From the *Departments of Rheumatology and †Internal Medicine, Hospital Clinico Universitario, Santiago de Compostela, Spain.
E.P.-P. has received honoraria from Abbott, Schering-Plough, Roche, Wyeth, and Bristol Meyers Squibb. J.C.-F. has no competing interest. J.B. has received honoraria from Abbott, Schering-Plough, and Roche. A.M. has received honoraria from Abbott, Schering-Plough, Roche, Wyeth, and Bristol Meyers Squibb.
Correspondence: Eva Perez-Pampin, MD, Department of Rheumatology, Hospital Clinico Universitario, 15706 Santiago de Compostela, Spain. E-mail: firstname.lastname@example.org.
Behçet disease (BD) is a chronic relapsing multisystem inflammatory vascular disorder with a broad spectrum of clinical manifestations, some of them being associated with high morbidity and mortality.1 In some patients, BD showed an aggressive course despite escalating immunosuppressive therapies.2 We report here a case of refractory BD treated with alemtuzumab.
In October 1996, an 18-year-old woman was admitted to our hospital because of fever, polyarthralgias, microhematuria, orogenital aphthosis, and erythema nodosum. A complete evaluation was started including cultures and serologic tests, imaging studies (transthoracic echocardiogram, thoracoabdominal computed tomography [CT], and brain CT and magnetic resonance imaging), cerebrospinal fluid analysis, immunological tests (including antinuclear antibodies, anti–neutrophil cytoplasmic antibodies, anti–glomerular basement membrane, and anticardiolipin), electromyography, and bone marrow aspiration, all with normal or negative results. A cutaneous biopsy showed a septal panniculitis without signs of small vessel vasculitis. Ophthalmologic evaluation demonstrated corneal ulcers and posterior uveitis, and gynecologic evaluation showed genital ulcers. She was diagnosed as having BD, and naproxen and colchicine were started without response. In the following 3 years, she had recurrent flare-ups and remissions. Different immunosuppressive drugs were attempted (cyclosporine, methotrexate, chlorambucil, and azathioprine) with various adverse reactions or clinical ineffectiveness. Despite these drugs, the activity of the disease continued its progression, adding new complications: peripheral neuritis of the external popliteal nerves and superficial thrombophlebitis. In December 1999, she suffered bilateral simultaneous acute amaurosis; funduscopic examination revealed bilateral optic neuritis. Bolus therapy with corticosteroids was urgently started, but the patient did not recover the vision. Interferon α2b was tested but discontinued because of severe thrombopenia. In May 2001, she was admitted again because of generalized seizures. Brain CT and magnetic resonance imaging and cerebrospinal fluid analysis revealed no pathological findings. Cyclophosphamide was initiated with good response. To reduce the cumulative dose of cyclophosphamide and corticosteroids, infliximab therapy was begun, but severe infusional reactions forced to discontinue the treatment. Given the increasing cumulative dosage of cyclophosphamide, the failure of other treatments, and the clinical evidence of active disease, in August 2006 alemtuzumab (MabCampath-1H; Genzyme Europe BV, Naarden, the Netherlands) therapy was started as a compassionate use. Routine premedication including methylprednisolone and prophylaxis with famciclovir, nystatin, and pentamidine were used according to standard protocols. Also, blood count and cytomegalovirus antigenemia were monitored weekly by polymerase chain reaction. After the first dose of intravenous alemtuzumab, a good clinical response was achieved and sustained over 5 months, but finally she developed a new relapse. In February 2007, a second intravenous pulse with half-dose was administrated. In the follow-up visit (September 2007), the patient presented with fever, panniculitis, orogenital aphthosis, arthritis, microhematuria, and peripheral neuritis; a third dose of intravenous alemtuzumab was started. Clinical signs of activity and microhematuria disappeared in the follow-up visit. In February 2008, she presented again with active disease, and subcutaneous alemtuzumab was initiated without adverse effects. The patient improved clinically with resolution of symptoms. In May 2008, 12 weeks after the pulse, she presented again fever, aphthosis, microhematuria, erythema nodosum, and arthritis; corticosteroids were increased, and symptoms gradually lessened. In June 2008, a routine hemogram revealed severe leucopenia with an absolute neutrophil count of 330 cells/µL (Figure). Urgent hematologic evaluation was started including bone marrow aspiration that revealed maturation arrest of myeloid series. In the following weeks, hemograms demonstrated a progressive recuperation of neutrophils counts without requiring extra dose of glucocorticoids. In March 2009, coinciding with the leukocyte count improvement, a new BD flare-up was present. A pulse of subcutaneous alemtuzumab was initiated. After this fifth pulse, the patient remained virtually asymptomatic for 14 months, representing the longest period of inactivity since the diagnosis of BD. In April 2010, she began again with manifestations of disease activity; corticosteroids and oral cyclophosphamide failed to control the disease. In August 2010, a sixth pulse of subcutaneous alemtuzumab was administrated without significant adverse reactions. At this time, she remains asymptomatic.
FIGURE. Evolution of...Image Tools
Behçet disease is a systemic inflammatory vasculitis with a worldwide distribution.1,2 The etiology of the BD remains unknown, but some genetic predisposing factors (presence of HLA-B51 allele) have been implicated, in association with infectious agents as triggers of a TH1-polarized autoimmune response.1 Typically, this condition is characterized by relapsing episodes of orogenital aphthous ulcers, uveitis, and skin lesions.1,2 A wide variety of drugs are available, but despite this, in a subset of patients, BD may progress to more severe forms and result in increased morbidity and mortality.2
Alemtuzumab is a humanized immunoglobulin G1 monoclonal antibody that targets CD52, a glycosylated antigen that is highly expressed on the surface of lymphocytes (T and B) and other leukocytes, but not in the hematopoietic stem cells. It was originally developed as a lymphocyte depletion agent for transplantation, and it has been estimated that it binds to the cell membrane of more than 95% of normal human blood lymphocytes, as well as malignant B and T lymphocytes.3 Alemtuzumab is currently indicated as a first-line treatment of chronic lymphocytic leukemia. Also, it has demonstrated a promising clinical effect in patients with T-cell leukemias,4,5 mycosis fungoides/Sézary syndrome,6 and multiple sclerosis.7 Subcutaneous administration of alemtuzumab has been shown to be as effective as intravenous infusion.8
To the best of our knowledge, previous reports about alemtuzumab and BD are scarce.9,10 Lockwood et al.9 reported a series of 18 patients with active BD treated with a single dose of intravenous alemtuzumab. After the first 6 months, 13 patients (72%) achieved remission, and 7 of them had a relapse after a mean follow-up of 25 months. Two patients presented hypothyroidism requiring replacement therapy with thyroxine. In our patient, thyroid function tests were normal throughout the duration of the therapy. Dick et al.10 also reported the improvement of retinal inflammation in a patient with ocular BD after a single dose of intravenous alemtuzumab.
The efficacy of alemtuzumab is probably based on its ability to cause a long-lasting lymphopenia. However, the lymphocyte pool is modified after a dose of alemtuzumab and characterized by a reduced memory T-cell numbers and a predominance of regulatory TCD4+ cells.11 Based on this, some authors have proposed that alemtuzumab facilitates a “tolerogenic environment” for the newly generated lymphocytes.12 Factors that may affect the effects of alemtuzumab include the levels of soluble CD52, the levels of CD52 expression in lymphocytes, and those that affect the drug metabolism and clearance.13 Also, a large interpatient variability in serum alemtuzumab concentrations has been reported, as a result of a complex pharmacokinetic.13
In our patient, alemtuzumab was the only drug (except for cyclophosphamide) that controlled the disease, responding during 4 years of follow-up and requiring repeated doses (3 intravenous and 3 subcutaneous, to date). During the course of the illness, there was a close relationship between lymphocyte count and the appearance of disease activity. After the infusion, lymphocyte depletion was accompanied by a rapid clinical improvement, and on the other side, lymphocyte count elevation clearly correlated with BD flare-ups (Figure). Although the occurrence of antiglobulin response to alemtuzumab was not documented in our case, it could explain the lack of complete lymphopenia after the second course and the need for repeated doses. Leukopenia, as presented here, and pancytopenia have previously been observed in patients treated with alemtuzumab.4 Studies in multiple sclerosis patients suggest that lymphocytes can be deleted despite the administration of alemtuzumab at very low doses.14 Low dosages of alemtuzumab could be explored to improve the hematologic toxicity in BD patients. In our patient, recovery was achieved with conservative management, and there were no infectious complications during the follow-up period.
The European League Against Rheumatism has provided guidelines for the management of BD,2 but in refractory cases, there is a paucity of recommendations. In such cases, experimental treatments could be the last resorts. However, given the risk of infection, alemtuzumab requires a cautious use that should be reserved for cases where other therapies have failed. Also, the impact of repeated doses requires a further evaluation. Recently, anakinra, an interleukin 1 blocker, has been proposed as an alternative in patients with BD unresponsive to other therapies.15
In summary, alemtuzumab can represent a hopeful drug in cases of refractory BD. Alemtuzumab must be taken into account in patients with severe forms of BD refractory to other conventional treatments.
* In some cases, BD is unresponsive to conventional therapies.
* Alemtuzumab and other experimental therapies, such as anakinra, should be used only as an alternative if other therapies have failed.
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