Pulsed Intravenous Methylprednisolone For Mucous Membrane Pemphigoid (MMP): A Pilot Randomised Clinical Trial

1. Pulsed Intravenous Methylprednisolone For Mucous Membrane Pemphigoid (MMP): A Pilot Randomised Clinical Trial 1Moorfields Eye Hospital, 2Birmingham & Midlands Eye Unit, 3Bristol Eye Hospital VPJ Saw1, JKG Dart1, C Bunce1, S Hau1,S Rauz2, D Tole3,T Peto1 A newly developed upper conjunctival fornix measure used in this clinical trial The authors have no financial interest in the subject matter of this poster VPJ Saw was supported by an Action Medical Research Fellowship

2. INTRODUCTION In actively inflamed ocular mucous membrane pemphigoid (MMP), current conventional treatment is to commence cyclophosphamide in combination with a 6 to 12 week course of tapering oral corticosteroids (1,2). Steroids act more rapidly than cyclophosphamide. However, with this conventional treatment ,corneal perforation and progressive cicatrisation still occur in 10.5% and 21% of eyes respectively, and disease control is achieved in only 26% by 6 weeks (3). More rapid control of inflammation with the use of adjunctive pulsed IVMP could more effectively suppress aggressive inflammation, and perhaps also delay cicatrisation. Pulsed IVMP is used anecdotally by physicians managing ocular MMP. It is clearly beneficial in treating optic neuritis, but its use in ocular MMP has not formally been evaluated. The majority of treatment studies in ocular MMP are case series or cohort studies. This is the 3rd only prospective randomised treatment trial in ocular MMP (4). As part of this study, in 2004 we (VPJS, SH, D Carpenter ocular prosthetist at Moorfields Eye Hospital) also designed a hand-made modified fornix depth instrument to objectively assess progression of upper and lower conjunctival fornix cicatrisation. Almost all previous reports on cicatrisation in MMP have been limited to assessing the lower fornix, overlooking the upper fornix (5). In parallel with the clinical trial we conducted a repeatability and reliability study using this instrument, and a preliminary study establishing the normal range of upper conjunctival fornix depth; these results are also presented here.

3. PURPOSE Primary purpose: To establish the feasibility of conducting a randomised clinical trial to evaluate the additive effect of pulsed intravenous methylprednisolone (IVMP) on rapidity of control of inflammation, and control of scarring, in patients with active ocular MMP commencing oral cyclophosphamide and oral corticosteroids. Secondary purpose: To evaluate the use of a newly designed fornix depth instrument to measure upper conjunctival fornix depth METHODS CLINICAL TRIAL: Research Ethics Committee approval was obtained and all participants had informed consent. Patients were recruited from July 2005 through April 2008. The trial is registered on the International Standard Randomised Controlled Trial Number Register (ISRCTN51714283). Inclusion criteria: patients with progressive conjunctival cicatrisation, with positive direct immunofluorescence (DIF) and/or a positive indirect immunofluorescence (IIF) result. Presence of a clinical indication to commence cyclophosphamide because of grade 3 or grade 4 ocular inflammation and/or active inflammation uncontrolled by non-cyclophosphamide immunosuppression was a criterion for inclusion. The study eye was the eye with the greatest conjunctival inflammation at enrolment. Where both eyes had similar inflammation, the right eye was chosen. Recruitment: consecutive cases from Moorfields Eye Hospital (n=16), Birmingham Eye Centre (n=3) and Bristol Eye Hospital (n=1). Intervention: adjunctive intravenous methylprednisolone (IVMP) 1 gram daily for 3 consecutive days. Oral cyclophosphamide 1.5-2 mg/kg/day was commenced simultaneously, and a 12 week tapering course of oral prednisolone was commenced after the 3rd dose of IVMP. At the week 4 visit, if the conjunctival inflammation was still grade 2 or above in each of the 4 bulbar quadrants (see Outcome Measures below), a second pulse of 3 grams IVMP was given. Control: conventional therapy with oral cyclophosphamide 1.5 - 2mg/kg/day and a 12 week tapering course of oral prednisolone 1mg/kg/day. In all patients, cyclophosphamide was continued for up to 1 year unless there were adverse events. All patients were commenced on alendronic acid 70mg weekly with oral calcium and vitamin D3, and omeprazole until the oral corticosteroid doses had reduced to <7.5mg/day. Randomisation: A randomisation list was generated by Moorfields statisticians, using random permuted blocks of varying sizes. A masked observer graded conjunctival inflammation at each visit and the cicatrizing conjunctivitis severity score (see below) at enrolment and the final visit, and masked photographic grading of conjunctival inflammation at each visit was carried out in parallel (Moorfields Eye Hospital Reading Centre:TP). Study investigators and patients were not masked.

4. A newly developed upper conjunctival fornix measure used in this clinical trial METHODS continued The primary outcome measure was the proportion of patients achieving control of conjunctival inflammation in the study eye at 6 weeks. Control of conjunctival inflammation was defined as bulbar conjunctival inflammation grade 1.5 or less in all 4 quadrants, giving a total bulbar inflammation score of 6 or less. Conjunctival inflammation was graded 0 (nil), grade 1 (minimal), grade 2 (moderate), grade 3 (marked), or grade 4 (severe). Conjunctival inflammation was assessed at 2-weekly intervals for months 1-3, 4-weekly for months 4 -6, then 8-weekly for months 6-12. Secondary outcome measures included progression of cicatrisation, change in cicatrizing conjunctivitis severity score, visual acuity, and adverse side effects. Progression of cicatrisation between the enrolment and 12 month visit was evaluated by using a custom-made fornix depth instrument, the design of which was modified by us to enable measurement of the upper conjunctival fornix (see below) A cicatrizing conjunctivitis severity score out of 63 was devised based on previous grading schemes (Bernauer, Francis). This evaluated visual acuity, conjunctival inflammation, lid pathology and cicatrization as well as keratopathy, to give an indication of the severity of disease affecting all aspects of the ocular surface. The cicatrizing conjunctivitis severity score was assessed by the masked observers at enrolment and at the final visit, for each patient. Blood pressure, blood sugar, dipstick urinalysis, full blood count, renal function and electrolytes, liver function tests were monitored in all patients. Bone densitometry was performed at enrolment and at the final visit. Statistical Analysis: Baseline characteristics of the treatment groups were compared to assess the adequacy of randomization. Given that it was a pilot study, descriptive statistics are presented. The number of patients required for a definitive study was computed based on success rates. Agreement between photographic and observer grading of bulbar inflammation was assessed using Bland Altman methods. Analysis was by intention to treat. UPPER FORNIX DEPTH MEASUREMENT: In 2004, in preparation for the clinical trial, a modification of the Schwab fornix depth instrument (5) was designed by us (VPJS, SH, D Carpenter ocular prosthetist Moorfields Eye Hospital). It was used at Moorfields and distributed to trial investigators in Birmingham and Bristol. The biconcave handmade instrument is made of polymethylmethacrylate (PMMA), designed to fit between the globe and upper lid or lower lid, and measures 30mm x 8mm with a 17mm x 4mm handle. Ethics committee approval was obtained for a prospective study investigating the repeatability and reproducibility of our newly designed fornix depth measure, and aiming to establish the normal range of upper central conjunctival fornix measurements in healthy subjects aged 50 onwards. The mean difference in intra- and inter-observer variation and 95% limits of agreement were calculated using SPSS (SPSS v11.5 for Windows). Preliminary upper conjunctival fornix measurements for 127 healthy patients were taken. For a definitive study, it is planned that 120 healthy patients per decade of age will be measured, to establish the range of upper central fornix depth in healthy eyes.

5. RESULTS • CLINICAL TRIAL • The primary outcome measure was analysed at 6 weeks for all 20 patients. Two patients in the IVMP group died of unrelated causes (pulmonary embolism, lung carcinoma), as did two in the control group (pneumonia in both) before the 12 month final visit. (see Figure 1) • The 2 study groups were comparable regarding disease duration, prior immunosuppressive therapy, lid surgery, and use of topical steroids (Table 1). Prognostic variables in the IVMP group appeared to be slightly worse than in the control group, suggesting that any definitive trial would need to stratify for such factors in the randomisation. The study eye in the IVMP group had a higher initial bulbar inflammation score (median 12.5) compared with the control group (median 11), more advanced cicatrisation (10/10 Tauber stage IIb or above and 10/10 Tauber stage IIIa or above) as well as shorter upper and lower fornix depths and a higher initial cicatrising conjunctivitis severity score (Table 2). • Inflammation was controlled in 20% (2/10) of IVMP patients and 20% (2/10) of control patients at 6 weeks (Table 3). A rapid response to IVMP was observed at 2 weeks, but the effect was not maintained at 4 weeks. At 6 months, inflammation was controlled in 37.5% (3/8) patients in the IVMP and 33.3 % (3/9) patients in the control groups. Median time (range) to control of inflammation in the IVMP group was 8 (2, 32) weeks, and in the control group 14 (2, 52) weeks. Factors associated with control of inflammation at 6 months are described in Table 4. • Fibrosis: Of the 16 patients with 12 month follow-up data, there was a decrease in fornix depth of at least 2mm in 25% (2/8) of both the IVMP and control groups (Table 5). Characteristics of patients in whom progression of fibrosis was detected are described in Table 6. • Adverse effects: IVMP was associated with transient increased blood sugar levels in 40% (4/10), increased intraocular pressure, and bone loss in one patient who had other osteoporosis risk factors. Major adverse effects occurred in 2 patients in the IVMP group: haemorrhagic cystitis when cyclophosphamide was withdrawn because of leucopenia and hepatotoxicity in 1 patient, another developed bacterial pneumonia. And in 2 patients in the control group: pneumocystis pneumonia with disseminated cytomegalovirus infection in 1 patient, and another patient developed bacterial pneumonia.

6. RESULTS continued

7. RESULTS continued Figure 1 Flowchart of the trial

8. RESULTS continued • UPPER FORNIX DEPTH MEASUREMENT • Used with topical anaesthesia, the fornix depth measure permitted rapid measurement and was well • tolerated. No patients reported prolonged discomfort or pain. • Intra-observer variation: Duplicate measurements taken by a single observer were identical in 92% (23/25) of measurements. Inter-observer variation: The mean difference in fornix depth measurement between 2 observers was 0.55 mm with 95% agreement (± 2SD) of -2 and +2mm. • Based on preliminary results from 127 patients aged 50 years and older, the mean upper conjunctival fornix depth was 15.2 ± 1.6mm, range 12 – 20mm (see Table 7). These results will be refined in a current ongoing larger study of 840 eyes (120 eyes per decade of age from 20 years old, up to 80years+).

9. CONCLUSIONS 1.This pilot randomised trial has shown that adjunctive pulse IVMP is unlikely to provide any additional effect in controlling either inflammation or fibrosis, although to make a definitive statement about this would require a trial that we believe is too large to be justified by these pilot data. 2.Our study suggests that if a difference between IVMP and no IVMP does exist, it is small and very large numbers of patients would be required for a definitive study. For example, if we assume a success rate of 20 % at 6 weeks and believe that the smallest clinically relevant treatment difference to detect at the 5 % level is 20 %, to have a study of power 85 % we would need 93 patients per treatment group. We would then need to inflate these figures to allow for loss to follow-up which our pilot study suggests might be considerable. We did employ randomisation so that differences at baseline between study groups are known to have occurred by chance but this does emphasise the need to consider whether or not to stratify randomisation for a definitive trial. 3. Our newly designed fornix depth measure is well tolerated and has low intra- and inter-observer variation. A preliminary study of average upper central conjunctival fornix depth using our measure is 15.2 ± 1.6mm, range 12 – 20mm.

10. REFERENCES • Thorne JE, et al 2008. Treatment of ocular mucous membrane pemphigoid with • immunosuppressive drug therapy. Ophthalmology 115: 2146-2152. • 2. Letko E, et al 2004. A nonrandomized comparison of the clinical outcome of ocular • involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional • immunosuppressive and intravenous immunoglobulin therapies. Clin Immunol; • 111: 303-310 • 3. Elder MJ, Lightman S, and Dart JK: Role of cyclophosphamide and high dose steroid in • ocular cicatricial pemphigoid. Br J Ophthalmol 1995, 79: 264-2664. • 4. Foster CS: Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986, 84: 527-663 • 5. Schwab IR,et al. Foreshortening of the inferior conjunctival fornix associated with chronic • glaucoma medications. Ophthalmology 1992;99:197-202. • 6. Kawakita T, et al. Measurement of fornix depth and area: a novel method of determining • the severity of fornix shortening. Eye 2009;23:1115-9. The fornix depth measure can be purchased from Moorfields Eye Hospital. For details email v.saw@ucl.ac.uk