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Dr.Ruchika Lakra,Dr.Jyotirmay Biswas,Dr.Parthopratim Dutta Majumder

Abstract

Purpose: To evaluate the efficacy of adalimumab (ADL) and golimumab (GLM) on patients with HLA B-27 associated uveitis.

Method: Retrospective analysis of patients with HLA B-27 associated uveitis refractory to at least one immunosuppressive drug, who subsequently received ADL or GLM between January 2014 and January 2018.

Results: The study included 14 patients -12 of them received ADL and GLM was administered in 2 patients. Mean age of the patients was 32.1 years (17-53 years).The most common underlying systemic disease was ankylosing spondylitis (92.8%). Biological was administered as monotherapy (3;21.4%) and in combination with  methotrexate (11; 78.5%). The mean BCVA improved from 0.923 log MAR to 0.315 log MAR (p value=0.001). Most common complication was complicated cataract (50%) followed by hypotony (42.8%), glaucoma (14.2 %) and cystoid macular edema (7.1%).

Conclusions: Human Monoclonal Antibodies may be a useful therapeutic option in refractory cases of HLA B-27 associated uveitis.

Keywords: Adalimumab, golimumab, biological,HLA-B 27 uveitis

Introduction

Uveitis is the most common form of inflammatory eye disease and an important cause of visual impairment and blindness. Extensive ocular involvement along with its recurrent nature makes HLA B27 associated uveitis to have worse visual prognosis.

Over the past two decades, the introduction of biologic treatments, especially those targeting antitumor necrosis factor α (anti-TNFα agents) has dramatically improved the management of rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis (JIA) and the spondyloarthritides(SpA). Similarly,anti-TNFα agents have become a valuable addition to the therapeutic armamentarium for patients with associated uveitis that is refractory or intolerant to conventional treatment. Biologic agents are a class of therapeutic drugs that target different mediators involved in the pathogenesis of human diseases. A proposed definition is: “a biologic is a protein or nucleic acid based pharmaceutical substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non-engineered) biological source.”1

Methods

We conducted a retrospective analysis of the case records of 14 patients with HLA B-27 associated uveitis refractory to at least one immunosuppressive who received ADL orGLMbetween January 2014 and January 2018.All patients attended SankaraNethralaya, Medical Research Foundation,Chennai, Tamil Nadu,where they were always under the care of  uveitis specialist. Patients included in the study were those who had an inadequate response in controlling intraocular inflammation to at least one immunosuppressive. Screening before initiation of biological treatment included serum biochemical and hematologic profiles with complete hemogram, liver and renal function tests, chest X-ray, and electrocardiography. All patients had already been pre-screened for the presence of active or latent tuberculosis.

Data collected included age, gender, age at onset of uveitis and arthritis, characteristics of the uveitis, ocular complications, previous systemic immunosuppressant therapies, previous systemic and topical corticosteroid therapy, and followup after biological treatment. Biological was administered as monotherapy in three patients and in combination with  methotrexate in rest of the patients .

The primary outcome measure evaluated was clinical response to treatment, including decrease in disease activity (reduction of cells and flare in the anterior and posterior chamber), improvement in visual acuity, reduction of concomitant systemic corticosteroid and/or immunosuppressants, reduction of topical corticosteroid therapy, and occurrence of adverse events.

Results

In this study, 20 eyes of 14 patients of HLA-B27-associated uveitiswho received biological therapy were included. Twelve patients were maleand 5were female. Eight cases had unilateral involvement, five cases had alternatingbilateral involvement and only one case had simultaneous bilateral involvement. The majority of patients had anterior uveitis (10, 71%) followed by intermediate (2, 14%) and pan-uveitis (2, 14%). Twopatients (14%) had cystoid macular edema and 5patients (36%) had ocular hypotony. The most common underlying systemic disease was ankylosing spondylitis (13, 92.8 %).Systemic involvement could not be detected in one patient.

Mean age of the patients was 32.1 years (17-53 years). Past systemic medication history included, oral and pulse corticosteroids.All the patients were treated with topical corticosteroid with cycloplegic therapy for the management of anterior chamber inflammation in the past. Nine patients received oral corticosteroid (1mg/kg/day). Pulse corticosteroid was administered in two patients (14%).Eleven patients (78%) had already received posterior subtenon injection of corticosteroid. Twopatients (14%) were put on salicyl-azo-sulfapyridineand  11patients(78%)   were administered methotrexate before the treatment withbiological. 3patients(21%)  had raised IOP and was under anti-glaucoma medications prior to the biologic therapy.

All patients underwent a detailed investigation to rule out other possible etiologies of uveitis which included serology for HIV, Mantoux test and high-resolution computed tomography of the chest. Systemic ADLwas administered subcutaneously 40 mg every 2 weeks in 12 patients and injection of GLM (SIMPONI®) was administered subcutaneously 50 mg and repeated every 4 weeks for two patients. The choice of biological was decided and subsequently administered by the rheumatologist. None of the patients developed rash, reaction at the injection site or any other serious adverse effects after the injection. Three patients (21.4%) received biological as monotherapy and in 11 patients (78.5%) oral methotrexate was continued as maintenance therapy. 7 out of 14 patients (50%) required topical therapy after starting biologicals.The median follow-up time was 23 (range: 7–36) months. 9 out of 14 patients (64%) had a single episode of recurrence after the use of biologicals.For 5patients(36%) there was a significant improvement of intraocular pressure with resolution of hypotony.Only one patient (7%) developed CME post treatement with biologic and one (7%) had pre-existing CME. Three patients (21%) with raised IOP continued anti-glaucoma medications after the biologic therapy.

No patient was reported to develop chronic granulomatous infection during the follow-up period. The average number of attacks of inflammation in these patients was 2 per year prior administering biologicals. All the patients reported subjective improvement in joint pain, movement restriction, though we did not document these findings with a uniform score.

The mean BCVA prior to thetreatment with biologicswas 0.923 log MAR which improved to 0.315 log MAR. This improvement in BCVA was statistically significant (p = 0.001).

Discussion

We evaluated the efficacy of ADL and GLM in patients with the most recalcitrant forms of HLA-B27 -associated uveitis who had an inadequate response to previous immunosuppressives. The presented cases are the most severe forms of uveitis and this is also confirmed by the multiple ‘‘switch’’ of immunosuppressive drugs that had been previously employed in our patients.Most common complication due to the chronic nature of uveitis and long term use of immunosuppressiveswas complicated cataract (50%) followed by hypotony (42.8%), glaucoma (14.2 %) and cystoid macular edema (7.1%). The high number of ocular complications at beginning of treatment is another supportive element that confirms the severity of longstanding uveitis in our treated group. But there were no serious adverse effects after the use of biologics. A number of studies have also reported more serious adverse events including but not limited to: multiple sclerosis, malignancy, lupus-like reaction and reactivation of tuberculosis.2–4. Anti-TNFα agents carry a specifically increased risk of tuberculosis (TB), usually reactivations of latent disease5 but also primary infection. Important differences in the risk of latent TB reactivation exist, with the risk being higher with infliximab andADL than with others.6,7 According to the literature, upper respiratory tract infections are among the most frequent adverse events encountered in patients treated with GLM.8–10The mean follow-up period of our retrospective study was too short and sample size too small to detect rarer adverse events.

In the present study, favorable response to treatment with biological was obtained in majority with long-term control of uveitis.10 patients (71%) had significant visual acuity improvement and for 4 patients (29%) vision was maintained.9 out of 14 patients (64%) had a single episode of recurrence after the use of biologics.Hypotony is an uncommon, but not rare in HLAB‐27‐associated uveitis.While chronic cases are thought to develop due to prolonged  inflammatory activity, with ciliary body atrophy or the development of cyclitic membranes, acute hypotony in uveitis has been proposed to be due to ciliary body inflammation, with reduced aqueous production, or increased uveoscleral outflow. Although hypotony during acute attack of HLA B‐27‐associated uveitis is usually transient, reversible, and reported to have a favorable outcome with aggressive treatment with corticosteroid, there are reports of protracted hypotony recalcitrant to local and systemic corticosteroid.11In our study, 5 patients(36%) showed significant improvent of intraocular pressure with resolution of hypotony after the use of biologicals.

Biological was administered as monotherapy in three patients (3; 21.4%) and in rest of the patients combination with methotrexate was administered (11; 78.5%). Significant improvement in the best corrected visual acuity was noted in both the groups.

There is an important variability in the response to the biologics among patients with ocular inflammatory diseases and not all patients respond to their first biologic. Thus, patients are frequently treated with more than one TNF-ainhibitor. Many studies indicate that TNF-a inhibition may result in rapid control of intraocular inflammation and in remission during maintenance. However, even when administration of these agents appears to be beneficial, several patients did not adequately respond to treatment, thus highlighting the need for treatment individualization.12–14Further research is also warranted in order to address issues of optimal dosage regimens, duration of treatment, and long-term safety. It is therefore clear that it’s becoming more important to have a wide range of effective therapeutic options available to treat the most serious uveitis cases. The development of biologicals with a more convenient dosing schedule than that of available drugs might be beneficial and might also improve the patient’s quality of life.

In conclusion, biological is a new therapeutic option for treatment of patients with autoimmune diseases, particularly those who have not previously responded to other immunosuppressives. We believe that biological may be a promising treatment option for refractory uveitis cases. Our conclusions are limited by the retrospective nature of our study and the small number of patients studied.

References

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