The development of anti-tumor necrosis factor (TNF) therapies is a milestone in the treatment of rheumatic diseases.1 It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe clinical presentations that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.
A 65-year-old woman presented with gradual painless loss of vision in her right eye. There was no history of trauma or ocular surgery. She had no symptoms of floaters or photopsia.
Past medical history included rheumatoid arthritis, a knee replacement two months back, ischemic heart disease and hypothyroidism.
Her present medications included prednisolone 2.5 mg, methotrexate 2.5 mg weekly, folic acid, didronel, losec 20 mg and thyroxin 75 mg. She had been recently commenced on IV infliximab (Remicade) 3 mg/kg body weight, reconstituted in 0.9% sodium chloride repeated after two weeks and six weeks. On review, the patient's health had been poor over the preceding six months with a flare-up of her rheumatoid symptoms and recurrent urinary tract infections.
Examination demonstrated an apyrexial patient in no distress with a blood pressure of 136/65 mmHg. Visual acuities were hand movements in the right eye and 20/30 in the left eye. There was a right afferent pupillary defect. The right anterior chamber demonstrated cellular activity with cells 1+ and extensive keratic precipitates [Fig. 1]. The IOP was normal.
There was limited view of the posterior segment with vitreous cells 3+, a diffuse red reflex [Fig. 2], without detailed view of the fundus. Examination of the left eye was normal.
Initial clinical differential diagnosis included the possibility of primary or metastatic malignancy with secondary exudative or infiltrative retinal detachment or diffuse vitreous hemorrhage.
Investigations included complete blood count, erythrocyte sedimentation rate, C reactive protein, urea and electrolytes, liver function tests, angiotensin converting enzyme, anti-nuclear antibody, anti-nuclear cytoplasmic antibody and anti-nuclear factor. The erythrocyte sedimentation rate was elevated at 62 mm per hour, compatible with her clinical rheumatoid condition. Other blood tests including white cell count were normal. Urine analysis demonstrated moderate pus cells and debris and further culture was positive for coliforms. A chest X-ray was also normal.
B scan ultrasonography of the right eye demonstrated extensive vitreal debris, with vitreoretinal adhesions evident at the disc margin. There was extensive subretinal fluid with possible hemorrhage involving both lower quadrants. There were no discrete masses identified [Figs. 3 and 4].
A presumptive diagnosis of endogenous endophthalmitis was made and the infliximab therapy was stopped. The patient was treated initially with trimethoprim 200 mg every 12h for her urinary tract infection, topical dexamethasone six times a day for her right anterior chamber activity and was referred for vitreoretinal assessment. A posterior vitrectomy was performed with intravitreal injections of vancomycin (1000 mg in 0.1 ml) and amphotericin (5 mcg in 0.1 ml).
Microscopy of vitreous aspirate demonstrated a degenerative cellular fluid containing polymorphs, lymphocytes and histiocytes. Modified gram stains demonstrated short chains of gram-positive cocci. The patient's visual acuity in the right eye remained stable at hand movements, with a small inferior nonrhegmatogenous detachment which was managed conservatively.
Endogenous endophthalmitis accounts for 5-7% of documented cases in a previous large series of endophthalmitis.23 Schiedler et al. in their recent retrospective series of 21 patients with culture-proven endogenous endophthalmitis found that patients are more likely to have fungal isolates (62%), with a predominance of Candida albicans. Gram-positive isolates, as was demonstrated in this case were found in 33% of patients, with gram-negative isolates in 5% of cases.
Risk factors associated with the previously documented series include chronic immuno-compromising illnesses, indwelling or long-term intravenous catheters, immunosuppressive diseases and therapy, recent invasive surgery, endocarditis, gastrointestinal procedures, hepatobiliary tract infections and intravenous drug abuse.4
This case represents a patient with multiple risk factors who had been recently commenced on TNF alpha blockers. Infections are common in patients with rheumatic disorders. The reasons for vulnerability include alterations of immunoregulation, disease severity, co-morbid illnesses and the use of immunosuppressive medications. Our patient while on maintenance therapy of low-dose prednisolone and methotrexate, had in addition recurrent urinary infections and knee replacement surgery two months prior to ophthalmic presentation.
The presentation in this case with masquerading features of anterior uveitis, the lack of subjective systemic infective features and a low to normal white cell count, makes initial clinical assessment difficult and may delay diagnosis. Previous published series demonstrate that candida endogenous endophthalmitis has a gradual onset with an indolent course and can masquerade as uveitis with an initial incorrect diagnosis.56
The TNF alpha blockers have not been previously implicated with endogenous endophthalmitis. Seven types of adverse events seem to be of special concern for patients treated with TNF alpha blockers:
- Anemia and pancytopenia
- Demyelinating disorders/neuropathy
- Worsening of congestive heart failure
- Occurrence of auto antibodies and autoimmunity and
- Infusion/injection and hypersensitivity reactions.7
The food and drug administration reports the numbers of postlicensure adverse events in patients on infliximab therapy to be approximately 1100 events in 150,000 patients. Twenty per cent of the infliximab reports were infections, with a variety of opportunistic cases, including herpes zoster, various fungal infections, herpes simplex and candida, with smaller number of cases of tuberculosis, aspergillosis and cryptococcosis.8
The TNF alpha blockers are highly valuable drugs with a straightforward clinical effect in selected inflammatory disorders, but can increase the risk of infections. The rarity of this clinical case, balanced against the benefits of TNF blockade for this patient resulted in the recommencement of treatment once her ocular condition had settled.
Early detection of endogenous endophthalmitis remains difficult. The gradual onset and relatively indolent course coupled with masquerading signs of uveitis can delay diagnosis. Furthermore, the systemic features of infection such as elevated white cell count may be masked by immunosupression. The ophthalmologist needs to maintain a high level of suspicion for endogenous endophthalmitis in patients with intraocular inflammation and a recent history of hospitalization, significant medical co-morbidities and in those receiving immunosuppressive therapy.
1. Antoni C, Braun J. Side effects of Anti-TNF therapy: Current knowledge Clin Exp Rheumatol. 2002;20:S152–7
2. Bohigian GM, Olk RJ. Factors associated with a poor visual result in endophthalmitis Am J Ophthalmol. 1986;101:332–41
3. Puliafito CA, Baker AS, Haaf J, Foster CS. Infectious endophthalmitis. Review of 36 cases Ophthalmology. 1982;89:921–9
4. Schiedler V, Scott IU, Flynnjr HW Jr, Davis JL, Benz MS, Miller D. Culture-proven endogenous endophthalmitis: Clinical features and visual acuity outcomes Am J Ophthalmol. 2004;137:725–31
5. Okada AA, Johnson RP, Liles WC, D'Amico DJ, Baker AS. Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study Ophthalmology. 1994;101:832–8
6. Binder MI, Chua J, Kaiser PK, Procop GW, Isada CM. Endogenous endophthalmitis: An 18-year review of culture-positive cases at a tertiary care center Medicine (Baltimore). 2003;82:97–105
7. Antoni C, Braun J. Side effects of anti-TNF therapy: Current knowledge Clin Exp Rheumatol. 2002;20:S152–7