Clinical Rheumatology

, Volume 32, Supplement 1, pp 97–101

Successful remission induction with a combination therapy of rituximab, cyclophosphamide, and steroids in a patient with refractory optic neuritis in Wegener’s granulomatosis


    • Department of OphthalmologyUniversity of Erlangen-Nuremberg
  • Christian Mardin
    • Department of OphthalmologyUniversity of Erlangen-Nuremberg
  • Leonard Holbach
    • Department of OphthalmologyUniversity of Erlangen-Nuremberg
  • Jochen Zwerina
    • Department of Internal Medicine III, Institute for Clinical ImmunologyUniversity of Erlangen-Nuremberg
  • Georg Schett
    • Department of Internal Medicine III, Institute for Clinical ImmunologyUniversity of Erlangen-Nuremberg
  • Jürgen Rech
    • Department of Internal Medicine III, Institute for Clinical ImmunologyUniversity of Erlangen-Nuremberg
Case Report

DOI: 10.1007/s10067-010-1561-9

Cite this article as:
Huchzermeyer, C., Mardin, C., Holbach, L. et al. Clin Rheumatol (2013) 32: 97. doi:10.1007/s10067-010-1561-9


A 56-year old patient with a history of limited Wegener's granulomatosis presented with signs and symptoms of optic neuritis. Radiologic signs of orbital inflammation were absent. Testing of visual acuity and visual field allowed close monitoring of disease activity. Thus, rapid improvement of visual function was achieved with high-dose steroids. Despite maintenance therapy with cyclophosphamide recurrence occurred repeatedly as soon as tapering of steroids was begun. After remission induction with rituximab, the patient retained good visual function under maintenance therapy with azathioprine and low-dose corticosteroids. Optic neuritis in Wegener's granulomatosis without signs of orbital involvement is rare and most likely caused by occlusive vasculitis of the vasa nervorum. In this patient with optic neuritis refractory to conventional therapy, rituximab in combination with cyclophosphamide and corticosteroids was well tolerated and successfully used for remission induction, followed by maintenance therapy with azathioprine and low dose corticosteroids.


Eye involvementOptic neuritisRemission inductionRituximabWegener’s granulomatosis

Wegener’s granulomatosis (WG) is a chronic small vessel vasculitic syndrome associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA). It classically involves the respiratory and renal systems [1].

The sinonasal tract is the most commonly affected region in patients with WG. Therefore, the presenting symptoms include rhinorrhea, facial pain, and nasal deformity, although laryngotracheal stenosis, hearing loss, and even cranial nerve deficits may occur [2]. In the context of sinonasal involvement, lacrimal duct obstruction is common. However, ocular manifestations may occur only in 8–16% as part of the initial presentation. Eye involvement includes conjunctivitis, keratitis, episcleritis, uveitis, retinal vasculitis, optic neuropathy, and orbital infiltration [3, 4].

In randomized controlled trials, approximately 90% of the patients achieved remission with the standard regimen with cyclophosphamide and corticosteroids within 6 months, which was successfully maintained with oral azathioprine as well as methotrexate [57].

However, in refractory patients who failed remission or those with contraindications, numerous experimental therapies have recently been used [8].

We report on a patient with refractory optic neuritis successfully treated with a combination therapy of rituximab, cyclophosphamide, and steroids.

Case report

A 56-year-old female patient was referred to our eye clinic with unilateral visual loss in the right eye. Blurry vision and orbital pain had started a week before. Vision had been deteriorating profoundly since then.

She had a history of surgical reconstruction of the nasal septum and severe nasal crusting. Three years ago, infrasaccal lacrimal duct obstruction had led to recurrent dacryocystitis, necessitating external lacrimal duct surgery. Two years after surgery, painless tearing of the right eye had recurred and a saddle nose deformity had developed. Due to this, suspicion of Wegener’s granulomatosis had been raised. Laboratory tests revealed positive PR3-ANCA.

At the time of presentation, she was under treatment with methotrexate 15 mg/week, low-dose steroids, and trimethoprim/sulfomethoxazole.

On examination, visual acuity was 20/100 OD and 20/25 OS. Visual field testing revealed a large central defect in the right eye. A relative afferent pupillary deficit was present. Slit-lamp examination showed unremarkable anterior and posterior segments. In particular, there were no morphologic abnormalities of the macula or the optic disc.

Visual evoked potentials (pattern VEP) were of normal amplitude on both sides, but latency was prolonged in the right eye. Altogether, these finding were compatible with the diagnosis of optic neuritis.

The patient received a 3-day course of high-dose intravenous steroids (1,000 mg prednisolone/day) in accordance with the protocol of the Optic Neuritis Treatment Trial [9, 10]. Fast recovery was followed by rapid deterioration when the steroids were discontinued. A second course of high-dose steroids was administered and therapy with cyclophosphamide 15 mg/kg body weight every 3 weeks was begun. Visual acuity recovered to 20/20 in the right eye.

However, 10 days after the second dose of cyclophosphamide (2 months after the first symptoms), visual acuity dropped to light perception, and a large central scotoma could be demonstrated once again (Fig. 1a).
Fig. 1

Goldmann kinetic perimetry of the right eye. The circles are lines of equal sensitivity (isopters). The hatched areas denote relative scotoma (reduced light perception in this area) and the cross-hatched areas absolute scotoma (no light perception in this area) a Visual field at the time of recurrence after the patient had been treated twice with high-dose steroids according to the ONTT study. Visual acuity was hand movement. There is a large centrocecal defect. b Two days later. Meanwhile, the patient had been treated with prednisolone 250 mg daily. Visual acuity had improved to 20/50. The central defect had disappeared c Another 2 days later. A centrocecal defect reappeared as soon as steroids were tapered to 125 mg prednisolone daily. Visual acuity had deteriorated to 20/500. As a consequence, the daily dose of prednisolone was raised to 250 mg. Simultaneously, 800 mg of cyclophosphamide and 1,000 mg rituximab were administered. Visual acuity recovered rapidly and the visual field normalized. It was now possible to slowly taper steroids without recurrence

This time, a different strategy was pursued and steroid therapy with prednisolone 250 mg daily for 3 days was begun. Again, there was rapid response to steroids and visual acuity improved to 20/50 OD within 2 days (Fig. 1b). However, when prednisolone was tapered to 125 mg, visual acuity worsened again to 20/500 (Fig. 1c). Two doses of rituximab were administered (Fig. 2). Additionally, the steroid dose was raised to 250 mg daily and the patient received another 15 mg/kg body weight of cyclophosphamide. Visual acuity recovered rapidly to 20/25 OD.

It was now possible to slowly taper the systemic steroids while the patient remained free of severe ocular symptoms.

Two months later, the patient presented again with intermittent binocular diplopia with vertical separation of the images. She was currently taking 12.5 mg of prednisolone daily and cyclophosphamide had been administered the last time 5 weeks ago. In the right eye, movements were slightly restricted in adduction and downgaze. Clinical findings were compatible either with N. VI palsy or mechanical restriction of the right superior oblique muscle. Complete remission could be achieved by raising systemic steroids to 70 mg prednisolone/day. In addition, the patient was commenced on azathioprine (Fig. 2).
Fig. 2

Serum levels of c-ANCA antibodies over time. The arrows denote the application of the anti-CD20 mAb. The bars denote the application of cyclophosphamide i.v

Since then, the patient has been seen on a regular basis. Chronic steroid treatment has been complicated by moderate ocular hypertension and subcapsular cataract.

However, she has remained free of severe ocular symptoms. She is treated with maintenance therapy azathioprine 150 mg/daily and low-dose steroids (5 mg prednisolone daily).

Last time the patient was seen in our clinic, visual acuity was 20/25 OD and 20/20 OS. Visual evoked potentials had regular amplitude and latency in both eyes. The patient is now stable in clinical and serological terms and the B cells remained low with 6% after 9 months.


We present the case of a 56-year-old patient treated with a combination therapy with rituximab, cyclophosphamide, and systemic steroids for refractory optic neuritis in the context of WG. Clinical or radiological signs of orbital involvement were absent. The rapid response of the functional parameters visual acuity and visual field to changes in therapy allowed very close monitoring of disease activity.

Causes of optic neuritis include idiopathic, multiple sclerosis, infectious, contiguous spread of inflammation (meninges, orbit, sinuses), and granulomatous inflammation (infectious, sarcoidosis).

Frequently, optic neuritis is the initial manifestation of multiple sclerosis. The risk to develop multiple sclerosis within 2 years after isolated optic neuritis is approximately 20% [10]. This cannot be completely excluded in our patient at this time. However, there were no neurological deficits apart from optic neuritis, oligoclonal bands were absent, and no signal abnormalities of the white matter were seen in the MRI scans. Other differential diagnoses were excluded.

Several large case series of ocular involvement in WG have been reported [3, 1116]. In most cases, ocular manifestations of WG are either caused by contiguous orbital involvement in sinus or nasal disease or by focal occlusive vasculitis [3]. The optic nerve can be affected by both mechanisms. Cases of focal optic neuritis in WG without clinical or radiological signs of orbital involvement have been reported, but appear to be exceptionally rare [3, 17].

While visual prognosis of optic neuritis as a manifestation of WG is often poor, some patients show a good response to steroids [3]. Manteiro et al. [18] have hypothesized that occlusive vasculitis can be treated effectively early in the course of optic neuritis before irreversible ischemic damage occurs. Therefore, the authors have stressed the importance of rapid aggressive treatment.

The standard therapy regimen for systemic Wegner’s granulomatosis is cyclophosphamide either alone or in combination with systemic steroids. If this regimen failed, different experimental therapies have recently been used. With increasing evidence that B lymphocytes play a crucial role during the pathogenesis of ANCA-associated vasculitis, specific B cell therapy is a highly interesting alternative treatment option. The direct pathogenic role of ANCA has been shown in animal models [19], and subsequent studies were able to demonstrate ANCA-producing lymphocytes in peripheral blood and granulomatous lesions [2022].

The ratio for the combination therapy in our patient was that after tapering the high-dose steroids while still on monthly i.v. cyclophosphamide therapy, the centrocecal defect reappeared repeatedly. Regarding the excellent results of rituximab in multiple case reports in patients with ANCA-associated vasculitis reported by Oristrell et al. [23], we decided to add rituximab in our patient to the standard regimen (cyclophosphamide and glucocorticoids).


In conclusion, the combination of cyclophosphamide, corticosteroids, and rituximab for remission induction followed by maintenance therapy with azathioprin and low-dose corticosteroids was successful and well tolerated. This combination seemed to be feasible without increasing toxicity or risk for infections, so far. However, a routine recommendation for its use is not yet possible and should await further studies in refractory patients with Wegener’s granulomatosis.



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