated C reactive protein (CRP) at 33.8 mg/L (normal is less than 5). Urinalysis was performed due to his slightly elevated creatinine demonstrated the presence of 3+ haemoglobin and 3+ protein in the urine.

On ophthalmological follow-up, the presence of ocular inflammation in the setting of decreased kidney function, haematuria and proteinuria along with elevated inflammatory serum markers prompted further testing. The patient was investigated for systemic autoimmune and infectious diseases, including angiotensin-converting enzyme (ACE), c-ANCA (antineutrophil cytoplasmic antibodies) and p-ANCA as well as syphilis serology, QuantiFERON-Gold and a chest X-ray (CXR).

Before the initial laboratory investigations were completed, the patient represented to the ED with significant left leg swelling. Urgent laboratory testing revealed significantly elevated creatinine at 442 mmol/L, ESR of 85 mm/hour and CRP of 72 mg/L. A diagnosis of acute renal failure was made and urgent renal biopsy was performed demonstrating necrotising crescentic glomerulonephritis. In conjunction with the presence of very high titres of c-ANCA antibodies of >8.0 Antibody Index (normal <1.0) in the serum, the diagnosis of GPA was made.

Differential diagnosis

Ocular inflammation has a wide differential diagnosis. However, in the setting of iritis and renal dysfunction, the differential diagnosis is narrowed considerably to the infectious and systemic inflammatory aetiologies listed in table 1.

Table 1.

Differential diagnosis of renal dysfunction with ocular inflammatory disease

Infectious aetiologies	Syphilis, tuberculosis, toxoplasmosis, leptospirosis, lyme
Systemic inflammatory aetiologies	Sarcoidosis, granulomatosis with polyangiitis, rheumatoid arthritis, tubulointerstitial nephritis and uveitis syndrome, Behcet syndrome, Sjögren’s syndrome, systemic lupus erythematous

Treatment

Immunosuppressive therapy is warranted in almost all patients with active GPA, and treatment typically involves both an induction phase and a maintenance phase. In this case, once a diagnosis of GPA was made, the patient’s induction treatment involved intravenous methylprednisolone and plasmapheresis followed by an oral prednisone taper and intravenous rituximab infusions. Recent studies contrasting rituximab and cyclophosphamide use in ANCA-associated vasculitis showed significantly improved 6-month remission rates in those treated with rituximab as an induction agent (64% vs 53%, respectively).⁴ Thus, the choice of rituximab in this case likely played a crucial role in the clinical outcome obtained in this case.

Outcome and follow-up

The patient was at ophthalmology follow-up 2 months after the diagnosis of GPA was made. The ophthalmological examination was unremarkable at this time. The CXR was normal.

Discussion

Although rare, a few reports have documented ocular involvement as the initial presenting feature in GPA.^{5 6} Most commonly, these patients will present with scleritis as the initial ocular finding.⁷ In our case though, the patient did not have sclertis and instead presented with a unique constellation of ocular findings, including bilateral conjunctivitis, episcleritis and unilateral mild acute anterior uveitis. Infectious conjunctival involvement in GPA is relatively uncommon and has only been reported in 4%–6% of patients. These patients typically present with areas of necrosis, fibrovascular change or granulomata involving the conjunctiva.⁷ Episcleritis is also a rare manifestation of GPA, and when it occurs in association with anterior uveitis, it confers a poorer prognosis.⁷ The presence of conjunctivitis, episcleritis and anterior uveitis in our patient in the setting of elevated inflammatory markers and unexplained kidney dysfunction were suggestive of an underlying autoimmune, inflammatory or atypical process. The absence of any other systemic symptoms of an infection suggested autoimmune and inflammatory aetiologies as the most likely culprits. Elevated ESR and CRP were suggestive of vasculitis.⁸

GPA is the most common vasculitis that affects both the eye and the kidney. It cannot be diagnosed on clinical grounds alone though and requires laboratory investigations, imaging and histological examination to confirm the diagnosis. The 1990 ACR criteria for GPA are comprised of four items as follows: (1) nasal or oral inflammation, (2) nodular, fixed or cavitary pulmonary involvement, (3) urinary abnormality (microhaematuria or red blood cell casts) and (4) granulomatous inflammation on histology.⁹ Evidence of any two of these findings (such as abnormal urinary sediment and granulomatous inflammation of the kidney in this case) is highly suggestive for GPA as the underlying aetiology (sensitivity 88.2%, specificity 92.0%).⁹

Thus, a standard set of investigations for all patients with evidence of ocular inflammation and renal dysfunction should include urinalysis, complete blood count, ESR, CRP, ACE, antinuclear antibodies, c-ANCA, p-ANCA as well as syphilis serology, and tuberculin skin test or QuantiFERON-Gold. A positive c-ANCA test result has a specificity as high as 90% for GPA when other clinical features of this disease are present.⁸ In patients with pulmonary symptoms, a chest radiograph or CT scan should also be done. Clinical, laboratory and imaging findings should guide the site of biopsy to confirm the diagnosis of GPA.

These results can be critical as the vast majority (94.1% of children and 76.8% of adults) who develop end-stage renal disease (ESRD) from GPA will do so within the first 3 months of their diagnosis.¹⁰ Early treatment and intervention have been shown to delay progression to ESRD as well as reduce in-hospital mortality rates, length of hospital stay and hospital readmission rates.¹⁰

This case highlights many of the clinical challenges associated with GPA, including the unusual clinical presentation, initiating a timely and appropriate set of investigations and making the diagnosis. Ophthalmologists can play a critical role in the diagnosis of GPA and other systemic vasculitides. Early diagnosis of GPA is difficult, but critical, because of its life-threatening fulminant nature when untreated.

Learning points.

• Red eye can be the first presenting feature of a life-threatening diagnosis such as granulomatosis with polyangiitis (GPA).

• Intraocular inflammation in cases of GPA can be mild and the main finding might be conjunctivitis.

• According to the 1990 ACR criteria, a patient is considered to have GPA if two of the following criteria are met: (1) nasal or oral inflammation, (2) nodular, fixed or cavitary pulmonary involvement, (3) urinary abnormality, and (4) granulomatous inflammation on histology. When ocular inflammation is present along with abnormal renal function, GPA as well as other infectious and inflammatory entities should be considered and further workup is indicated.

• All patients with ocular inflammation and clinical manifestations of an acute kidney injury (ie, leg swelling, decreased urine output, shortness of breath, nausea or vomiting) should have renal function testing checked as abnormal renal function can allow one to make a correct diagnosis and initiate appropriate treatment quickly improving overall prognosis.

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