The Rheumatology Unit of Prato Hospital is a secondary referral center which serves around 300,000 people living in the Prato province and the surrounding industrial areas. About 75% of patients are sent by their general practitioners, and the remaining are self-referred.
In March 2004, the Rheumatology Unit was appointed as the tertiary referral center for rare rheumatic diseases. Patients with these conditions are self-referred or sent by other specialists from all parts of Italy.
From January 2005 to December 2010, in collaboration with the Ophthalmology Department of Prato Hospital, all consecutive new patients with refractory PU underwent the same diagnostic and therapeutic schedule and all data were recorded in an individual computed chart.
At baseline all patients underwent the following investigations: history taking, physical examination, purified protein derivative (PPD) test, laboratory tests including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood cell count with differential count, renal and liver function, human leukocyte antigen typing, antinuclear antibody titer, and serology for toxoplasma, human immunodeficiency virus, syphilis, lysozyme, or angiotensin-converting enzyme. Ophthalmologic evaluation consisted of a complete ocular examination including best-corrected VA (Snellen chart of 0.1–1.0), slit-lamp biomicroscopy, tonometry and ophthalmoscopy, optical coherence tomography (OCT), and fundus fluorescein angiography (FFA).
To be enrolled, patients should have a diagnosis of idiopathic or BD-associated chronic PU, with or without retinal vasculitis, resistant to a dose of prednisone or equivalent greater than 10 mg/day, and at least one immunosuppressive drug after at least 12 months of treatment.20
The diagnosis of BD was formulated according to the International Study Group (ISG) criteria.21
As VA loss during BD flare-ups may be reversible following treatment,22
we also included in the study patients with active PU and unilateral or bilateral loss of vision of recent onset (<3 months).
Patients with permanent blindness, with contraindications to IFX use, as recommended by by Centocor Ortho Biotech, Inc (Malvern, PA), or with a history of recent infections and malignancies were excluded from the study. Pregnancy and breastfeeding constituted additional exclusion criteria and contraception was recommended to all females of childbearing potential.
Moreover, a careful screening for tuberculosis was made by detailed medical history, chest X-rays, and PPD test. Over the last 3 years the QuantiFERON TB Gold test was also performed.
The primary end-point was to assess the long-term efficacy of IFX therapy in patients with idiopathic or BD-associated refractory PU uveitis as expressed by VA improvement from baseline.
Secondary end-points were to investigate the efficacy of IFX to reduce disease flare-up, to assess the proportion of relapse-free subjects at the end of follow-up, and the percentage of patients achieving a complete or partial remission, and to evaluate the tolerability and safety of the treatment.
Primary outcome measure
The primary outcome measure was improvement in VA mean values at the end of follow-up compared to baseline.
Secondary outcome measures
Secondary outcome measures were a proportion of patients achieving an improvement of best-corrected right eye and left eye VA from baseline; proportion of patients achieving a complete or partial remission; timing of remission; proportion of relapse-free patients at the end of follow-up; number of ocular attacks during the treatment period; and number and severity of adverse events (AEs).
Definition of response
The response to therapy was calculated by a composite score from 0 to 7 obtained by the sum of the grade of severity of inflammatory infiltrate and retinal vasculitis as reported previously.19
The response was graded as follows:
- Complete remission: presence of less than 1+ cellular reaction (scale 0–4), and remission of vasculitis evaluated by a score (0–3) at fundus examination and FFA (0 = absence of vasculitis, 1 = vasculitis of peripheral retinal vessels, 2 = posterior pole vasculitis, and 3 = vasculitis with evidence of areas of retinal necrosis). FFA examinations were scheduled at baseline, week 6, 22, and 54, and yearly thereafter.
- Partial remission: improvement of at least 50% of inflammation and retinal vasculitis scores.
- Absent: absence of any improvement or less than 50% of uveitis scores.
At baseline, all patients suspended the current immunosuppressive therapy, and received prednisone at the dose of 1 mg/kg/day. In addition, all subjects received IFX 2-hour intravenous infusions at the dose of 5 mg/kg at weeks 0, 2, 6, and every 8 weeks thereafter. IFX-dose escalation through infusion-interval shortening to 6 weeks was allowed in nonresponder patients or in those with partial remission according to the judgment of the physician. IFX infusions were administered for the whole duration of follow-up.
During the drug infusion and for 1 hour afterwards, blood pressure, pulse, and temperature were measured every 30 minutes. Moreover, at every visit, complete blood count, liver, and kidney function tests were examined. Antinuclear antibodies (ANA) were measured at baseline and every 6 months.
In responders, the following CS-dose tapering was scheduled: 10 mg/day every 1 week until the dose of 20 mg/day, then 5 mg/day/week until a maintenance dose of 10 mg/day is achieved. This dose was continued for at least 2 weeks before attempting to further reduce the dose of 5 mg/week until withdrawal. In case of relapse, prednisone was increased by 20 mg/day. Other immunosuppressant agents and concomitant local CS injections were not allowed.
Patients failing to achieve at least a partial remission after the third infusion of IFX withdrew from the study and received prednisone 1 mg/kg/day and an immunosuppressant different from that employed before the study entry.
All patients had a complete evaluation by an ophthalmologist and a rheumatologist at baseline and over the follow-up visits that were scheduled 2 weeks after the third IFX infusion (week 8) and then every 4 months or before in case of relapse. The date of last visit constituted the end of follow-up.
At every visit, all patients were monitored for clinical and laboratory evidence of adverse events (AEs) defined as mild (transient and easily tolerated), moderate (subject discomfort with interruption of usual activities), or severe (incapacitating or life-threatening). The study was approved by the local ethical Committee and written informed consent from the patients was obtained.
Data statistical analysis was done using the SPSS statistical package (SPSS Inc, Chicago, IL). Wilcoxon’s matched pairs signed rank test were used to measure the changes from baseline of ocular inflammation and ocular attacks. Chi-square test for nominal variables was used to calculate the differences between the BD-associated and idiopathic PU results. Analysis of variance (ANOVA) for repeated measures was used to measure the VA changes. P values less than 0.05 were accepted as significant.