Clin Rheumatol (2010) 29:107–110 DOI 10.1007/s10067-009-1291-z
CASE REPORT
Successful treatment of hypertrophic pachymeningitis in refractory Wegener’s granulomatosis with rituximab Aman Sharma & Susheel Kumar & Ajay Wanchu & Vivek Lal & Ramandeep Singh & Vishali Gupta & Surjit Singh & Amod Gupta
Received: 27 August 2009 / Revised: 16 September 2009 / Accepted: 21 September 2009 / Published online: 3 October 2009 # Clinical Rheumatology 2009
Abstract Central nervous involvement (CNS) is uncommon manifestation of Wegener’s granulomatosis (WG). We are describing a patient with refractory WG with CNS involvement which responded to rituximab. This lady presented with nodular scleritis. Three months later, she developed headache, vision loss with complete opthalmoplegia, and relative afferent papillary defect. The brain MRI showed thickened dura along ant temporal region and enlargement of right cavernous sinus. C ANCA and PR 3 ELISA were positive. Non-contrast CT scan of orbit and paranasal sinuses showed soft tissue swelling of the right orbit along with mucosal thickening of right maxillary sinus. There were bilateral upper lobe nodules on HRCT of the chest. She responded to 3 days of methylprednisolone pulses and 1 g pulse cyclophosphamide but had multiple relapses while receiving high dose oral steroids and pulse cyclophosphamide. Then she was given four infusions of rituximab (375 mg/m2) at one-weekly interval. She had complete remission following rituximab. She relapsed after 6 months but again responded to repeat rituximab infusion.
A. Sharma (*) : S. Kumar : A. Wanchu : S. Singh Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail:
[email protected] V. Lal Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India R. Singh : V. Gupta : A. Gupta Department of Ophthalmology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Keywords Pachymeningitis . Refractory . Rituximab . Wegener’s granulomatosis
Introduction Wegener’s granulomatosis (WG) is a granulomatous necrotizing vasculitis. Central nervous involvement (CNS) is an uncommon manifestation of WG. Rituximab has been used in patients with refractory disease. We are describing a patient with refractory WG with CNS involvement which responded to rituximab.
Case report A 22-year-old female presented to the uveitis clinic with swelling and redness of right eyelid for 5 months and decreased vision of the left eye since 5 days. There was circumcorneal congestion in the left eye along with scleral nodularity medially. There was past history of self-limiting bilateral knee joint pain without swelling or early morning stiffness 6 months back. The visual acuity was 6/9 on the left side and 6/6 on the right side. A diagnosis of nodular scleritis was made. Monteux was negative, ANA was 3+ speckled and ANCA was indeterminate. Chest X-ray, C3, C4, and urine examination was normal. The rest of the investigations were unremarkable except for elevated ESR of 56 mmHg first hour. She was started on prednisolone 1 mg/kg/day along with methotrexate 7.5 mg/week. She had a near complete recovery over the next 3 months .Three months later, she presented with sudden onset headache and vision loss in the left eye for 1 day along with repeated vomitings. Visual acuity of the right eye was only limited to perception of light. There was ptosis, dilatation of pupil
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Fig. 1 Post-contrast T1 FS showing sheet-like meningeal thickening along right sylvian fissure
along with complete opthalmoplegia, and relative afferent papillary defect on the right side. Pain sensation was decreased in the V1 distribution of trigeminal nerve along with diminution of gag reflex on the right side with deviation of tongue towards the right side. The ocular movements were normal on the right side. On review of history, there was bloody nasal discharge 6 months back which was diagnosed to be due to right maxillary sinusitis. She also had history of recurrent painful oral ulcerations along with dysphagia since 1 year. There was no history of skin rash, cough, or decreased urine output C ANCA and PR 3 ELISA were positive. Brain MRI showed thickened dura along ant temporal region and enlargement of right cavernous sinus. Non-contrast CT scan of orbit and para-
Fig. 2 Post-contrast coronal T1 S showing homogenous enhancement of abnormal extraconal soft tissue with right maxillary sinusitis
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Fig. 3 Axial CT orbit showing soft tissue thickening of right lateral rectus
nasal sinuses showed soft tissue swelling of the right orbit along with mucosal thickening of right maxillary sinus. There were bilateral upper lobe nodules along with ground glass opacities on high resolution computerized tomograhy of the chest (see Figs. 1, 2, 3, and 4). A diagnosis of Wegener’s granulomatosis with pachymeningitis and lung involvement was made and she was started on intravenous methyprednisolone 1 g/day along with intravenous 1 g cyclophosphamide (CYC) pulses. She responded with complete recovery of external ophthalmoplegia and other lower cranial nerve palsies and partial improvement in vision on the right side within 4–5 days. She was started on oral prednisolone (1 mg/kg/day) along with three-weekly pulses of intravenous 1 g CYC. After two three-weekly pulses of CYC, she had a relapse with total external ophthalmoplegia and lower cranial nerve palsies similar to the first admission. Here, she was again given methylprednisolone pulses for 5 days along with CYC. She again had a
Fig. 4 HRCT of the chest showing the lung nodules
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dramatic response. Now the interval between the CYC pulses was decreased to every 2 weeks. After three twoweekly CYC pulses, she had a similar relapse again. This time, she was given rituximab injection (Mabthera) 375 mg/ m2 every week for 4 weeks. She again had a complete recovery of ophthalmoplegia and lower cranial nerve palsies. She had a relapse after 6 months but it responded to reinfusion of rituximab.
Discussion Wegener’s granulomatosis is a systemic necrotizing small vessel vasculitis associated primarily with pulmonary and renal involvement which is highlighted by the fact that both ACR and Chapel Hill Consensus conference classification criteria take only these into account. The neurological manifestations have been reported in up to 34% patients in a large series of 324 patients [1]. Various neurological manifestations reported in this study were peripheral neuropathy which occurred in 53, cranial neuropathy in 21, external ophthalmoplegia in 16, cerebrovascular events in 13, seizures in ten, and cerebritis in five. Hypertrophic pachymeningitis has been reported in 2–8%. CYC is the backbone of all treatment regimes for induction of remission. Oral as well as two- to three-weekly pulses of intravenous cyclophosphamide have been recommended for remission induction in systemic disease [2–5]. In a metaanalysis of the use of pulse intravenous CYC compared with daily oral CYC in ANCA associated vasculitis(AAV) which had combined the available data from prospective, unblinded, randomized controlled trials with a total of 143 patients, it has been suggested that pulse CYC was more likely to induce remission and had a significantly lower risk of infection and leukopenia. Cumulative CYC dose was lower with pulse CYC; however, there was a trend toward a greater risk of relapse with pulse CYC. Rates of end-stage renal failure and death were similar in both groups [6]. This patient also received intravenous pulses of CYC initially three weekly and then two weekly. Every time she had a good response but she came back with a relapse. So a diagnosis of refractory WG was made and she was started on rituximab (Mabthera) 375 mg/m2 every week for 4 weeks. This case highlights the usefulness of rituximab in refractory WG. Rituximab is a chimeric monoclonal antibody directed against the CD20 molecule on the B lymphocytes, which leads to B-cell depletion by complement-mediated activities and through antibody-dependent cellular cytotoxicity. It has been used in treatment of refractory WG. In an open label study of 11 patients of refractory AAV, of whom ten were of WG, rituximab in a dose of 375 mg/m2 was able to achieve remission in all the 11 patients [7]. This was
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associated with decrease in ANCA titers and the depletion of peripheral blood B cells. However, all these patients also received high dose corticosteroids and plasma exchange was also done in three patients; the exact contribution of rituximab to the clinical improvement and the decline in ANCA titers cannot be estimated. In another study of nine patients who had AAV with rituximab, eight patients responded completely and one patient had partial improvement [8]. There has been another study which has shown the lack of efficacy of rituximab in eight patients with refractory WG [9]. The patients reported in this series had predominantly granulomatous manifestations whereas the patients in the earlier studies had predominantly vasculitis (alveolar hemorrhage and glomerulonephritis). It has been postulated that the patients with refractory granulomatous disease represent a subset of patients who are particularly difficult to treat and are likely to be pathogenetically different from the vast majority of patients with WG with predominantly vasculitic manifestations [9]. Based upon a review of 72 patients of refractory WG in 11 open label studies/case series of use of rituximab, it has been suggested that it appears to be effective in vasculitic complications like alveolar hemorrhage and glomerulonephritis, whereas its role in necrotizing granulomatous manifestations of WG, such as orbital pseudotumor and subglottic stenosis, is controversial [10]. The results of presently underway Rituximab for ANCAassociated Vasculitis trial to determine the efficacy of rituximab for the treatment of severe WG and MPA may provide answers to some of these questions. The other therapies which may be useful in treatment of refractory/ relapsing WG are 15 deoxyspergualine, infliximab, and intravenous immunoglobulin therapy.
Disclosures None.
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