Ocular Immunology & Inflammation, Early Online, 1–6, 2014 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.945600
ORIGINAL ARTICLE
Herpes Simplex Keratitis in Rheumatoid Arthritis Patients
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Paula Larran˜aga Fragoso, MD1, Ana Boto de los Bueis, MD1, Luciano Bravo Ljubetic, MD1, Almudena Del Hierro Zarzuelo, MD1, M. Pilar Romero Go´mez, MD2, and Marta Mora Rillo, MD3 1
Department of Ophthalmology, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain, 2Department of Microbiology, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain, and 3Department of Infectious Disease, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain
ABSTRACT Purpose: To describe a series of 5 patients with herpes simplex virus keratitis (HSK) and rheumatoid arthritis (RA) under immunosuppressive treatment. Methods: Retrospective study. Detailed data were obtained regarding symptoms and signs at the initial evaluation, treatment, microbiological diagnostic tests, evolution, and outcomes. Results: Five patients with HSK and RA were identified. Bilateral involvement occurred in 2 patients (40%). Epithelial keratitis was diagnosed in 5 eyes. Three eyes showed severe melting with eye perforation. Grampositive bacterial co-infections were common in the group with stromal keratitis. We did not find differences in the evolution of the disease based on anti-rheumatoid treatment. Conclusions: The characteristics of HSK in patients with RA differed from HSK in immunocompetent patients. The stromal keratitis cases were very aggressive and difficult to manage, with perforation and gram-positive bacterial co-infection as frequently associated conditions. Prophylactic therapy at standard doses was unsuccessful to avoid recurrences. Keywords: Herpes simplex keratitis, peripheral ulcerative keratitis, polymerase chain reaction, rheumathoid arthritis, stromal keratitis
Rheumatoid arthritis (RA) affects 1% of the adult population, and 25% of patients with RA will develop ocular involvement.1 However, there are a limited number of data in the current literature about herpes simplex keratitis (HSK) in patients with rheumatoid arthritis (RA) under immunosuppressive therapy. Opportunistic herpes simplex infections due to immunosuppressed status may affect the cornea; e.g. about 1 out of 100 renal transplant patients developed dendritic keratitis, which seems to be a higher rate of infection than the expected rate in the normal population.2
RA could result in an increased risk of herpes virus infections due to the dysregulation of the immune system.3–5 In addition, many of the medications used to treat RA act as immune system modulators and may increase the risk of herpetic infections. Furthermore, immunosuppression status could alter the clinical manifestations of the disease, with atypical presentations of the herpetic keratitis with mild ocular symptoms and a more insidious course.2 Tumor necrosis factor a (TNF-a)-blocking agents have demonstrated efficacy in inflammatory rheumatic diseases,6 but little is known about the
Received 5 May 2014; revised 11 July 2014; accepted 14 July 2014; published online 19 August 2014 Correspondence: Paula Larran˜aga Fragoso, Servicio de Oftalmologı´a, Hospital Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Espan˜a. E-mail: [email protected]
1
2
P. Larran˜aga Fragoso et al.
reactivation of latent viral infections during treatment with TNF-a inhibitor.7 Recent studies performed on RA patients conclude that there is no increased risk of varicella zoster virus (VZV) in patients on TNF blocker treatment,8 but there are no strong data regarding herpes simplex virus (HSV) infections. We have studied the features of HSK in RA patients under several immunosuppressive treatments, the diagnosis, and the response to treatment.
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PATIENTS AND METHODS We retrospectively reviewed the clinical records of patients with HSK who suffered from RA and who were referred to the Cornea Unit of a tertiary hospital between January 2003 and August 2013. Patients with a diagnosis of RA and evidence of HSK were included. Herpes simplex keratitis was diagnosed by the presence of typical dendritic keratitis or by suspected herpetic keratitis plus the detection of DNA HSV-1 by multiplex polymerase chain reaction (PCR, CLART ENTHERPEX (Genomica, Spain) performed on corneal epithelial scrapings at least once. Exclusion criteria included (1) a positive result for another herpes virus—human herpes virus 6 (HHV6), VZV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV)—in the multiple PCR test; (2) patients with HIV infection or an immunosuppressed condition other than RA; (3) patients with inadequate clinical records. Detailed data regarding symptoms and signs at the initial evaluation, treatment, diagnostic tests, evolution, and outcome were studied (available from computerized databases used within the outpatient clinic). Slit-lamp-recorded pictures from the affected eye were also evaluated from all the patients.
treatment. Only 1 of these 2 patients had HSK simultaneously in both eyes. Five eyes presented an epithelial form (Figure 1)—1 eye with two limbocorneal dendrites and 4 eyes with geographic epithelial keratitis. Characteristically, the geographic ulcers were multiples and they extended to the limbus and also affected the conjunctiva with mild limbal injection. The epithelial forms healed in a mean time of 16.5 days after correct treatment was begun. None of these patients had been treated with topical steroids before the keratitis. Three eyes showed stromal forms (Figure 2) with severe melting and needed further surgical procedures because of perforation, which was the initial form of presentation of HSK in 2 of the eyes (2 cases with central perforation (Figure 2a); 1 case as a peripheral ulcerative keratitis (PUK) (Figure 2d)). One of the 3 patients (case 2) with stromal keratitis suffered severe and multiple recurrences under prophylactic treatment (famciclovir 250 mg/day), as stromal and also epithelial forms. The recurrences occurred 4 months after the prophylactic doses was established in 250 mg of famciclovir per day., and they stopped after maintaining the prophylactic doses with famciclovir 750 mg/day, with no new episodes during 28 months until last examination. Gram-positive bacterial co-infections (Staphylococcus aureus, Staphylococcus epidermidis, and Estreptoccocus pneumonia) were common in the stromal keratitis group, with 1.6 episodes per patient. S. aureus was the most frequent agent isolated. One of these cases (case 1) evolved to pneumococcal endopthalmitis and had to be eviscerated despite aggressive medical treatment. The final visual results are shown in Table 1. In 4 of the 7 eyes, the final visual acuity decreased, while in 3 cases it was better than previously. This improvement in visual acuity occurred in the epithelial forms.
RESULTS A total of 5 patients (7 eyes) with HSK and RA were identified from this database. The mean patient age was 71.2 years (median 72; range 68–76 years). The mean follow-up was 18.7 months (range 45–6 months). None of these patients had previous history of keratoconjunctivitis sicca or Sjo¨gren syndrome before the diagnosis of the HSK. The clinical features of 5 patients with RA and HSK are summarized in Table 1. The 5 patients suffering from RA had a mean duration of the disease of 19.6 years (range 14–20 years). Systemic methotrexate (MTX) with steroids was the treatment combination used most frequently (3 patients), with systemic monoclonal antibodies also included in 2 of them. Bilateral involvement occurred in 2 patients (40%), both of whom were on methotrexate and prednisone
DISCUSSION Herpes simplex corneal infections have been reported in acquired immune deficiency syndrome (AIDS) patients and are associated with severe ocular complications and a high incidence of visual loss,9 but information is limited in patients with other immunosuppressed conditions. There are few reports in the literature related to non-ocular herpes simplex infection in patients with rheumatoid arthritis; in these cases the disseminated herpetic infections occurred in patients under strong immunosuppressive treatment.10,11 Our study describes a series of 7 eyes affected by HSK in 5 patients with RA treated with immunosuppressive drugs. We did not find differences in the course of the disease depending on the baseline treatment. Ocular Immunology & Inflammation
!
2014 Informa Healthcare USA, Inc.
F
M
M
M
2/68
3/72
4/66
5/76
20
14
20
16
18
RA, years
Etanercept (50 mg/ week sc) Methotrexate (10 mg/ week po) Metrotrexate (7.5 mg/ week po) Prednisone (7.5 mg/day)
Prednisone (15 mg/day)
Tocilizumab (8 mg/kg iv) Methotrexate (2.5 mg twice weekly po) Prednisone (10 mg/day) Methotrexate (7.5 mg twice weekly po) Prednisone (10 mg/day)
Immunosupressive treatment
Yes
No
6
20
No
12
Yes (simultaneously)
No
24
45
Bilateral
Follow-up (months)
Yes
No
LE
No
RE
LE
Yes
No
LE
LE
No
Yes
RE
RE
Eye
Previous HSK
Epithelial dendritic keratitis
Postherpetic leucoma
– Ulcerative peripheral keratitis Positive PCR – Geographic epithelial keratitis Positive PCR with perforation Geographic epithelial keratitis Positive PCR and anterior diffuse scleritis Central perforation Geographic epithelial keratitis Positive PCR Geographic epithelial keratitis Positive PCR
Stromal necrotizing Positive PCR
HSK form
30 days
–
8 days
–
15 days
13 days
–
Closure time (epithelial forms)
M, male; F, female; RE, right eye LE, left eye; AMT, amniotic membrane transplantation; HM, hand motion. *Eviscerated.
F
Gender
1/74
Patient number/ age
TABLE 1. Clinical features of 5 patients with HK and RA.
–
–
–
Corneal perforation
–
– Bacterial co-infection – Corneal perforation
– Bacterial co-infection – Corneal perforation – Endophthalmitis
Ocular complications
–
–
–
AMT (1)
–
– AMT (4) – Tectonic keratoplasty – Penetrating keratoplasty
– AMT(2) – Penetrating keratoplasty – Evisceration
Surgical procedures
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No
No
No
Famciclovir 6 months
40 months Famciclovir
Valganciclovir 36 months
Prophylaxis/ duration (months)
No
No
No
No
No
Yes (during treatment)
Yes (during treatment)
Recurrence
20/63
20/200
20/80
HM
20/32
20/160
20/160
Initial visual acuity
20/32
20/32
20/32
20/125
20/40
20/200
*
Final visual acuity
Herpes Simplex Keratitis and Rheumatoid Arthritis 3
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P. Larran˜aga Fragoso et al.
FIGURE 1. Epithelial keratitis. (a, b) Patient 2, left eye: (a) first episode of dendritic ulcer that evolved into multiple geographic ulcers in cornea and conjuntiva; (b) resolution of the keratitis. (c, d) Patient 2, right eye: (c) geographic ulcer after penetrating keratoplasty under prophylactic treatment; (d) resolution of the geographic ulcer after the treatment. (e, f) Patient 3: (e) geographic epithelial ulcer with central perforation (Figure 2a); (f) residual amniotic patch without signs of inflammation. (g, h) Patient 4: (g) multiple dendritic ulcers with a geographic soma and mild limbal injection; (h) resolution of herpetic keratitis. (i–k) Patient 5: current presentation with two peripheric postherpetic leucomas with mild fluorescein retention.
The characteristics of the HSK differed from HSK in immunocompetent patients. The herpetic epithelial ulcers were often multiple, geographic, and covered a large area of the cornea, limbus, and the conjunctival epithelium. The stromal keratitis cases were more aggressive and difficult to manage than in the normal population, with a high incidence of gram-positive co-infections and perforations. Although a clinical diagnosis of HSV-1 epithelial keratitis is relatively straightforward, the clinical features in stromal HSV keratitis can often be obscure, which may further be confounded by superinfection with bacteria, as happened in our cases. It is necessary to determine whether the necrosis is a part of rheumatoid melting or if it is caused by infection in RA patients.12,13 In some cases, the DNA HSV isolation by PCR has been the only microbiological test that supported the diagnosis of stromal necrosis due to herpetic infection.14 Other authors suggest that a combination of at least two laboratory tests, such as
PCR for HSV-1 DNA, Giemsa stain for multinucleated giant cells, or immunofluorescence assay (IFA) for HSV-1 antigen, could be required to confirm the diagnosis in atypical cases of HSV keratitis.15 Finally, the invasive but definitive methods to diagnose the infective cause of the stromal lysis in these RA patients would be the immunohistopathology of the corneal biopsy,16 as was described in 1 of the 2 cases reported by Zaher; electron microscopy was performed and showed clusters of typical herpes virus particle within almost all of the keratocytes. In contrast to our experience, in those 2 cases the ulcers responded well to topical trifluorothymidine and topical steroids, while in the other series, all of them required surgical procedures, such as amniotic membrane transplantation and keratoplasty.17 The keratitis was bilateral in 2 out of 5 patients, a higher rate than expected from previous studies on non-RA patients.18 Bilateral HSK is very rarely Ocular Immunology & Inflammation
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Herpes Simplex Keratitis and Rheumatoid Arthritis
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FIGURE 2. Stromal keratitis. (a–c) Patient 3: (a) central stromal necrosis of the geographic ulcer (Figure 1e); (b) sealing of the corneal perforation using cyanoacrylate tissue adhesive; (c) AMT. (d–f) Patient 2, right eye: (d) second episode of corneal melting over the tectonic transplant; (e) allograft necrosis with anterior scleritis and corneal infiltrate; (f) after penetrating keratoplasty and cataract extraction.
reported in the literature and bilateral herpetic keratitis presenting as PUK is considered an even rarer manifestation of herpetic disease.14 The recurrence of some form of ocular HSV occurred in 2 of 5 patients (40%) during follow-up, both having recurrences even during the prophylactic oral regimen considered standard for immunocompetent patients,19–21 one as the typical geographic ulcer pattern after penetrant keratoplasty and the other as stromal necrotizing with positive PCR. Case 2 experienced recurrence with famciclovir 250 mg/day but stopped at 750 mg/day. As a result we observe that these patients should be covered initially with a higher dose of prophylactic treatment and during longer time, as the disease appears to be more aggressive, to avoid or minimize recurrences. This study is limited by its small size, the wide range of RA disease severity, and the differing treatments of the patients. It is important to make clear that the findings in these patients may simply be secondary to immunosuppressed status. More studies are needed to study the influence of these factors in this relatively unexplored group of patients, those with RA under immunosuppressive treatment who develop HSK. In conclusion, ophthalmologists should be alert for atypical presentations of herpes in immunosuppressed patients. In the cases where herpes simplex !
2014 Informa Healthcare USA, Inc.
is suspected, corneal laboratory or immunohistopathology studies should be necessary. Prophylactic therapy, at standard doses, was unsuccessful to avoid recurrences, thus highlighting the need for reviewed regimens for this blinding eye disease.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Koffler D. The immunology of rheumatoid diseases. Clin Symp Ciba. 1979;31:21–25. 2. Kremer I, Wagner A, Shmuel D, et al. Herpes simplex keratitis in renal transplant patients. Br J Ophthalmol. 1991; 75:94–96. 3. Koetz K, Bryl E, Spickschen K, et al. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 2000;97:9203–9208. 4. Dobloug JH, Førre O, Kvien TK, et al. Natural killer (NK) cell activity of peripheral blood, synovial fluid, and synovial tissue lymphocytes from patients with rheumatoid arthritis and juvenile rheumatoid arthritis. Ann Rheum Dis. 1982;41:490–494. 5. Fox RI, Fong S, Tsoukas C, et al. Characterization of recirculating lymphocytes in rheumatoid arthritis patients:
6
6.
7.
8. 9.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
10.
11.
12. 13.
P. Larran˜aga Fragoso et al. selective deficiency of natural killer cells in thoracic duct lymph. J Immunol. 1984;132:2883–2887. Che H, Lukas C, Morel J, et al. Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients with rheumatoid arthritis: systematic review and metaanalysis. Joint Bone Spine. 2013 Aug 7. pii: S1297319X(13)00194-2. DOI: 10.1016/j.jbspin.2013.07.009. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with antiTNF-alpha agents. JAMA. 2009;301:737–744. No link between TNF antagonists and herpes zoster. BMJ. 2013;346:1432. Pepose JS, Holland GN, Nestor MS, et al. Acquired immune deficiency syndrome: pathogenic mechanisms of ocular disease. Ophthalmology. 1985;92:472–484. Justice EA, Khan SY, Logan S, et al. Disseminated cutaneous herpes simplex virus-1 in a woman with rheumatoid arthritis receiving infliximab: a case report. J Med Case Rep. 2008;2:282–286. Van der Klooster JM, Bosman RJ, Oudemans-van Straaten HM, et al. Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection in a patient with infliximab and methotrexate. Intensive Care Med. 2003; 29:2327–2329. Messmer EM, Foster CS. Vasculitic peripheral ulcerative keratitis. Surv Ophthalmol. 1999;43:379–396. Yagci A. Update on peripheral ulcerative keratitis. Clin Ophthalmol. 2012;6:747–754.
14. Praidou A, Androudi S, Kanonidou E, et al. Bilateral herpes simplex keratitis presenting as peripheral ulcerative keratitis. Cornea. 2012;31:570–571. 15. Farhatullah S, Kaza S, Athmanathan S, et al. Diagnosis of herpes simplex virus-1 keratitis using Giemsa stain, immunofluorescence assay, and polymerase chain reaction assay on corneal scrapings. Br J Ophthalmol. 2004;88: 142–144. 16. Zaher SS, Sandinha T, Roberts F, et al. Herpes simplex keratitis misdiagnosed as rheumatoid arthritisrelated peripheral ulcerative keratitis. Cornea. 2005;24: 1015–1017. 17. Heiligenhaus A, Li H, Hernandez-Galindo E, et al. Management of acute ulcerative and necrotising herpes simplex and zoster keratitis with amniotic membrane transplantation. Br J Ophthalmol. 2003;87:1215–1219. 18. Liesegang TJ, Melton LJ, Daly PJ, et al. Epidemiology of ocular herpes simplex: incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol. 1989;107:1155–1159. 19. Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus. N Engl J Med. 1998;339:300–306. 20. Eye H, Study D. Predictors of recurrent herpes simplex virus keratitis. Cornea. 2001;20:123–128. 21. Miserocchi E, Modorati G, Galli L, et al. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol. 2007;144:547–551.
Ocular Immunology & Inflammation
ORIGINAL ARTICLE
Herpes Simplex Keratitis in Rheumatoid Arthritis Patients
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Paula Larran˜aga Fragoso, MD1, Ana Boto de los Bueis, MD1, Luciano Bravo Ljubetic, MD1, Almudena Del Hierro Zarzuelo, MD1, M. Pilar Romero Go´mez, MD2, and Marta Mora Rillo, MD3 1
Department of Ophthalmology, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain, 2Department of Microbiology, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain, and 3Department of Infectious Disease, IdiPAZ – Hospital Universitario La Paz, Madrid, Spain
ABSTRACT Purpose: To describe a series of 5 patients with herpes simplex virus keratitis (HSK) and rheumatoid arthritis (RA) under immunosuppressive treatment. Methods: Retrospective study. Detailed data were obtained regarding symptoms and signs at the initial evaluation, treatment, microbiological diagnostic tests, evolution, and outcomes. Results: Five patients with HSK and RA were identified. Bilateral involvement occurred in 2 patients (40%). Epithelial keratitis was diagnosed in 5 eyes. Three eyes showed severe melting with eye perforation. Grampositive bacterial co-infections were common in the group with stromal keratitis. We did not find differences in the evolution of the disease based on anti-rheumatoid treatment. Conclusions: The characteristics of HSK in patients with RA differed from HSK in immunocompetent patients. The stromal keratitis cases were very aggressive and difficult to manage, with perforation and gram-positive bacterial co-infection as frequently associated conditions. Prophylactic therapy at standard doses was unsuccessful to avoid recurrences. Keywords: Herpes simplex keratitis, peripheral ulcerative keratitis, polymerase chain reaction, rheumathoid arthritis, stromal keratitis
Rheumatoid arthritis (RA) affects 1% of the adult population, and 25% of patients with RA will develop ocular involvement.1 However, there are a limited number of data in the current literature about herpes simplex keratitis (HSK) in patients with rheumatoid arthritis (RA) under immunosuppressive therapy. Opportunistic herpes simplex infections due to immunosuppressed status may affect the cornea; e.g. about 1 out of 100 renal transplant patients developed dendritic keratitis, which seems to be a higher rate of infection than the expected rate in the normal population.2
RA could result in an increased risk of herpes virus infections due to the dysregulation of the immune system.3–5 In addition, many of the medications used to treat RA act as immune system modulators and may increase the risk of herpetic infections. Furthermore, immunosuppression status could alter the clinical manifestations of the disease, with atypical presentations of the herpetic keratitis with mild ocular symptoms and a more insidious course.2 Tumor necrosis factor a (TNF-a)-blocking agents have demonstrated efficacy in inflammatory rheumatic diseases,6 but little is known about the
Received 5 May 2014; revised 11 July 2014; accepted 14 July 2014; published online 19 August 2014 Correspondence: Paula Larran˜aga Fragoso, Servicio de Oftalmologı´a, Hospital Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Espan˜a. E-mail: [email protected]
1
2
P. Larran˜aga Fragoso et al.
reactivation of latent viral infections during treatment with TNF-a inhibitor.7 Recent studies performed on RA patients conclude that there is no increased risk of varicella zoster virus (VZV) in patients on TNF blocker treatment,8 but there are no strong data regarding herpes simplex virus (HSV) infections. We have studied the features of HSK in RA patients under several immunosuppressive treatments, the diagnosis, and the response to treatment.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
PATIENTS AND METHODS We retrospectively reviewed the clinical records of patients with HSK who suffered from RA and who were referred to the Cornea Unit of a tertiary hospital between January 2003 and August 2013. Patients with a diagnosis of RA and evidence of HSK were included. Herpes simplex keratitis was diagnosed by the presence of typical dendritic keratitis or by suspected herpetic keratitis plus the detection of DNA HSV-1 by multiplex polymerase chain reaction (PCR, CLART ENTHERPEX (Genomica, Spain) performed on corneal epithelial scrapings at least once. Exclusion criteria included (1) a positive result for another herpes virus—human herpes virus 6 (HHV6), VZV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV)—in the multiple PCR test; (2) patients with HIV infection or an immunosuppressed condition other than RA; (3) patients with inadequate clinical records. Detailed data regarding symptoms and signs at the initial evaluation, treatment, diagnostic tests, evolution, and outcome were studied (available from computerized databases used within the outpatient clinic). Slit-lamp-recorded pictures from the affected eye were also evaluated from all the patients.
treatment. Only 1 of these 2 patients had HSK simultaneously in both eyes. Five eyes presented an epithelial form (Figure 1)—1 eye with two limbocorneal dendrites and 4 eyes with geographic epithelial keratitis. Characteristically, the geographic ulcers were multiples and they extended to the limbus and also affected the conjunctiva with mild limbal injection. The epithelial forms healed in a mean time of 16.5 days after correct treatment was begun. None of these patients had been treated with topical steroids before the keratitis. Three eyes showed stromal forms (Figure 2) with severe melting and needed further surgical procedures because of perforation, which was the initial form of presentation of HSK in 2 of the eyes (2 cases with central perforation (Figure 2a); 1 case as a peripheral ulcerative keratitis (PUK) (Figure 2d)). One of the 3 patients (case 2) with stromal keratitis suffered severe and multiple recurrences under prophylactic treatment (famciclovir 250 mg/day), as stromal and also epithelial forms. The recurrences occurred 4 months after the prophylactic doses was established in 250 mg of famciclovir per day., and they stopped after maintaining the prophylactic doses with famciclovir 750 mg/day, with no new episodes during 28 months until last examination. Gram-positive bacterial co-infections (Staphylococcus aureus, Staphylococcus epidermidis, and Estreptoccocus pneumonia) were common in the stromal keratitis group, with 1.6 episodes per patient. S. aureus was the most frequent agent isolated. One of these cases (case 1) evolved to pneumococcal endopthalmitis and had to be eviscerated despite aggressive medical treatment. The final visual results are shown in Table 1. In 4 of the 7 eyes, the final visual acuity decreased, while in 3 cases it was better than previously. This improvement in visual acuity occurred in the epithelial forms.
RESULTS A total of 5 patients (7 eyes) with HSK and RA were identified from this database. The mean patient age was 71.2 years (median 72; range 68–76 years). The mean follow-up was 18.7 months (range 45–6 months). None of these patients had previous history of keratoconjunctivitis sicca or Sjo¨gren syndrome before the diagnosis of the HSK. The clinical features of 5 patients with RA and HSK are summarized in Table 1. The 5 patients suffering from RA had a mean duration of the disease of 19.6 years (range 14–20 years). Systemic methotrexate (MTX) with steroids was the treatment combination used most frequently (3 patients), with systemic monoclonal antibodies also included in 2 of them. Bilateral involvement occurred in 2 patients (40%), both of whom were on methotrexate and prednisone
DISCUSSION Herpes simplex corneal infections have been reported in acquired immune deficiency syndrome (AIDS) patients and are associated with severe ocular complications and a high incidence of visual loss,9 but information is limited in patients with other immunosuppressed conditions. There are few reports in the literature related to non-ocular herpes simplex infection in patients with rheumatoid arthritis; in these cases the disseminated herpetic infections occurred in patients under strong immunosuppressive treatment.10,11 Our study describes a series of 7 eyes affected by HSK in 5 patients with RA treated with immunosuppressive drugs. We did not find differences in the course of the disease depending on the baseline treatment. Ocular Immunology & Inflammation
!
2014 Informa Healthcare USA, Inc.
F
M
M
M
2/68
3/72
4/66
5/76
20
14
20
16
18
RA, years
Etanercept (50 mg/ week sc) Methotrexate (10 mg/ week po) Metrotrexate (7.5 mg/ week po) Prednisone (7.5 mg/day)
Prednisone (15 mg/day)
Tocilizumab (8 mg/kg iv) Methotrexate (2.5 mg twice weekly po) Prednisone (10 mg/day) Methotrexate (7.5 mg twice weekly po) Prednisone (10 mg/day)
Immunosupressive treatment
Yes
No
6
20
No
12
Yes (simultaneously)
No
24
45
Bilateral
Follow-up (months)
Yes
No
LE
No
RE
LE
Yes
No
LE
LE
No
Yes
RE
RE
Eye
Previous HSK
Epithelial dendritic keratitis
Postherpetic leucoma
– Ulcerative peripheral keratitis Positive PCR – Geographic epithelial keratitis Positive PCR with perforation Geographic epithelial keratitis Positive PCR and anterior diffuse scleritis Central perforation Geographic epithelial keratitis Positive PCR Geographic epithelial keratitis Positive PCR
Stromal necrotizing Positive PCR
HSK form
30 days
–
8 days
–
15 days
13 days
–
Closure time (epithelial forms)
M, male; F, female; RE, right eye LE, left eye; AMT, amniotic membrane transplantation; HM, hand motion. *Eviscerated.
F
Gender
1/74
Patient number/ age
TABLE 1. Clinical features of 5 patients with HK and RA.
–
–
–
Corneal perforation
–
– Bacterial co-infection – Corneal perforation
– Bacterial co-infection – Corneal perforation – Endophthalmitis
Ocular complications
–
–
–
AMT (1)
–
– AMT (4) – Tectonic keratoplasty – Penetrating keratoplasty
– AMT(2) – Penetrating keratoplasty – Evisceration
Surgical procedures
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No
No
No
Famciclovir 6 months
40 months Famciclovir
Valganciclovir 36 months
Prophylaxis/ duration (months)
No
No
No
No
No
Yes (during treatment)
Yes (during treatment)
Recurrence
20/63
20/200
20/80
HM
20/32
20/160
20/160
Initial visual acuity
20/32
20/32
20/32
20/125
20/40
20/200
*
Final visual acuity
Herpes Simplex Keratitis and Rheumatoid Arthritis 3
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P. Larran˜aga Fragoso et al.
FIGURE 1. Epithelial keratitis. (a, b) Patient 2, left eye: (a) first episode of dendritic ulcer that evolved into multiple geographic ulcers in cornea and conjuntiva; (b) resolution of the keratitis. (c, d) Patient 2, right eye: (c) geographic ulcer after penetrating keratoplasty under prophylactic treatment; (d) resolution of the geographic ulcer after the treatment. (e, f) Patient 3: (e) geographic epithelial ulcer with central perforation (Figure 2a); (f) residual amniotic patch without signs of inflammation. (g, h) Patient 4: (g) multiple dendritic ulcers with a geographic soma and mild limbal injection; (h) resolution of herpetic keratitis. (i–k) Patient 5: current presentation with two peripheric postherpetic leucomas with mild fluorescein retention.
The characteristics of the HSK differed from HSK in immunocompetent patients. The herpetic epithelial ulcers were often multiple, geographic, and covered a large area of the cornea, limbus, and the conjunctival epithelium. The stromal keratitis cases were more aggressive and difficult to manage than in the normal population, with a high incidence of gram-positive co-infections and perforations. Although a clinical diagnosis of HSV-1 epithelial keratitis is relatively straightforward, the clinical features in stromal HSV keratitis can often be obscure, which may further be confounded by superinfection with bacteria, as happened in our cases. It is necessary to determine whether the necrosis is a part of rheumatoid melting or if it is caused by infection in RA patients.12,13 In some cases, the DNA HSV isolation by PCR has been the only microbiological test that supported the diagnosis of stromal necrosis due to herpetic infection.14 Other authors suggest that a combination of at least two laboratory tests, such as
PCR for HSV-1 DNA, Giemsa stain for multinucleated giant cells, or immunofluorescence assay (IFA) for HSV-1 antigen, could be required to confirm the diagnosis in atypical cases of HSV keratitis.15 Finally, the invasive but definitive methods to diagnose the infective cause of the stromal lysis in these RA patients would be the immunohistopathology of the corneal biopsy,16 as was described in 1 of the 2 cases reported by Zaher; electron microscopy was performed and showed clusters of typical herpes virus particle within almost all of the keratocytes. In contrast to our experience, in those 2 cases the ulcers responded well to topical trifluorothymidine and topical steroids, while in the other series, all of them required surgical procedures, such as amniotic membrane transplantation and keratoplasty.17 The keratitis was bilateral in 2 out of 5 patients, a higher rate than expected from previous studies on non-RA patients.18 Bilateral HSK is very rarely Ocular Immunology & Inflammation
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Herpes Simplex Keratitis and Rheumatoid Arthritis
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FIGURE 2. Stromal keratitis. (a–c) Patient 3: (a) central stromal necrosis of the geographic ulcer (Figure 1e); (b) sealing of the corneal perforation using cyanoacrylate tissue adhesive; (c) AMT. (d–f) Patient 2, right eye: (d) second episode of corneal melting over the tectonic transplant; (e) allograft necrosis with anterior scleritis and corneal infiltrate; (f) after penetrating keratoplasty and cataract extraction.
reported in the literature and bilateral herpetic keratitis presenting as PUK is considered an even rarer manifestation of herpetic disease.14 The recurrence of some form of ocular HSV occurred in 2 of 5 patients (40%) during follow-up, both having recurrences even during the prophylactic oral regimen considered standard for immunocompetent patients,19–21 one as the typical geographic ulcer pattern after penetrant keratoplasty and the other as stromal necrotizing with positive PCR. Case 2 experienced recurrence with famciclovir 250 mg/day but stopped at 750 mg/day. As a result we observe that these patients should be covered initially with a higher dose of prophylactic treatment and during longer time, as the disease appears to be more aggressive, to avoid or minimize recurrences. This study is limited by its small size, the wide range of RA disease severity, and the differing treatments of the patients. It is important to make clear that the findings in these patients may simply be secondary to immunosuppressed status. More studies are needed to study the influence of these factors in this relatively unexplored group of patients, those with RA under immunosuppressive treatment who develop HSK. In conclusion, ophthalmologists should be alert for atypical presentations of herpes in immunosuppressed patients. In the cases where herpes simplex !
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is suspected, corneal laboratory or immunohistopathology studies should be necessary. Prophylactic therapy, at standard doses, was unsuccessful to avoid recurrences, thus highlighting the need for reviewed regimens for this blinding eye disease.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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