Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.

Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.

OBJECTIVES: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over ß-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. METHODS: Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes. RESULTS: Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland. CONCLUSIONS: Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis.

OBJECTIVE: We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value. DESIGN: Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity. RESULTS: The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility. CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.

Keratinocyte growth factor impairs human thymic recovery from lymphopenia.

BACKGROUND: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates. METHODS: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30. FINDINGS: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime. TRIAL REGISTRATION: ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.

Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series.

Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis. Here, we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. A retrospective case review of patients treated with alemtuzumab in Cambridge, UK, was conducted to identify those who fulfil the criteria for NMO spectrum disorder. Three cases were identified. Case 1, 9-year-old female, presented with transverse myelitis and bilateral optic neuritis,with one lower medullary and several longitudinally extensive cord lesions. Despite immunosuppression including two courses of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41-year-old female, presented with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three courses of alemtuzumab, she had five relapses with visual impairment and new cord lesions. She later developed tumefactive white matter lesions and died aged 51.Case 3, 31-year-old female, presented with transverse myelitis with longitudinally extensive cervical cord lesions and positive aquaporin-4 antibody. After one course of alemtuzumab, she relapsed with 4 episodes of myelitis with new enhancing lesions and accumulating disability. She became relapse free after rituximab and mycophenolate mofetil. From this case series, we conclude that alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. We hypothesise that rituximab is more effective, as in case 3, because it causes much more prolonged B lymphocyte depletion than alemtuzumab. We therefore caution against the use of alemtuzumab in NMO.

Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.

OBJECTIVE: To test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 10(6) cells/mL at 12 months can be used to identify patients who may benefit from further treatment. METHODS: A total of 108 patients were followed for a median of 99 months post alemtuzumab. Patients were classified as active or nonactive after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts. RESULTS: Of 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment. CONCLUSION: This study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab.

The outlook for alemtuzumab in multiple sclerosis.

Alemtuzumab is a humanized anti-CD52 monoclonal antibody. Treatment in humans results in a rapid, profound, and prolonged B- and T-cell lymphopenia. Subsequently, lymphocyte reconstitution by homeostatic mechanisms alters the composition, phenotype, and function of T-cell subsets, thus allowing the immune system to be 'reset'. One phase II and two phase III randomized, multicenter, single-blinded (outcomes assessor) clinical trials of alemtuzumab in relapsing-remitting multiple sclerosis have now been completed. Against an active comparator and the current first-line therapy for relapsing-remitting multiple sclerosis (interferon-beta), alemtuzumab showed a significant reduction in annualized relapse rate as well as a significant reduction in the accumulation of disability. These outcomes are sustained over at least 5 years following treatment. The most common adverse effects are mild infusion reactions, an increased incidence of mild-to-moderate severity infections and secondary autoimmunity. The latter is observed in a third of treated patients, commonly thyroid disease but other target cells have been described including cytopenias. Marketing authorization applications have been submitted for the use of alemtuzumab in multiple sclerosis to the Food and Drug Administration and the European Medicines Agency, with licensing expected in 2013. Here, we discuss the outlook for alemtuzumab in multiple sclerosis in light of the currently available therapies, outcomes of and lessons learnt from clinical trials, and the overall position of monoclonal antibodies in modern treatment strategies.

Myxoedema madness.

A 59-year-old man was referred for Mental Health Act Assessment following several months of 'odd behaviour' and self-neglect reported by his neighbours. He presented as unkempt and expressed delusional ideas with respect to age, employment and identity of family members. He was fully oriented but lacked insight into his mental state and capacity for self-care. Physical examination revealed dry skin and slow relaxing reflexes. Blood investigations revealed a raised thyroid stimulating hormone and free T4 with positive thyroid peroxidise antibodies. MRI of the brain revealed frontal lobe and cerebellar atrophy, while neuropsychological assessment identified deficit in memory processing and executive functions. Despite appropriate correction of primary hypothyroidism with levothyroxine, the patient remained delusional with respect to age and employment although he showed some improvement in memory. Capacity for self-care remained poor; thus, he was eventually transferred to sheltered housing with rehabilitation.