Daniel El Fassi

Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease

The possible adverse consequences of biological therapies in inflammatory bowel diseases (IBDs) were recently highlighted in this journal by D’Haens ( Gut 2007; 56 :725–32). We here describe a hitherto unappreciated adverse effect to treatment with the B lymphocyte (B cell) depleting agent rituximab (RTX),1 namely the occurrence of ulcerative colitis and arthritis shortly after treatment with RTX. Our patient, a 45-year-old Caucasian female, had had mild irritable bowel symptoms since 1992 at which time rigid sigmoidoscopy and bowel x ray were normal. She had never received any therapy, had never previously had joint pain, and was not predisposed to IBD. In April 2005 she was diagnosed with Graves’ disease, and after uncomplicated standard methimazole therapy she received four weekly doses of 375 mg/m2 RTX from day 1 to 22 as part of a clinical trial.2 The trial was approved by the local ethics committee …

B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves' ophthalmopathy the latest addition to an expanding family

In this review, the authors summarise the clinical results obtained after therapy with rituximab in autoimmune dieases, including Graves’ disease and Graves’ ophthalmopathy. On the basis of qualitative and quantitative analyses of B- and T-cell subsets, and autoantibody levels obtained in other diseases before and after rituximab therapy, the authors interpret the results of the only two clinical investigtions of the efficacy of rituximab in the treatment of Graves’ disease and Graves’ opthalmopathy reported so far. No significant effect on autoantibody levels was observed. Nonetheless, 4 out of 10 Graves’ disease patients remained in remission 400 days after rituximab treatment versus none in the control group, and remarkable improvements in the eye symptoms of patients with Graves’ ophthalmopathy were observed. This supports a role for B cells in the pathogenesis of Graves’ ophthalmopathy, and the authors suggest that abrogation of antigen presentation by B cells accounts for the effect of rituximab. In the authors’ opinion, the use of rituximab in severe Graves’ ophthalmopathy could be contemplated.

Evidence of orbital B and T cell depletion after rituximab therapy in Graves' ophthalmopathy

lus. No mitoses or necrosis were present. The cytoplasm was eosinophilic and coarsely granular. The granules were periodic acid-Schiff stain-positive, diastase-resistant and stained red–brown with Masson trichrome stain. Immunohistohemically, the tumour cells expressed focal staining for S100 protein and vimentin. Binding of Ki-67 antibodies revealed a low mitotic index (< 1%). The tumour cells were negative in the following immunostains: a-1-antichymotrypsin; CD20; CD31; CD34; CD68; CK7; CKAE-CAM; EMA (epithelial membrane antigen); GCDFP (gross cystic disease fluid protein); inhibin-a; Leu7; MU213-UC; NSE (neuron specific enolase), and SMA (smooth muscle actin). Small nerve branches were observed adjacent to the tumour cells. The section margins showed tumour involvement. Electron microscopy of tumour tissue retrieved from the paraffin block showed numerous secondary lysosomes with undistinguishable content (Fig. 1D) and a small amount of endoplasmatic reticulum. The findings are consistent with a diagnosis of granular cell tumour (GCT). No recurrence was observed in 4 years of follow-up. Granular cell tumour has been reported in almost every part of the body, but is rare in the orbit and ocular adnexae (Ordonez & Mackay 1999); as far as we know, it has never been reported in the lacrimal gland. The term describes a slowgrowing tumour that occurs in patients of all ages, but most commonly during the fourth to sixth decades and twice as often in females as in males (Ordonez & Mackay 1999). In the orbital and periocular locations, the tumour often presents with displacement of the eyeball and ⁄or impairment of eye movements (Jaeger et al. 1987). Several differential diagnostic considerations should be taken into account because some may have clinical implications. Acinic cell carcinoma and oncocytoma may resemble GCT, but the former stains positively for cytokeratin and the granules in the latter represent mitochondria rather than lysosomes (Ellis & Auclair 1995). The treatment of choice is complete surgical removal. Granular cell tumour rarely recurs and the prognosis is good (Ordonez & Mackay 1999). The predominant theory of origin is derivation from Schwann cells. That GCT has been found in almost every tissue and organ confirms that the cell of origin is found everywhere (Ordonez & Mackay 1999). The tumour cells are often located adjacent to small nerve branches (Ordonez & Mackay 1999), as seen in our case. This is consistent with a Schwann cell origin and is further supported by the result of immunohistochemical studies (Le et al. 2004) demonstrating S100 positivity, as in the present case. The GCT granules represent secondary lysosomes and have occasionally been found to contain digested myelin (Jaeger et al. 1987). However, granular cell change can occur in a wide variety of neoplastic conditions and some authors have suggested that the lysosomes may represent a metabolic alteration that is not exclusively associated with Schwann cell tumours (Rosai 1996).

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.