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Clinical course and poor prognostic factors of Vogt–Koyanagi–Harada disease in a tertiary uveitis clinic

      Vogt–Koyanagi–Harada (VKH) disease is an autoimmune inflammatory disorder that can present with ophthalmic, neurologic, auditory, and dermatologic manifestations.
      • Burkholder BM.
      Vogt–Koyanagi–Harada disease.
      In this study, we investigated possible factors that might subsequently result in poor visual function.
      This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis.
      Twenty-six patients were included in this retrospective case series. There were 2 patients (7.7%) diagnosed with complete, 11 patients (42.3%) with incomplete, and 13 patients (50%) with probable VKH disease. The average age of the patients in this study was 42.9 ± 13.7 years (range, 21–64 years). The average duration between the first symptoms and first treatment was 23.5 ± 38.8 weeks. There were 6 patients (23%) in acute phase and 20 patients (77%) in recurrent/chronic phase. The average logMAR best-corrected visual acuity (BCVA) was 0.66 ± 0.83 (20/60; range, –0.1 to 2.8). All patients, except for one, were started on immunomodulatory therapy (IMT). This patient underwent fluocinolone acetonide intravitreal implant (0.59 mg) implantation in both eyes. The IMT regimens are shown in Table 1. The average duration of the follow-up period was 8.1 ± 3.1 years (range, 2–16 years). Patients were divided into 2 groups defined at last visit as good visual outcome (BCVA ≥ 20/40; no significant scotoma: 17 patients [65.3%]) or poor visual outcome (BCVA < 20/40; significant scotoma on visual field 24 degrees: 9 patients [34.7%]).
      Table 1Immunomodulatory therapy (IMT) regimens in patients with Vogt–Koyanagi–Harada disease
      IMT regimensPatients, n (%)Remission on IMTRemission off IMT
      Azathioprine6 (23%)1 (3.8%)None
      Mycophenolate mofetil9 (34.6%)
      Methotrexate6 (23%)1 (3.8%)1 (3.8%)
      Cyclosporine3 (11.5%)
      Chlorambucil3 (11.5%)
      Cyclophosphamide1 (3.8%)
      Adalimumab3 (11.5%)2 (7.6%)None
      Infliximab5 (19.2%)1 (3.8%)None
      Tocilizumab1 (3.8%)
      Rituximab1 (3.8%)
      Azathioprine + cyclosporine3 (11.5%)3 (11.5%)2 (7.6%)
      Methotrexate + cyclosporine3 (11.5%)
      Mycophenolate mofetil + cyclosporine14 (53.8%)2 (7.6%)1 (3.8%)
      Methotrexate + sirolimus1 (3.8%)1 (3.8%)None
      Mycophenolate mofetil + adalimumab4 (15.3%)3 (11.5%)2 (7.6%)
      Infliximab + methotrexate3 (11.5%)1 (3.8%)None
      Chlorambucil + cyclosporine1 (3.8%)
      Mycophenolate mofetil + tacrolimus1 (3.8%)
      Mycophenolate mofetil + infliximab1 (3.8%)1 (3.8%)1 (3.8%)
      The boldface signifies the IMT regimens that induced and maintained durable remission even after IMT discontinuation.
      Poor visual function was defined as uncorrectable BCVA less than 20/40, significant scotoma secondary to VKH disease, or VKH complications on visual field 24 degrees at last visit. Significant scotoma was defined as 3 or more significant (p < 0.05) contiguous points, with at least 1 at the p < 0.01 level on the same side as the horizontal meridian.
      • Maleki A
      • Swan RT
      • Silpa-Archa S
      • Preble JM
      • He Y
      • Foster CS.
      Short-wavelength automated perimetry parameters at baseline and following remission in patients with birdshot retinochoroidopathy.
      Patients’ BCVA at the first visit was classified as BCVA ≥ 20/40 and BCVA < 20/40 for statistical analysis. The demographic and clinical variables were compared in these two groups (Table 2).
      Table 2Comparison of demographic and clinical features between poor and good visual outcome groups
      Demographic and Clinical CharacteristicsPoor Visual Outcome, (9 [34.7%])Good Visual Outcome (17 [65.3%])p Value*
      Age, y41.33 ± 15.7343.76 ± 12.490.662
      Female sex9 (100%)14 (82.4%)0.066
      Other systems involvement66.7%57.1%0.691
      Duration between the first symptoms and first treatment (months)38.783 ± 51.6412.00 ± 18.180.077
      Systemic corticosteroid therapy before first visit62.5%50.0%0.564
      Immunomodulatory therapy before first visit37.5%37.5%1.000
      Duration between first treatment and first visit (months)90.13 ± 175.40123.62 ± 310.660.729
      Disease status at first visit (active/inactive)77.8%88.2%0.488
      LogMAR BCVA at first visit0.65 ± 0.650.68 ± 0.920.996
      BCVA < 20/40 at initial visit54.5%57.1%0.7
      Anterior chamber inflammation66.7%44.1%0.426
      Intraocular pressure (mmHg)13.13 ± 3.0715.12 ± 5.160.179
      Vitreous inflammation55.6%55.9%0.988
      All positive FFA findings75.0%65.6%0.548
      Disc leakage on FFA66.6%47.1%0.4
      Pinpoint leakage on FFA66.6%46.1%0.2
      All positive OCT findings66.7%70.0%0.952
      Cystoid macular edema (CME)37.5%54.5%1.0
      Subretinal fluid66.6%75%0.72
      Treatment ≤ 4 weeks50%46.1%1.0
      Oral corticosteroid > 6 months with first IMT44.4%41.6%0.66
      Number of IMT regimens tried4.22 ± 2.732.41 ± 1.480.016
      Number of IMT agents tried4.22 ± 1.923.17 ± 1.420.13
      Number of IMT agents per regimen1 ± 0.071.82 ± 0.890.011
      Duration of oral corticosteroid therapy with first IMT (months)7.89 ± 7.8416.59 ± 42.120.242
      Number of procedures2.44 ± 2.571.00 ± 1.560.055
      Procedure (yes/no)77.8%41.2%0.017
      Number of recurrences2.44 ± 2.280.41 ± 0.860.034
      Recurrence (yes/no)88.9%23.5%0.007
      Presence of complication (yes/no)88.9%52.9%0.093
      BCVA, best corrected visual acuity; FFA, fundus fluorescein angiography; OCT, optical coherence tomography; IMT, immunomodulatory therapy.
      The boldface numbers are the variables which were statistically significantly different between two groups.
      p value ≤ 0.05 were statistically significant.
      The presence and number of recurrences, number of IMT regimens tried, and presence of complications requiring procedures were correlated with poor prognosis in this case series. These parameters have been shown in previous studies,
      • Maruyama K
      • Noguchi A
      • Shimizu A
      • Shiga Y
      • Kunikata H
      • Nakazawa T.
      Predictors of recurrence in Vogt-Koyanagi-Harada disease.
      • Chee SP
      • Jap A
      • Bacsal K.
      Prognostic factors of Vogt-Koyanagi-Harada disease in Singapore.
      • Ohno S
      • Minakawa R
      • Matsuda H.
      Clinical studies of Vogt-Koyanagi-Harada's disease.
      • Read RW
      • Rechodouni A
      • Butani N
      • et al.
      Complications and prognostic factors in Vogt-Koyanagi-Harada disease.
      • Mondkar SV
      • Biswas J
      • Ganesh SK.
      Analysis of 87 cases with Vogt-Koyanagi-Harada disease.
      • Al-Kharashi AS
      • Aldibhi H
      • Al-Fraykh H
      • et al.
      Prognostic factors in Vogt-Koyanagi-Harada disease.
      • Sheu SJ
      • Kou HK
      • Chen JF.
      Significant prognostic factors for Vogt-Koyanagi-Harada disease in the early stage.
      but number of IMT regimens tried is a new factor. This suggests that a more aggressive IMT regimen to induce faster remission and use of a fewer number of IMTs may be important for better prognosis in patients with VKH disease. It is important to note that IMT regimens are different from IMT agents. In this case series, poor visual outcome was correlated with more IMT regimens and fewer IMT agents in each regimen tried (Table 2). It was shown that a combination of conventional IMT (including azathioprine or mycophenolate mofetil) and a T-cell inhibitor (including cyclosporine or tacrolimus) or a combination of conventional IMT and tumor necrosis factor alpha inhibitors (including adalimumab or infliximab) was more effective than monotherapy using conventional or biologic response modifier agents (42.3% vs 25%; see Table 1). This case series did not show any correlation between the age of the patients and poor visual outcomes. This suggests that older patients may require more aggressive IMT therapy than younger patients because prognosis is poorer in older patients
      • Ohno S
      • Minakawa R
      • Matsuda H.
      Clinical studies of Vogt-Koyanagi-Harada's disease.
      ,
      • Mondkar SV
      • Biswas J
      • Ganesh SK.
      Analysis of 87 cases with Vogt-Koyanagi-Harada disease.
      and that IMT improves the visual prognosis in older patients with VKH disease. Fluocinolone acetonide intravitreal implants induced and maintained remission in all eyes (9 eyes), with no IMT employment, during the active period of the intravitreal implant. The main objections to this study were its retrospective nature and small sample size, unavailability of indocyanine green angiography and enhanced depth imaging optical coherence tomography for all patients, and selection bias from being a referral tertiary centre.
      The combination of conventional IMT or biologic response modifier agents, including tumor necrosis factor alpha inhibitors, with T-cell inhibitors may be a promising regimen in the treatment of patients with VKH disease, especially in chronic/recurrent cases. The sooner the disease is controlled and the fewer experimental IMT regimens tried, the lesser is the chance of poor visual function.

      Footnotes and Disclosure

      C. Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, Mass.), Allakos (Redwood City, Calif.), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, Calif.), Eyegate Pharma (Waltham, Mass.), Genentech (South San Francisco, Calif.), Novartis (Cambridge, Mass.), and pSivida (Watertown, Mass.); grants or grants pending with Aciont (Salt Lake City, Utah), Alcon (Aliso Viejo, Calif.), Aldeyra Therapeutics (Lexington, Mass.), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, Ga.), Dompé Pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, Mass.), Mallinckrodt Pharmaceuticals (Staines-upon-Thames, U.K.), Novartis Pharmaceuticals (Cambridge, Mass.), pSivida (Watertown, Mass.), and Santen (Osaka, Japan); and payments for lectures including service on speaking bureaus: Alcon (Aliso Viejo, Calif.), Allergan (Dublin, Ireland), and Mallinckrodt Pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock.
      Stephen D. Anesi declares the following: consultancies with Santen (Osaka, Japan), Mallinckrodt Pharmaceuticals (Staines-upon-Thames, U.K.), Allakos (Redwood City, Calif.), Eyepoint (Watertown, Mass.), and Takeda (Tokyo, Japan); speakerships with AbbVie (Chicago, Ill.), Mallinckrodt Pharmaceuticals (Staines-upon-Thames, U.K.), and Eyepoint (Watertown, Mass.); and options: Eyegate Pharma (Waltham, Mass.) The other authors have nothing to declare.
      This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis.
      This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.

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