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Clinical science
Safety profile and efficacy of tacrolimus in the treatment of birdshot retinochoroiditis: a retrospective case series review
  1. Farrah Islam1,2,
  2. Mark Westcott1,3,
  3. Angela Rees1,
  4. Anthony George Robson1,3,
  5. Bharat Kapoor1,
  6. Graham Holder1,3,
  7. Carlos Pavesio1,3
  1. 1 Department of Medical Retina, Moorfields Eye Hospital, London, UK
  2. 2 Vitreoretinal department, Al-ShifaTrust Eye Hospital, Rawalpindi, Pakistan
  3. 3 Medical retina, Institute of Ophthalmology, University College London, London, UK
  1. Correspondence to Dr Farrah Islam, Department of Vitreo retina, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan; farrahislam{at}gmail.com

Abstract

Aim Evaluation of the use of tacrolimus in the treatment of birdshot retinochoroiditis (BRC) at a tertiary referral centre with the aim to describe its safety and efficacy.

Methods The medical records of 25 patients diagnosed with BRC at uveitis service, Moorfields Eye Hospital, and who had received tacrolimus treatment were retrospectively reviewed. The main outcome measures of the study were (1) safety of tacrolimus in terms of side effects and (2) efficacy, as measured both by control of inflammation and visual function assessed by Humphrey visual fields and electrophysiological testing over at least 6 months and then 1 year.

Results Tacrolimus was commenced in 25 patients (mean age 50.4±10.8 years) and was well tolerated in 21 patients (84%). It was necessary to stop the tacrolimus in four patients. No patient showed major changes in renal function: 3/21 patients (14.28%) showed slightly abnormal (less than 30%) function at the end of the first month of treatment; 1/21 (4.76%) patients at 3 months, but at the end of a 6-month treatment period only 1/21 patients (4.76%) showed minor abnormality in renal function. The mean daily prednisolone dose was 19.7 mg at the beginning of the study, which had fallen to 6.9 mg at the end (t=5.071, p=0.001). Visual acuity mostly remained stable. Visual fields improved over time (mean improvement in Humphrey mean deviation, right eye=1.8±2.4 dB, t=3.821, p=0.004; left eye=1.9±2.7, dB, t=3.06, p=0.007). Electrophysiological function showed improvement in 10 patients, and in four patients an initial deterioration in function improved following tacrolimus dose adjustment.

Conclusion Tacrolimus has a good safety profile for long-term use in patients with BRC as a second-line agent enabling steroid sparing and visual function stabilisation or improvement.

  • drugs
  • immunology
  • retina
  • inflammation

https://doi.org/10.1136/bjophthalmol-2017-310436

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    Introduction

    Birdshot retinochoroiditis (BRC) is an uncommon, bilateral, intraocular inflammatory disease classically characterised by vitritis and multiple cream-coloured fundus lesions.1 The term was first used by Ryan and Maumanee to describe the characteristic fundus appearance, but a similar phenotype had previously been described.2 The aetiology is unknown, but there is a strong human leucocyte antigen (HLA)-A29 association suggesting that the disease may result from an inherited immune dysregulation.3 The diagnosis is essentially clinical, supported by HLA-A29 haplotype testing. Standard clinical examination and investigations  accompanied by fundus fluorescein angiography (FFA), indocyanine green angiography (ICG) and electroretinography (ERG) enable the diagnosis of BRC and guide in the management of BRC by providing objective evidence of the efficacy of treatment.4 5 Like some other ocular inflammations,6 7 a subset of patients continue to lose retinal function despite aggressive therapy with corticosteroids and conventional immunosuppressive agents (ISA)8 with only 10%–15% of patients showing a relatively mild course.9 Early, aggressive and sustained treatment can modify the course of the disorder.8 9

    T-lymphocytes are likely to be involved in the pathogenesis of the disorder, and this is supported by the efficacy of the T-cell inhibitor, ciclosporin (CSA), in the management of BRC.3 However, problems with renal toxicity and systemic hypertension limit the widespread and long-term use of CSA.10 Moreover, some patients either do not respond or become refractory to treatment after time.11 Antimetabolites, such as mycophenolate mofetil, azathioprine and methotrexate, have also been used with varying outcomes and success. However, no randomised clinical trials are available to inform current practice.1

    Tacrolimus is a potent ISA of fungal origin acting by inhibiting phosphatase activity of calcineurin. There is indirect inhibition of T-cell proliferation and a direct effect on the transcription of interleukin 2. Tacrolimus is much more potent than CSA in this respect.12 13 Further, safety data from transplant patients suggest tacrolimus to have a far better safety profile in terms of renal toxicity and the risk of systemic hypertension.14 15

    The present study examines the clinical efficacy and safety of tacrolimus treatment in patients with BRC who either did not tolerate conventional ISA treatment regimes or in whom ISA failed. A further set of patients had tacrolimus introduced as an additional second-line agent.

    Methods

    Patients were identified via a search of the electronic pharmacy records at Moorfields Eye Hospital for ‘tacrolimus’ and ‘birdshot retinochoroiditis’ between 2011 and 2015 and the clinical case notes were reviewed. All patients reviewed retrospectively met the published diagnostic criteria for BRC.16 17 The data recorded demographic characteristics including date of presentation and of starting tacrolimus, previous immunosuppressive treatment, indication for starting tacrolimus, time to achieve prednisolone dose of 10 mg or less, prednisolone dose at last follow-up and concomitant use of other immunosuppressant medication. Clinical data included Snellen visual acuity (VA) at start, at least 6 months of treatment and at 1 year of treatment; the findings on standard ophthalmological examination; changes in blood pressure and antihypertensive medication and requirement for antihypercholesterolaemic medication. We reviewed both Humphrey visual field (HVF) (24-2) and Swedish Interactive Threshold Algorithm standard programme of the Humphrey Field Analyzer (Humphrey Instruments, Dublin, California, USA)) at commencement of tacrolimus and following a minimum period of 6 months therapy and then at 1 year.

    The research was conducted in accordance with the principles of the Declaration of Helsinki.

    As a usual routine, tacrolimus is started at a dose of 2 mg daily and subsequently increased weekly to achieve a serum trough level of 5–10 ng/mL. A ‘stepladder’ approach to the initiation of ISAs was noted in these patients. Once the diagnosis of BRC was confirmed, patients were started on antimetabolite and steroids. In patients refractory to or intolerant of ISAs, other ISAs were considered including a different antimetabolite or a calcineurin inhibitor.

    The criteria of labelling a patient intolerant to any ISA were also noted. Patients were considered intolerant to an ISA if they developed significant gastrointestinal symptoms, leucopenia or clinically significant changes in liver function tests, creatinine level or blood pressure. ‘Flare-up’ or ‘active disease’ was defined as patients experiencing new onset of floaters, field loss, visual distortion, VA loss, colour vision problems or nyctalopia, clinical evidence of vitritis or vasculitis, the appearance of new characteristic BRC lesions, disc oedema or cystoid macular oedema, FFA or ICG evidence of activity and/or worsening on ERG as compared with previous records.4 Renal function toxicity was defined as a rise in creatinine level greater than 30% above baseline value. As per routine, tacrolimus blood levels were monitored weekly for 1 month, then monthly for 6 months and thereafter bimonthly. A patient was considered refractory to ISA if clinical examination and/or ancillary test results demonstrated persistent disease activity, such as persistent leakage on FFA, increased birdshot lesions on ICG or worsening function demonstrated with HVFs and/or electrophysiology. In the more recently diagnosed cases, there was a trend to start treatment early, with both tacrolimus and steroids.

    Full field and pattern ERGs (PERGs) and HVFs were usually performed at regular intervals of approximately 6 months and also depending on the clinical requirement as guided by subjective and objective improvement/stability. As per standard clinical routine at Moorfields' Medical retina service, the ISCEV standard18 19 is to use gold foil corneal recording electrodes. PERGs were recorded to a standard checkerboard field (15° × 12°) and to a large field (30° × 24°). PERG P50 and full-field ERG amplitude changes from baseline were considered to be a clinically meaningful and relevant if greater or worse than 30% (PERG P50 component; dark adapted (DA) 0.01 ERG b-wave; DA 10.0 ERG a-wave or b-wave; light adapted (LA) 3.0 b-wave; LA 3.0 30 Hz ERG) or if peak time change was 3 ms or greater (DA 10.0 a-wave; LA 3.0 30 Hz ERG) according to standard clinical criteria. All data were recorded on SPSS V.14.0 (released 2005; SPSS for Windows). Paired sample t-tests were performed to examine the significance of ERG and visual field (VF) changes; a p value of <0.05 was considered as statistically significant.

    Results

    The entry criteria were fulfilled by 25 patients. All were HLA-A29 positive and the majority were female (n=20, 80%). The mean age±SD at diagnosis was 50.4±10.8 years (range 32–86 years). The mean follow-up period was 19.14±9.46 months (range 12–48 months). Tacrolimus was the first second-line ISA (other than steroid) in seven (28% patients), used to replace a different second-line agent in four (16% patients) and used as an additional second-line agent in 14 (56%) cases. It was added to mycophenolate mofetil in most (n=13, 52%) patients and methotrexate in one patient (4%). Reason for starting tacrolimus in each patient and other demographic details are shown in table 1. Important clinical details are shown in table 2.

    View this table:
    Table 1

    Demographic and important clinical details of cases

    View this table:
    Table 2

    Important clinical details of cases

    Twenty-one patients (84%) tolerated tacrolimus well. The drug had to be stopped in four patients: one had severe diarrhoea and elevated cholesterol levels. One, with pre-existing Gilbert syndrome, developed hypertension and haematuria after 6 months (though renal function showed no significant change). Another patient had insomnia accompanied by tremors and increased bowel frequency and tacrolimus was stopped after 2 weeks. Tacrolimus was stopped in the fourth patient due to shortness of breath. Other patients developed side effects that were easily treatable or were well tolerated (table 2).

    Two patients (8%) required increased dose of antihypertensive drugs and three (12%) required increased dose of antihypercholesterolaemic medication. At the end of first month, three patients (14.28%) showed mild (less than 30% elevation in creatinine levels) abnormality in renal function; 1/21 (4.76%) at 3 months and one at the end of 6 months. None of these patients required discontinuation of treatment due to renal disturbance. One patient had transient disturbance in urea levels, but creatinine levels remained acceptable.

    Efficacy

    The mean number of flare-ups during the follow-up period was 0.48±0.73. One patient developed cystoid macular oedema (CME) during follow-up that required treatment with increased dose of systemic steroids, orbital floor injection and subsequent dose adjustment of tacrolimus, following which vision and symptoms stabilised. The central macular thickness was noted to be 522 μm on Topcon optical coherence tomography, initially which improved to 396 μm in 3 months and then to 261 μm in further 2 months. Further, a patient developed CME (326 μm) that improved and stabilised in 6 months after dose adjustment to 212 μm. The tacrolimus dose was reduced after successful and sustained control of inflammation in five patients. The mean time to this dose reduction was 11 months (range 7 months–1.8 years). The mean time taken to taper steroids to less than 10 mg after starting tacrolimus was 5.44±2.71 months (range 2–12 months). The difference between daily oral prednisolone steroid dose prior to tacrolimus and at most recent follow-up was statistically significant (mean 19.74±12.44 mg compared with 6.91±4.21 mg; t=5.071, p=0.001). The daily prednisolone dose, for each patient, at 6 months and 1 year follow-up has been given in table 2. Mean daily prednisolone dose at 6 months was 7.733±5.13 and was 6.58±4.28 mg at 1 year of follow-up.

    The Snellen VA either showed improvement or it stabilised on starting tacrolimus. The detailed changes in VA after at least 6 months and 1 year of treatment with tacrolimus are given in tables 1 and 2. On starting tacrolimus, cataract surgery was required in three patients during the study period which restored good VA. VFs improved over time (mean improvement in Humphrey after at least 6 months of therapy MD, right eye (RE)=1.8±2.4 dB, t=3.821, p=0.004; left eye (LE)=−1.9±2.7 dB, t=3.06, p=0.007; figure 1 and at 1 year after starting tacrolimus, RE=1.65±2.31 dB, t=3.20, p=0.005; LE=−1.75±2.72 dB, t=2.87, p=0.010) as compared with baseline values. The difference between 6 months and 1 year values was not statistically significant (RE, t=1.048, p=0.308; LE, t=1.623, p=0.120). The significant improvement in VF persisted even when reanalysed to exclude those patients who underwent cataract surgery during the study (mean improvement in Humphrey MD, RE=2.09±2.44 dB, t=3.53, p=0.003; LE=2.122±2.82 dB, t=3.10, p=0.007).

    Figure 1
    Figure 1

    Changes in visual fields in both eyes after at least 6 months of tacrolimus use. RE, right eye; LE, left eye.

    Imaging

    Pretreatment and post-treatment fluorescein angiograms and IGA were available for 21 patients. Since many of the patients were already on immunosuppressive therapy, therefore, vasculitis was noted in only eight patients at the start of tacrolimus. Later on, complete resolution of vasculitis was noted in three patients; in three patients it was better, stable in one and worse in one initially, which improved later on during the course of treatment. Hypofluorescent spots on ICG were seen in all patients. Resolution or improvement was noted in 17 patients. In two patients, hypofluorescence persisted but improved and in two patients atrophic spots developed on resolution. However, interestingly, electrodiagnostic tests (EDTs) remained stable in these patients.

    Electrophysiological parameters

    After at least 6 months of tacrolimus use, PERG P50 amplitude to a standard stimulus field increased in 14 eyes of 10 patients (median improvement 60%; range 36%–340%) compared with baseline (figure 2), consistent with significant improvement in macular function.

    Figure 2
    Figure 2

    Changes in electroretinography (ERG) parameters after 6 months of tacrolimus use. Pattern ERG (PERG) P50 amplitude to a standard stimulus field increased in 14 eyes of 10 patients (median improvement 60%; range 36%–340%) compared with baseline which is consistent with significant improvement in macular function. Values showing maximum reduction are those furthest beneath the diagonal line. DA, dark adapted; LA, light adapted.

    Values showing maximum reduction are those furthest beneath the diagonal line; PERG P50 values at 6 months were statistically significantly improved compared with baseline in both right and left eyes (table 3).

    View this table:
    Table 3

    Paired t-test results for electrophysiological parameter with tacrolimus treatment of at least 6 months

    Most other patients showed a high degree of PERG stability, but one eye showed borderline worsening (30% reduction). Large field PERG P50 showed improvement in 12 eyes of seven cases (median 84%; range 36%–243%) with no patient showing significant worsening (figure 2). The improvement was statistically significant for right eyes, but not for left eyes (table 3). Full-field ERG DA 10.0 ERG a-wave amplitudes were stable in most; b-wave amplitudes increased in six eyes of four patients (by 43%–105%). There was borderline improvement in one eye and marginal worsening (30% change) in one eye (figure 2). LA 3.0 30 Hz ERG peak times improved in 12 eyes of seven cases by 3–8 ms and worsened in three eyes of three patients by 3–4 ms; amplitudes improved in both eyes of two patients (47%–80%) and showed mild worsening in seven eyes of four cases (31%–44% reduction). LA 3.0 ERG (2 Hz) b-wave amplitudes showed a high degree of stability; there was borderline worsening of amplitude in one eye and improvement (44%) in one eye. None of these changes were statistically significant. For details please see the table 1 in the online supplementary file 1.

    Supplementary file 1

    After 1 year of Tac use, PERG P50 amplitude to a standard stimulus field increased in 19 eyes of 14 patients; the median improvement in amplitude in the 18 eyes with a detectable response at baseline was 58% (range 36%–240%), consistent with significant improvement in macular function. One other subject showed borderline (30%) improvement bilaterally. Analysis given in the figure 1 in the online supplementary file 2.

    Supplementary file 2

    All other patients showed a high degree of PERG stability. Large field PERG P50 showed improvement in 16 eyes of 14 cases including one eye with an undetectable response at baseline; the median improvement in others was 65% (range 31%–243%) with no patient showing significant worsening.

    Full-field ERG DA 10.0 ERG a-wave amplitudes were stable in most; b-wave amplitudes increased in four eyes of three patients (by 40%–105%) and showed borderline worsening (30% change) in two eyes. LA 3.0 30 Hz ERG peak times improved in 14 eyes of nine patients by 3–8 ms and worsened in five eyes of three patients by 3–6 ms; amplitudes improved in four eyes of three patients (31%–80%) and showed mild worsening in four eyes of three cases (33%–41% reduction). LA 3.0 ERG (2 Hz) b-wave amplitudes showed a high degree of stability in all, but one eye showed improvement (44%).

    Discussion

    This study is the first to evaluate the safety and efficacy of tacrolimus in the treatment of BRC. The data show a reasonable tolerability and a good safety profile, with cessation of treatment due to unacceptable side effects required in only 16% of patients. The majority showed sustained improvement in clinical and/or functional parameters and included patients that were resistant or intolerant to first-line ISAs.

    There was a positive effect of tacrolimus on VA with improvement and stabilisation in (20/21) 95.23% of patients. Other authors have reported a similar beneficial effect in other forms of non-infectious uveitis, especially Behçet’s disease.20–22 However, VA is not a good indicator of treatment response in BRC as it reflects the function of the central macula rather than generalised retinal function; patients may continue to experience photopsiae and other positive phenomena and show deterioration of retinal function on electrophysiology and VF examination without change in Snellen VA. It has previously been shown that objective monitoring of VF and electrophysiological indices of retinal function enable more effective monitoring than conventional clinical outcome measures.4 Since these parameters may keep on changing over the course of the disease, therefore, repeated examination are very important for the proper monitoring of the disease. It has been noted before that initiation of immunosuppressive therapy may halt or even reverse the VF loss associated with BRC.23

    Tacrolimus has been previously shown to be both effective and safe in the treatment of uveitis.11 24 However, monitoring of control of inflammation in BRC is more complex as the disorder is associated with subclinical, insidious progression and many patients do not show signs of worsening on cursory clinical examination. Any ISA needs to be safe, well tolerated and to have continuing efficacy during the intervals between follow-up visits when sophisticated indicators of disease activity such as VF, ERG and FFA can be used. There have been numerous anecdotal reports of the efficacy of various agents, including local and systemic therapies including ISAs and biologicals, but there have been no randomised clinical trials purely devoted to Birdshot and there is no consensus in relation to optimal treatment protocols for BRC. One major challenge is the early identification of those patients at risk of visual loss to enable appropriately aggressive treatment. Another is the development of effective treatment regimes, including appropriate monitoring techniques, in order to optimise management and reduce side effects.

    Previous authors have used CSA with good clinical results, supported by the addition of azathioprine in some patients.25 The outcome for treated eyes was better than untreated eyes but the inflammation returned on the discontinuation of therapy. A subsequent report from the same group used combination therapy with mycophenolate mofetil and CSA in an attempt to reduce the possibility of CSA-associated nephrotoxicity.26 There was effective control of inflammation (based on vitritis and angiographic leakage), but a 55% incidence of significant side effects, systemic hypertension being the most common. Other authors have reported tacrolimus to have similar potency but a better safety profile than CSA in the management of posterior and intermediate uveitis.27

    Tacrolimus was added as an additional ISA in >50% of the patients in the present study, the vast majority of them (93%) were taking mycophenolate but had not stabilised. Stabilisation was successfully achieved with tacrolimus in most patients, and therefore data suggest that mycophenolate is not always effective in achieving stabilisation as a single ISA. In both the group of patients in whom tacrolimus was used as an additional ISA in those refractory to previous ISA therapies and those in whom tacrolimus was started as the sole ISA other than steroids, there was marked clinical improvement with significant reduction in steroid requirement and a low incidence of side effects (16%). Tacrolimus appears to retain efficacy with satisfactory control of inflammation and reduced side effects over the moderately long duration of the study.

    It has been previously reported that the ERG data can show worsening when there are minimal clinical signs. In BRC, the 30 Hz flicker ERG has been shown to be a sensitive marker for impairment of retinal function.28 In addition, amplitude decrease and peak time delay on the PERG have been shown to be a marker for impaired macular function in BRC.4 28 For example, impaired PERG can occur with macular oedema. Stabilisation or improvement of the various electrophysiological parameters can therefore be used as reliable markers for monitoring disease activity and response to treatment.4 29

    The early introduction of biological or local agents has recently been shown to be a successful approach,8 30 but have mostly been studied in refractory BRC cases. In one study of daclizumab, ERG parameters did not improve despite the improvement in inflammation and stabilisation of VA, and it was suggested that the potential retinotoxic effects of such agents require further study.30 In addition, such agents are very expensive and are not widely available, compared with the ready availability and relative affordability of tacrolimus.

    The resolution of classic Birdshot spots on ICG has also been reported before with initiation of immunosuppressive therapy, especially with early initiation of ISAs.31

    In conclusion, the data from this small, retrospective study show tacrolimus to be a promising ISA in BRC, either as sole steroid-sparing agent or as an additional agent. The data demonstrate a clinically significant steroid-sparing effect and a good safety profile. In addition, visual stabilisation or improvement occurred on both standard white-on-white perimetry and electrophysiology. These two measures of visual function are therefore both important and are complimentary in the treatment of patients with BCR.5 Despite the limitations of the study, the data suggest that larger, prospective, multicentre studies are warranted in order to confirm the usefulness of tacrolimus therapy in the management of patients with BCR.

    Acknowledgments

    We are thankful to the Chrysoula Koutsiouki and Moorfields staff of Medical retina service for their help.

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    Footnotes

    • Contributors FI, MW substantially contributed to the conception and design of the work, the acquisition, analysis and interpretation of data for the work and drafting the work or revising it critically for important intellectual content. AR, AGR, BK contributed to acquisition, analysis and interpretation of data for the work and drafting the work or revising it critically for important intellectual content. GH and CP contributed to interpretation of data for the work and drafting the work or revising it critically for important intellectual content.

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval Ethical Review Board, Moorfields Eye Hospital, London.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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