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Improvement of Noninfectious Uveitis With Fumaric Acid Esters: Results of a Pilot Study
Carsten Heinz, MD;
Arnd Heiligenhaus, MD
Arch Ophthalmol. 2007;125(4):569-571.
Noninfectious endogenous uveitis often improves under corticosteroid therapy, second-line immunosuppressive drugs, or "biologicals." Although they are very helpful, their use might be limited by their adverse effects.
The aim of this pilot study was to investigate the effect of fumaric acid esters (FAEs), which are used for the treatment of psoriasis on endogenous noninfectious intermediate or posterior uveitis. Besides the clinical response, treatment-related modulation of the peripheral blood mononuclear cells was investigated.
Methods
Inclusion criteria were noninfectious endogenous uveitis and vision-threatening complications without inflammatory quiescence under current systemic steroid medication or a maintenance dosage that would otherwise be an indication for a second-line immunosuppressive medication. Visual acuity was above 20/200 in the better eye. The study design complied with the Declaration of Helsinki ethical standards. The local ethics committees approved the study. Informed consent was obtained from the patients. Overall, 4 patients with bilateral uveitis were treated with FAEs and were followed up prospectively (Table 1).
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Table 1. Epidemiological Data for Patients Treated for Uveitis With Fumaric Acid Esters
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After we established the diagnosis, all patients were first treated with systemic steroids with an initial dosage of approximately 1 mg per kilogram of body weight. After achieving quiescence of inflammation, the steroid dosage was tapered off. When inflammation recurred (a cell increase of >2 steps in the aqueous humor or the vitreous) or deterioration of visual acuity (>2 Snellen lines) or cystoid macular edema occurred, treatment with FAEs was started. The increase of FAE dosage was performed every week in accordance with recommended guidelines.1
All patients were seen at baseline; after 2, 6, and 12 weeks; and then at 3-month intervals. At each follow-up visit, we performed a routine clinical examination, including optical coherence tomography and fluorescein angiography. Blood tests, including assessments of leukocytes, lymphocytes, and subpopulations, were performed according to generally accepted protocols.
Results
The epidemiological data and the previous and current anti-inflammatory therapy of the patients are summarized in Table 1. In 3 patients, the FAE dose could be increased to the maximal effective dose. One patient developed gastrointestinal adverse effects, so the maintenance dose was reduced. Two patients were able to stop additional steroid medication under a maintenance dose of FAEs. In the patient treated with a lower FAE dose, the systemic steroids could be reduced from 20 mg (0.3 mg/kg) to 5 mg (0.08 mg/kg). In another patient with intermediate uveitis, prednisone was tapered down from 20 mg (0.28 mg/kg) daily to 6 mg (0.09 mg/kg). Tapering off the oral steroids was, in general, possible after the 12-week visit. At this point, a clinical improvement was also evident in all 4 patients.
The clinical course of uveitis noted under treatment is summarized in Table 2. Vision improved over time in all patients who had reduced visual acuity at the baseline visit. Cystoid macular edema was present at the last visit only in 1 eye by angiographic means, but this was not detectable by optical coherence tomography. In the other patients, cystoid macular edema was no longer detected (Figure 1). No significant numbers of anterior chamber cells were seen in any patient during the whole follow-up period. Uveitis did not recur in any of the patients under therapy. Fumaric acid ester therapy was continued in all patients, and no additional complications from uveitis developed during the follow-up period.
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Table 2. Clinical Data With Assessment of CME by Fluorescein Angiography and Optical Coherence Tomography*
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Figure 1. Representative course of cystoid macular edema of patient 3 by angiography and optical coherence tomography at the beginning of fumaric acid ester treatment (A and B) and 3 months after institution of therapy (C and D). The angiogram was taken 3 minutes after fluorescein injection.
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Compared with the baseline before FAE institution, average ± SD leukocyte counts dropped from 100% before FAE treatment to 79.9% ± 13.6 (P = .03) and the lymphocyte count to 77.2% ± 25.6 (P = .08) after 3 months of treatment. Figure 2A shows the pattern of peripheral blood leukocytes, lymphocytes, and their subpopulations of all patients. Additionally, Figure 2B describes a shift in T lymphocytes with an increased CD4+/CD8+ ratio.
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Figure 2. Individual changes in percentage of variation of patient 2 in peripheral blood white cells and the subpopulations (A) and in T cells and the CD4/CD8 ratio (B). NK indicates natural killer; T4, T helper lymphocytes; T8, T suppressor cells.
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No significant change in the liver enzyme, creatinine, or urea levels occurred during the whole treatment period in any of the patients. As the main adverse effect, dermal flush occurred in all patients immediately after institution of the therapy, and gastrointestinal disturbance was noticed in patient 1 after 3 months of FAE therapy.
Comment
Since 1994, a mixture of FAEs has been commercially available as Fumaderm (Fumapharm AG, Lucerne, Switzerland) and is used for the systemic therapy for severe psoriasis,3 which is a T-cell–mediated autoimmune disease. Double-blind, placebo-controlled studies revealed high efficacy as an anti-psoriasis medication.4 A phase 2 study for multiple sclerosis and a phase 3 study for psoriasis are currently being conducted with a new FAE formulation.
Fumaric acid ester treatment was necessary in all of the patients herein despite their relatively good visual acuity because all patients had adverse effects owing to systemic steroid therapy, or had a dosage above the acceptable level, and because they had vision-threatening complications. The improvement of vitreous opacities reflects the reduction of inflammation. Furthermore, FAE treatment also resulted in an improvement of cystoid macular edema in 4 patients. In this study, FAEs offered the opportunity to reduce or even to stop the steroid treatment in all 4 patients. The immunosuppressive effect of FAEs on the white blood cells seen in our patients was similar to those in psoriasis patients.5
In intermediate uveitis, an increased number of peripheral blood T cells was found. It has been shown that FAEs can modulate the immune response by a predominant reduction of CD8+ T lymphocytes5 and a shift of the T cell response to a T helper 2 subtype.6 In experimental autoimmune uveoretinitis, it has been shown that suppression of T helper 1 response successfully reduced the degree of inflammation. These preliminary data suggest that improvement of uveitis was associated with reduced T cell subsets.
One major problem with FAEs seems to be the adverse effects, mainly gastrointestinal disturbance (1 patient) and dermal flushing (all patients).4 No serious adverse effects, especially opportunistic infections, occurred. However, as no carcinogenic effect of FAEs is yet known, it may also be used in patients with malignancies or unspecified tumors.
This pilot study offers a promising perspective on FAEs, a new therapeutic agent treating selected patients with noninfectious uveitis with a chronic clinical course. Further prospective case-control investigations with larger study populations are required to define the role of FAEs in the treatment of uveitis in more detail.
AUTHOR INFORMATION
Correspondence: Dr Heinz, Department of Ophthalmology, St Franziskus-HospitalMuenster, Hohenzollernring 54, 48145 Muenster, Germany (carsten.heinz{at}uveitis-zentrum.de).
Financial Disclosure: None reported.
Acknowledgment: We thank Dr Loer and colleagues at Laboratory Dr Loer (Muenster, Germany) for their excellent support in performing the blood tests.
REFERENCES
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1. Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol. 1999;141:424-429.
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2. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 1985;92:467-471.
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3. Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity. Trends Mol Med. 2005;11:43-48.
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4. Altmeyer PJ, Matthes U, Pawlak F; et al. Antipsoriatic effect of fumaric acid derivatives: results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994;30:977-981.
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5. Hoxtermann S, Nuchel C, Altmeyer P. Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology. 1998;196:223-230.
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6. de Jong R, Bezemer AC, Zomerdijk TP; et al. Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent mono-methylfumarate. Eur J Immunol. 1996;26:2067-2074.
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SECTION EDITOR: W. RICHARD GREEN, MD
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