Primary systemic vasculitis (PSV) is a heterogeneous group of autoimmune conditions. There is an unmet need for alternative therapies that lead to sustained remission in patients with refractory disease. Alemtuzumab, an anti-CD52 antibody, depletes lymphocytes for prolonged periods and, in retrospective studies, has induced sustained, treatment-free remissions in patients with refractory/relapsing vasculitis but has raised safety concerns of infection and secondary autoimmunity. This phase IIb clinical trial aimed to assess the efficacy and safety of alemtuzumab, at two different doses, in inducing remission in refractory vasculitis patients.
The ALEVIATE trial was a randomised, prospective, open-label, dose ranging clinical trial. Patients with refractory ANCA-associated vasculitis (AAV) or Behçet’s disease (BD) were randomised to receive either 60 mg or 30 mg alemtuzumab. Treatments were administered at baseline and 6 months or earlier where clinically appropriate. A maximum of three treatments were allowed within the 12-month study period.
Twenty-three patients received at least one dose of alemtuzumab. Twelve had AAV, and 11 a diagnosis of BD. The median age was 40 years (range 28–44), with a prior disease duration of 61 months (42–103). Sixteen (70%) achieved either complete (6/23, 26%) or partial (10/23, 44%) response at 6 months. Eight (35%) maintained remission to the end of the trial without relapse. Ten severe adverse events were observed in 7 (30%) patients; 4 were related to alemtuzumab. There were no differences in clinical endpoints between the 60 and 30 mg alemtuzumab treatment groups.
In a selected group of refractory vasculitis patients, alemtuzumab led to remission in two thirds of patients at 6 months. Remission was maintained to 12 months in a third of the patients, and the safety profile was acceptable.
Seerapani Gopaluni and Rona Smith are primary authors.
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Primary systemic vasculitis (PSV) encompasses a group of autoimmune conditions, characterised by inflammation, neutrophilic infiltration, endothelial cell swelling and fibrinoid necrosis of blood vessels. PSV can affect multiple systems and lead to organ dysfunction.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a form of small vessel vasculitis, comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) and is one of the most common forms of PSV, but the spectrum is broad. Behçet’s disease (BD) is a type of variable vessel vasculitis and was included in the Nomenclature of Vasculitides at the 2012 Chapel Hill Consensus Conference [
Untreated, AAV has a 93% mortality within 2 years primarily due to pulmonary and renal failure [
BD is a heterogeneous condition, and in severe cases, organ or life-threatening vascular, neurological or gastrointestinal manifestations can occur. Tumour necrosis factor (TNF) blockade has transformed management of individuals with severe BD [
Autoreactive T cells contribute to the immune dysregulation and inflammation that causes organ damage in PSV [
A study of 71 patients with refractory or relapsing AAV treated compassionately with alemtuzumab demonstrated remission in 60 (85%), 24 of whom (40%) remained in remission for over 1 year and 10 (17%) for at least 3 years [
Alemtuzumab is a licensed therapy for multiple sclerosis, where the labelled dose is 60 mg (12 mg/day on 5 consecutive days, 60 mg total dose) repeated at 12 months (12 mg/day on 3 consecutive days, 36 mg total dose), but there is a paucity of data in other autoimmune indications or of the effects of different dosing regimens [
There is an unmet need for alternative therapies, with an acceptable safety profile, that lead to remission in patients with relapsing or refractory PSV. Prior experience has identified AAV and BD as forms of PSV likely to benefit from alemtuzumab. Even though the clinical phenotype and therapeutic strategies of these diseases differ, T cell dysregulation is at the core of the pathogenesis for both diseases. Alemtuzumab with its pan-lymphocyte activity may help to restore the immune homeostasis. Conducting studies in rare diseases is challenging, and with the advances in therapeutic strategies, the number of patients with refractory diseases is small. However, the effects of refractory diseases are devastating for the patients. Some compromises in trial methodology are necessary to overcome the challenges of recruiting refractory vasculitis patients.
The ALEVIATE trial was designed to test the hypotheses that alemtuzumab induces remission in vasculitis patients that have failed to respond to conventional therapies and that alemtuzumab has an acceptable safety profile in selected refractory or relapsing AAV and BD patients. Furthermore, the trial explored the effect of two dosing regimens on clinical and biomarker end-points.
The ALEVIATE trial was a randomised, single-centre, open-label, phase IIb, dose ranging clinical trial of alemtuzumab in refractory PSV, conducted at the Cambridge University Hospitals NHS Foundation Trust between June 2010 and May 2018. Patients were recruited from a specialised vasculitis clinic, and all provided written informed consent.
Key inclusion criteria were a diagnosis of GPA, MPA, EGPA or BD and active vasculitis with at least one severe or three non-severe items as recorded in the Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG). A GPA or MPA diagnosis required typical clinical features and confirmatory histology or proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA positivity; the EGPA patients met the 1990 American College of Rheumatology (ACR) classification criteria, whilst those with BD met either the ISG (International Study Group) or ICBD (International Criteria for Behçet’s Disease) diagnostic criteria. For AAV patients, previous induction therapy with either cyclophosphamide or methotrexate or rituximab, in combination with prednisolone for at least 3 months, and for BD at least 6 months of anti-tumour necrosis factor (TNF) therapy was required for inclusion. Background immunosuppression with immunomodulators such as azathioprine and mycophenolate mofetil was stopped before recruitment to the trial. Refractory disease reflected disease activity despite induction therapy or relapse whilst receiving relapse prevention therapy.
Exclusion criteria were age < 18 years or > 60 years; serum creatinine > 150 μmol/L; total white cell count < 4 × 109/L or lymphocyte count < 0.5 × 109/L or neutrophil count < 1.5 × 109/L; lung haemorrhage with hypoxia; previous alemtuzumab therapy at any time; rituximab in the last 6 months or anti-TNF therapy in the last month; active infection with HIV, hepatitis B or C; or other systemic infections.
Patients were randomised to receive either low dose (LD) 30 mg (15 mg/day for two consecutive days) or high dose (HD) 60 mg (30 mg/day for two consecutive days) of alemtuzumab by intravenous (IV) infusion. The treatment allocation was determined using the minimisation procedure of Pocock and Simon. The minimisation was balanced by ANCA type (MPO, PR3 and negative). The course was repeated at 6 months, but the interval could be reduced to 3 months for uncontrolled or relapsing disease. Patients were allowed to have a maximum of 3 courses of alemtuzumab over the trial period of 1 year for incomplete response or relapse with a minimum gap of 3 months between treatments and only if the total lymphocyte count had recovered to more than 0.3 × 109/L.
All patients received 500 mg of IV methylprednisolone, 10 mg chlorpheniramine and 1 g paracetamol before each infusion, for infusion reaction prophylaxis. All patients received sulphamethoxazole/trimethoprim 480 mg daily and aciclovir 200 mg twice a day as
Patients were assessed at 6-week intervals and followed for 1 year from enrolment into the trial or until withdrawal. Disease activity was assessed by BVAS/WG and, in addition, for BD patients, the Behçet’s disease current activity form (BDCAF) to document BD disease activity [
The primary outcomes were: The proportion of patients with a vasculitis response (complete or partial) at 6 months. Complete response (CR) was defined as a BVAS/WG* of zero and partial response (PR) as BVAS/WG score ≤ 50% of baseline with no severe items and The proportion of patients with a serious adverse event (SAE).
* BVAS/WG was used as primary outcome measure for both disease groups for consistency. BVAS/WG is not validated for use with BD; however, all the items that were present in BDCAF and not represented in BVAS/WG were recorded in the ‘other’ items section of the BVAS/WG form when present.
Secondary outcomes were: The proportion of patients with treatment failure (failure to achieve a vasculitis response (either complete or partial) by 6 months or a vasculitis relapse between 6 and 12 months) Relapse (defined as the appearance or re-appearance of severe disease (major BVAS/WG item) or appearance or re-appearance of at least two minor BVAS/WG items) Time to first relapse Accrual of damage (according to the Combined Damage Assessment, CDA) Non-severe adverse events Glucocorticoid exposure.
Peripheral blood mononuclear cells (PBMC) were extracted from whole blood from all patients at time points 0, 1.5, 3, 4.5, 6, 7.5, 9 and 12 months. T cell and B cell panels were used to investigate T cell and B cell subsets and the changes associated within these subsets in relation to treatment. Briefly, PBMC were separated over a Ficoll gradient and were incubated with a live-dead stain initially followed by an FcR blocker. One million cells were aliquoted to 6 different polystyrene FACS tubes and incubated with fluorochrome master mixes for 20 min at 4oC. After the washing steps, single cell suspensions were acquired on BD Fortessa flow cytometer and analysed in FlowJo™ 10 software for Mac (TreeStar). Statistical analysis of flow cytometric data at entry visit was compared to 4.5 months visit data.
The sample size was determined based on feasibility for this phase IIb study. Given the rarity of these conditions, it would not be practical to recruit a large number of patients to satisfy the power calculation requirements to discriminate the effect of different dosing regimens. Continuous variables were expressed as medians and interquartile ranges. Categorical variables were presented as percentages and frequencies. The chi-square test was used for categorical variables, and Student’s
Twenty-four patients were recruited (
The median age was 41 years (range 28–44), with a prior disease duration of 61 months (range 42–103) (Table Baseline demographics All subjects ( Low dose ( High dose ( Age in years (median; IQR) 40.5 (28.0–44.0) 35.0 (25.0–46.5) 41.0 (33.0–44.0) Sex (M to F) 8:15 6:7 2:8 Disease (AAV to BD) 12:11 6:7 6:4 GPA 8 4 4 MPA 1 1 0 EGPA 3 1 2 BD 11 7 4 BVAS/WG score at entry (median; IQR) 4.0 (4.0–5.5) 4.0 (4.0–6.0) 4.5 (4.0–5.0) Prior disease duration in months (median; IQR) 61.0 (42.0–102.5) 76.0 (52.0–115.0) 51.0 (40.0–68.5) Number of previous treatments received (median; IQR) 4 (3–5) 5 (3–5) 4(3–4.75) ANCA specificity (PR3:MPO:Neg) 7:1:15 4:1:8 3:0:7 Prior median cumulative cyclophosphamide dose (AAV only) in grams ( 9.1 (7–19.4) 6.4 (4.2–25.8) 9.6 (8.7–17.3) Prior median cumulative rituximab dose (AAV only) in grams ( 4.5 (3–5.75) 5 (3–6) 4 (3–5) Baseline demographics by disease sub-group and alemtuzumab dose received AAV (high dose) AAV (low dose) BD (high dose) BD (low dose) Age 41 (41–46) 42 (22–49) 39 (28–41) 29 (25–44) Median disease duration in months 52 (38–95) 108 (52–109) 61 (50–71) 68 (16–108) BVAS/WG score at entry (median; IQR) 4.5 (4.0–5.0) 5.0 (4.0–6.0) BDCAF at entry (median, IQR) 10.5 (9.75–11.2) 8 (8–8) BVAS/WG score 6 M 1 (0–1) 1 (0–3) BDCAF score at 6 M 8 (6.5–9.25) 5 (0–8) BVAS/WG score at 12 M 0 (0–2) 0 (0–0) BDCAF score at 12 M 0 (0–3.5) 4.5 (0–9)
The involvement of different organ systems identified as new/worse or persistent on BVAS/WG scoring tool at the time of recruitment are shown in Figs. BVAS/WG items scored at randomisation Proportion of patients with different organ system involvement at the time of recruitment into the trial
The median BVAS/WG score at entry was 4 (range 4–6), and the median number of prior immunosuppressive drugs received was 4 (range 3–5). All AAV patients had previously received cyclophosphamide or rituximab. Ten of 12 AAV patients (one with EGPA and one with MPA) had received cyclophosphamide (cumulative median dose of 9 g (range 7–19 g) and 11/12 rituximab (cumulative median dose of 5 g (range 3–6 g) previously. All BD patients had failed after anti-TNF agents and 10/11 after at least two anti-TNF agents sequentially used at least for 6 months (typically adalimumab subcutaneously 40 mg weekly or fortnightly or infliximab intravenous at 5 mg/kg every 4 weeks for 4 doses and then every 6 weeks or etanercept SC at 50 mg twice a week) with or without other immunomodulatory agents.
Sixteen patients (69.5%) achieved either complete (6/23, 26.1%) or partial (10/23, 43.5%) remission at 6 months (Table Response to alemtuzumab at 6 and 12 months AAV ( BD ( Total ( 4/12 (33.3%) 2/11 (18.2%) 6/23 (26.1%) 5/12 (41.6%) 5/11 (45.5%) 10/23 (43.5%) 9/12 (75%) 7/11 (63.6%) 16/23 (69.5%) 5/12 (41.6%) 4/11 (36.4%) 9/23 (39.1%) 0/12 (0%) 1/11 (9.1%) 1/23 (4.4%) 5/12 (41.6%) 5/11 (45.5%) 10/23 (43.5%)
Treatment failure, defined as failure to achieve a vasculitis response (complete or partial remission) by 6 months or vasculitis relapse between 6 and 12 months, occurred in 13/23 patients (56.5%). Of the 13, 6 were withdrawn (3 from each dose group; 2 with GPA, 2 with EGPA, 1 with MPA and 1 with BD) from the trial at 6 months due to progressive disease, and the other 7 (3 HD, 4 LD) (5 BD, 2 AAV) had a relapse between 6 and 12 months.
Fourteen of 23 (60.9%) had at least one relapse during the 1-year follow-up period; the median time to relapse was 150 days (range 130–150). There was no difference in the risk of relapse (70.0% in HD and 53.8% of the patients in the LD groups) between the two dosing groups (log rank test, Individual response to therapy for each patient at each visit during the trial
There were 6 SAEs (low probability of being related to alemtuzumab) and 4 serious adverse reactions (SARs) (high probability of being related to alemtuzumab) in 7 patients (3 HD, 4 LD groups). Two SAEs occurred in one subject after enrolment but before the administration of alemtuzumab (myocarditis and skin infection—both events due to uncontrolled severe disease). There were 3 disease relapses and 1 admission due to palpitations (unrelated to alemtuzumab). The 4 SARs were as follows: infusion-related reaction (cytokine storm), viral gastroenteritis, cytomegalovirus (CMV) colitis and
Non-severe adverse events were common (Table Number and proportion of patients affected by adverse events All subjects ( Low dose ( High dose ( 7 (30.4%) 4/13 (30.7%) 3/10 (30%) 10 8 2 23 (100%) 13 (100%) 10 (100%) 93 54 39 38 (40.8%) 21 (38.8%) 17 (43.5%)
On average, each patient received a median of 2 (2–2.5) courses of alemtuzumab therapy during the 1-year trial. Patients in the HD group received a median cumulative dose of 120 mg (120–180 mg) and in the LD group 60 mg (60–60 mg) of alemtuzumab. Compliance with the planned glucocorticoid withdrawal by 6 months was poor. Only 7/23 (30.5%) patients had withdrawn glucocorticoids by 6 months. The median prednisolone dose on entry was 10 mg (range 10–12.5 mg), at 6 months was reduced to 5 mg (range 0–10 mg) (
There were no changes in CDA scores or SF-36 questionnaire scores at 6 or 12 months compared to baseline or between the two dosing regimens. In terms of laboratory parameters, all patients had a reduction in total white cell count and lymphocyte count as expected following alemtuzumab treatment. Although there were trends to lower levels of CRP and ESR, most individuals started with low baseline levels. Thyroid stimulating hormone levels were normal in all but one patient throughout the trial, who went onto develop autoimmune thyroid disease during the 12 months follow-up period.
Lymphocyte subsets were measured at all visits (Fig. Absolute counts (1 × 109/L) of CD4, CD8 and CD19 subsets tracked over the course of the trial. Plots represent median, lower and upper quartiles
The potential for alemtuzumab to induce sustained remission in patients with refractory PSV, including AAV and BD was explored in a dose ranging study. Improvements in disease activity were seen in 70%, but only one third achieved sustained remission. No differences were observed between the two alemtuzumab doses. Alemtuzumab-related adverse events were common, but serious adverse event rates were no higher than seen with conventional therapies in this population [
The majority of individuals with BD and AAV will respond to standard immunosuppressive regimens including agents such as glucocorticoids, cyclophosphamide, rituximab and anti-TNF therapy [
The response rates for AAV patients in the ALEVIATE trial were similar to those reported from our previous compassionate use experience in refractory AAV disease and broadly equivalent to those seen with gusperimus and IVIg, although differences in trial design make comparison difficult [
Serious adverse events related to alemtuzumab occurred in 30% of patients; all resolved without long-term sequelae. Non-severe infections occurred commonly. The frequency and types of infection were similar to that seen in previous vasculitis studies with conventional agents [
This study has several limitations. Firstly, only a small number of patients were recruited into a single centre trial, and despite the refractory nature of disease, there was heterogeneity between individuals, both in terms of prior disease course and therapies received. None of the patients had severe organ threatening disease at the time of enrolment, and this restrictive inclusion criteria limit generalisability of the results. Furthermore, combining the data from two heterogenous disease cohorts would limit the generalisability of these results. However, as discussed previously, certain compromises in trial design are inevitable in the context of rare disease research.
Adherence to the glucocorticoid tapering regimen was poor, and only 30% of patients withdrew prednisolone, reflecting the refractory nature of disease in this population. However, there was reduction in the median prednisolone dose from 10 mg at baseline to 2.5 mg at 12 months. On average, patients received 4.2 g of prednisolone, and this may be adequate to partially treat non-severe manifestations of disease. This aspect may limit the interpretation of these results. The daily median dose of prednisolone was 6 mg/day (excluding intravenous methylprednisolone). As most of the patients had been on large doses of steroids for prolonged periods, it was difficult to completely withdraw steroids completely. However, it should be noted that this dose is half of what is typically given to treat AAV patients following induction and that these patients have previously failed to respond to high dose steroids.
The follow-up period was short, as the primary aim of the study was to demonstrate early efficacy and safety; we plan to collect long-term safety and efficacy follow-up data for these patients in order to understand the longer-term outcomes. Disease response was assessed by BVAS/WG which has not been validated in BD and in an open-label study may be subject to investigator bias. The study was designed prior to the extensive use of rituximab in AAV and the sequential use of anti-TNF therapy in BD, and as a result, the pool of patients with refractory vasculitis who were potentially eligible to enter this trial was smaller than anticipated. However, there is still a sub-group of patients who remain refractory to common treatment strategies and relapse frequently.
In the AAV subgroup, we observed a rapid rise in ANCA titres, following an initial fall in the majority of patients. This may be due to rapid early rebound in the B cell population following alemtuzumab therapy, partly driven by BAFF surge [
The proposed mechanism of action of alemtuzumab is through depletion of autoreactive T and B cells, followed by an alteration in the repertoire of reconstituting cells, favouring a less autoreactive phenotype [
Alemtuzumab administration led to severe depletion of the lymphocytes for prolonged periods irrespective of the dosing regimen. Within the T cell compartment, both CD4 and CD8 subsets were depleted for the entire duration of the trial. The proportion of T regulatory cells within the CD4 subset was higher after treatment when compared to baseline. This enrichment in T regulatory cells following alemtuzumab is in keeping with established literature [
We did not find a difference either in remission or relapse rates or adverse events between the two dosing regimens, but this study is underpowered to address this specific question. In addition, we did not identify any difference in the degree or duration of lymphocyte depletion between treatment groups.
There is a need for alternative therapies to treat patients with refractory vasculitis that do not respond to conventional therapies. In the ALEVIATE trial, we explored the therapeutic benefits and safety aspects of alemtuzumab in patients with refractory vasculitis. In a selected group of refractory vasculitis patients, alemtuzumab led to remission in two thirds of patients at 6 months. Remission was maintained to 12 months in a third of the patients, and the safety profile was acceptable. However, the effect was not sustained, and relapses were common, necessitating repeat dosing and precluding the withdrawal of glucocorticoids in the majority of individuals.
This research was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit (CCTU).
RS, AC and DJ designed the study; DG, HC, EB, RS, SG and EW acquired the data; SG, MP and MM performed the data analysis; SG, RS and DJ interpreted the data and wrote the manuscript; EW, AC and MM critically appraised the manuscript. The authors read and approved the final manuscript.
This investigator-initiated trial was supported by research grants from Sanofi-Genzyme and Vasculitis UK
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
This study was approved by the NRES Committee East of England – Cambridge East. REC reference number: 10/H0304/64. All patients gave informed and written consent to participate in the trial have read and understood the patient information sheet.
Not applicable
DJ has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme and consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda. RS has received lecture fess from Roche and consultancy fees from GSK and Nordic Pharma. SG, DG, HC, EB, EW, MM, AC none.
ANCA-associated vasculitis
American College of Rheumatology
Anti-neutrophil cytoplasmic antibody
Behçet’s disease
Behçet’s disease current activity form
Birmingham Vasculitis Activity Score for Wegener’s granulomatosis
Combined damage assessment
Complete response
Eosinophilic granulomatosis with polyangiitis
Granulomatosis with polyangiitis
High dose
International Criteria for Behçet’s Disease
International Study Group
Intravenous
Low dose
Microscopic polyangiitis
Myeloperoxidase
Peripheral blood mononuclear cells
Proteinase 3
Partial response
Primary systemic vasculitis
Serious adverse event
Serious adverse reactions
Short-Form 36
Tumour necrosis factor
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