Successful Treatment of Ocular Sarcoidosis with Rituximab

Sarcoidosis is a multisystem inflammatory disease of undetermined origin. Thoracic involvement is the most common, with lymphoadenopathy and a various degree of lung lesions, such as granulomatous nodules and diffuse interstitial thickening, potentially leading to lung fibrosis. Skin, joints, heart, brain, and eye, however, can also be involved with a wide spectrum of clinical manifestations. Ocular sarcoidosis occurs approximately in one-third of patients, also in apparent absence of disease manifestations in other locations and can potentially involve any element of the eye. Among ocular lesions, however, some are more suggestive of sarcoidosis, such as bilateral granulomatous uveitis.1–3 Despite the recent advances in the development of new therapeutic agents, sarcoidosis remains a great therapeutic challenge, because of the current lack of data on the efficacy of the immunosuppressive and biological treatments.

A 50-year-old woman was referred to our Center for relapsing uveitis. She had been facing recurrent severe uveitis involving both the eyes for 3 years, with poor and transitory responses to topical treatments and oral steroid therapy. Uveitis recurred regularly shortly after steroid withdrawal. A complete ophthalmic evaluation revealed a bilateral granulomatous panuveitis characterized by anterior chamber Tyndall, keratic precipitates, synechiae, vitreous opacity 3+ in RE and 1+ in LE, and cystoid macular edema OU. Best-corrected visual acuity (BCVA) was 0.70 logMAR RE and 0.20 logMAR LE (Figure 1).

Figure 1. Fluorescein angiography demonstrating 3+ vitreitis and cystoid macular edema RE and cystoid macular edema LE.

A systemic disease was suspected because of the concomitant presence of multiple, raised, erythematous lesions on the anterior surface of the lower legs, identifiable as erythema nodosum, and neurological symptoms, consisting of left arm paresthesias. A brain nuclear magnetic resonance (NMR) was performed, revealing the presence of multiple, nonenhancing lesions of the white matter, compatible with neurosarcoidosis.

Full blood count, metabolic panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and the other laboratory tests gave results within normal limits. Antinuclear antibodies (ANA), anti-dsDNA, anti-extractable nuclear antigens (ENA), anti-neutrophil cytoplasm antibodies (ANCA), anti-phospholipid antibodies (aPL), and lupus anticoagulant (LAC) tests were also negative. Angiotensin converting enzyme (ACE), however, was significantly increased (106 U/L).

A high-resolution CT of the lung with contrast revealed multiple nodular bilateral lung lesions with mild hilar and mediastinal lymphoadenopathies. To confirm the diagnostic hypothesis we also performed a scintigraphy that revealed abnormal gallium uptake by both parotid glands and lungs. The patient did not consent to a bronchoscopy, but the lung involvement was clinically mild, so the predictive value of such a procedure was low.

We started topical therapy (dexamethasone 2% and tropicamide 1%) and oral prednisone (0.5–1 mg/kg/day), but due to the poor response to such a treatment in the past 3 years, we evaluated the possibility of a more effective, steroid-sparing therapy. However, the patient had been diagnosed many years before with chronic hepatitis C, which represents a potential restriction to immunosuppressive treatment. The hepatitis C virus (HCV) genotype was 3a, quantitative HCV-RNA titer was 160.131 UI/mL and the clinical course of chronic HCV pathology was benign in absence of liver impairment. Ultrasonography documented an augmented liver volume, in absence of echostructure alterations. Due to the potential side effects of methotrexate and anti-TNFα agents in an HCV-RNA-positive patient, we administered intravitreal anti-TNFα monoclonal antibody infliximab at the dose of 0.5 mg/0.05 mL, an off-label solution chosen in the presence of controversial data, under strict clinical observation.4–6 Such a treatment was discontinued early because of the worsening of uveitis.

Due to the potential side effects of methotrexate and anti-TNFα agents in an HCV-RNA-positive patient, we attempted rituximab therapy at the dose of 1000 mg iv for 2 doses 2 weeks apart. The treatment was well tolerated and did not cause alterations of the liver function. In the next few weeks, we gradually tapered and then withdrew oral prednisone. Ocular inflammation steadily improved and a complete resolution of cystoid macular edema, vitreitis, and anterior chamber flare was obtained. Topical steroid therapy was then cautiously reduced. No further skin manifestation appeared. Thorax CT and brain NMR revealed no disease progression. ACE levels considerably decreased (60 U/L). After 6 months of remission, a mild anterior uveitis with keratic precipitates and anterior chamber Tyndall 2+ recurred in RE. Topical therapy (dexamethasone 2% and tropicamide 1%), however, led to a quick healing in few weeks. The patient underwent new rituximab infusion according to the same protocol and topical therapy was gradually tapered and then withdrawn. The patient did not present adverse events during the retreatment. Moreover, she did not present alterations of the hepatic function or increase of the HCV-RNA titer in 1 year of follow-up. Twelve months after the first rituximab infusion no further cutaneous, neurological, respiratory, or major ocular manifestations appeared. BVCA was restored to 0.00 logMAR OU and maintained stable. Brain and lung lesions did not progress. The main point, however, was the good control of eye disease activity, demonstrated by the unique mild episode of anterior uveitis we needed to treat during 1 year follow-up.

Rituximab, a chimeric monoclonal antibody against CD20, considerably reduces the number of mature B lymphocytes. In genetically predisposed subjects, an unidentified antigen leads to activation of CD4 T-cells and Th1 polarization of immune response, with the release of a large amount of cytokines, such as interferon γ (IFNγ) and tumor necrosis factor α (TNFα). The interaction between T cell and macrophage and the recruitment of other cells, such as fibroblasts, CD8 T cells, and B cells, are essential for the development of granuloma that represents the main lesion of sarcoidosis. Traditionally, B cells are not thought to play a key role in such a mechanism. However, the pathogenesis of sarcoidosis is still largely unknown. In addition, the immunological effects of rituximab are not limited to B cells, but can involve other immunological pathways, as is well demonstrated in different diseases.7–9

Four cases of sarcoidosis treated with rituximab have been described in the literature to date.10–12 To determine the role of rituximab as a new agent for refractory sarcoidosis an open-label trial is ongoing. Our case, however, particularly highlights the efficacy of rituximab as a treatment for ocular sarcoidosis. Anti-CD20 monoclonal antibody is not a first-choice therapy for such a disease, but in selected cases presenting resistance or specific contraindications to common therapies, rituximab can be considered as a possible alternative.13,14

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.