Article Text

Download PDFPDF

Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H)
  1. M Walsh1,2,
  2. A Chaudhry2,
  3. D Jayne2
  1. 1
    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
  2. 2
    Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, UK
  1. M Walsh, Vasculitis Clinic, Box 118, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK; mwwalsh{at}


Objective: Lymphocytes are a contributor to the pathogenesis of anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV). Conventional immunosuppressive therapy is associated with high rates of relapse and toxicity. Humanised monoclonal anti-CD52 antibodies (alemtuzumab, CAMPATH-1H) selectively deplete lymphocytes. We present long-term follow-up results of patients with relapsing/refractory AASV treated with CAMPATH-1H.

Patients and methods: Between 1991 and 1999, 71 patients with refractory or relapsing AASV received CAMPATH-1H at Addenbrooke’s Hospital, Cambridge, UK. Other immunosuppressive drugs were discontinued and prednisolone was tapered to 10 mg/day.

Results: The mean follow-up time was 5 years. In all, 79% had previously received cyclophosphamide (median dose 150 g). At the time of treatment, 42% had renal involvement (median creatinine for the cohort 101 μmol/litre excluding six patients who were dialysis dependent) and 18% were critically ill from AASV and required the intensive care unit. A total of 60 patients (85%) obtained a remission after treatment with CAMPATH-1H but 43 relapsed (median 9.2 months); 24 had a remission greater than 1 year, of which 10 had a remission of at least 3 years. A total of 31 patients died (median survival time of 106 months). Age >50 years, dialysis dependency and the development of a severe infection at the time of treatment were associated with an increased risk of death in multivariable analysis. Adverse events were common; 28 patients developed an infection, 3 malignancy and 8 thyroid disease.

Conclusions: CAMPATH-1H induced remission in most patients with difficult to treat AASV. However, relapse and adverse events were common. Further study of CAMPATH-1H as an induction agent in AASV is warranted.

Statistics from

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AASV) is a multi-system autoimmune disease. Conventional treatment with traditional cytotoxic immunosuppression and corticosteroids for at least 1 year induces remission in approximately 80% of patients.1 There are therefore a significant proportion of patients that inadequately respond to traditional therapy. Additionally, relapsing disease is common with approximately 50% of patients experiencing a relapse within 5 years.1 Relapse is associated with increased exposure to immunosuppressive medications and corticosteroids, exposing patients to harmful drug toxicities in addition to accruing damage to vital organs. Given these rates of refractory and relapsing disease despite treatment with potentially toxic medication, alternative therapies are needed.

Auto-reactive T cells are thought to play a major role in the development and subsequent organ damage of AASV.2 3 The humanised monoclonal antibody, anti-CD52 (alemtuzumab, CAMPATH-1H) depletes circulating lymphocytes and macrophages. Recovery of peripheral T lymphocytes after treatment with CAMPATH-1H may take up to many months or even years.4 5 Even then there may be incomplete recovery of CD4 positive cells and a predominance of memory cells in those that do recover.4 Lymphocyte repopulation is also associated with an increased proportion of regulatory T lymphocytes that may further benefit long-term disease control.7 In addition to T lymphocytes, CAMPATH-1H is known to deplete other lymphocytes and monocytes, both of which may be important to the pathogenesis of AASV.6 7

Despite profound lymphocyte depletion, CAMPATH-1H has not been associated with excess mortality in studies of other diseases such as Behçet disease, rheumatoid arthritis, multiple sclerosis and renal transplantation.5 810 CAMPATH-1H has been proposed as an alternative agent for inducing remission in AASV.11 We report the long-term results of 71 patients with chronically relapsing AASV or AASV refractory to traditional medications treated with CAMPATH-1H between 1991 and 1999.



A total of 71 patients between 1991 and 1999 with active AASV either refractory to standard immunosuppression or relapsing despite adequate courses of immunosuppression were studied. Patients were eligible to receive CAMPATH-1H if they had multiple relapses or life threatening disease despite the standard of care. Data regarding the severity of patient disease were characterised by organ involvement, prior treatments, cumulative cyclophosphamide exposure, renal function and the requirement for intensive care unit treatment due to disease at the time of CAMPATH-1H administration.


CAMPATH-1H was supplied by the Therapeutic Antibody Centre (Cambridge and Oxford, UK). Before administration, other immunosuppressive medications were discontinued except prednisolone, which was continued at 10 mg/day. CAMPATH-1H was administered intravenously (IV) on consecutive days at doses of 4, 10, 40, 40 and 40 mg (total 134 mg). Hydrocortisone 100 mg IV and chlorpheniramine 10 mg were given for infusion prophylaxis and acyclovir and nystatin swish and swallow medications were given for infection prophylaxis. Further courses of CAMPATH-1H were allowed for relapsing disease in those patients who tolerated the initial treatment.


Patients were followed prospectively with respect to the induction of remission, durability of remission, need for retreatment, renal failure, death and serious adverse events. Sequential haematological and serological parameters, including C-reactive protein (CRP) and ANCA status, were followed routinely for the first 12 months. ANCA subtypes were recorded when available. Long-term data was retrieved from hospital and clinic charts for those patients not followed in Cambridge.


The characteristics of patients who achieved remission or experienced an adverse event were compared using the Fisher exact test for categorical variables and Student t test for continuous variables. Risk factors for relapse and death were assessed using log-rank tests and Cox proportional hazard models. Renal function, the number and type of organs involved, severity of illness, autoantibody type, CD4 positive T lymphocyte counts, age, gender and clinical diagnosis were all considered in the assessment of potentially important factors for experiencing remission or death. Adverse events of particular interest were the development of serious infections, thyroid disease, persistent thrombocytopenia attributed to immune thrombocytopenic purpura, renal failure and death. All analyses were performed with Stata V.9.0 (StataCorp, College Station Texas, USA).



A total of 71 patients (32 males and 39 females) at a mean age of 48 years were treated and followed for a total of 341 patient years (mean follow-up 5 years). The median duration of disease before treatment with CAMPATH-1H was 3.4 years (range 0 to 21 years). A total of 56 patients (79%) had received cyclophosphamide with a median dose of 150 g (range 100 to 200 g). The median creatinine in non-dialysis patients was 101 μmol/litre (interquartile range 82 to 136 μmol/litre). In all, 24 patients (34%) had renal insufficiency characterised by a creatinine greater than 120 μmol/litre and 6 (8%) were dialysis dependent at the start of treatment. A total of 13 patients (18%) were in a medical intensive care unit at the time of treatment. CAMPATH-1H was administered to these patients due to the refractory and life threatening nature of their disease. Wegener granulomatosis accounted for the vast majority of cases and was diagnosed in 63 patients and microscopic polyangiitis in 8 patients. ELISA ANCA testing was performed in a subset of patients at the time of treatment; 22 were proteinase-3 positive, 4 were myeloperoxidase positive and 4 were ANCA negative at the time of treatment. Organ involvement is summarised in table 1. At the time of final follow-up, 40 patients had survived of whom 28 were in remission with or without the use of chronic immunosuppression, 7 had chronically relapsing or persistent disease despite continuing therapy and 5 patients had developed end-stage renal disease (ESRD).

Table 1 Organ involvement of systemic vasculitis at the time of treatment with CAMPATH-1H

Induction of remission

A total of 46 patients (65%) achieved a clinical remission defined as requiring 10 mg of prednisolone per day or less with no immunosuppressive agents and clinically inactive disease. An additional 14 patients (20%) had a clinically significant improvement in disease activity but required either greater than 10 mg of prednisolone per day or an additional immunosuppressive agent to control disease activity. In all, 30 patients (42%) required multiple treatments with CAMPATH-1H with 15 requiring 2 courses and 15 requiring 3 or more courses (maximum of 6). Patients who received at least two courses of treatment were significantly more likely to enter remission (p = 0.007) but remission did not appear more likely for patients who received three or more doses compared to those that received only two (p = 0.06). Patients who achieved a remission were not significantly different from those who did not achieve a remission in terms of age, autoantibody type, successful autoantibody depletion or successful CD4 positive cell depletion. However, patients who achieved clinical remission had significantly better renal function (mean creatinine 106 μmol/litre) compared to those who did not (mean creatinine 191 μmol/litre; p = 0.001) while those with a history of neurological involvement were less likely achieve remission (p = 0.04).


In all, 43 patients experienced a relapse and the median relapse-free survival time was 9.2 months (range 0.5 to 122 months) (fig 1). CD4 positive cell depletion was not found to be associated with an increased risk of relapse. Taken individually, activity in no organ system predicted an earlier time to relapse, however, taken together, retro-orbital granuloma and ear/nose/throat (ENT) disease at the time of treatment was associated with twice the hazard of relapse compared to those without involvement (hazard ratio 2.1; 95% confidence interval 1.1 to 3.9; p = 0.016). Relapses occurred most commonly in the organs that were actively affected at the time of treatment and in particular, retro-orbital granuloma, ENT disease and endobronchial lesions appeared to recur early. Of the 21 patients still in remission 1 year after treatment, 11 continued to have a remission of at least 3 years. Sustained remissions were more likely in patients who received at least two courses of CAMPATH-1H (p<0.001) Impaired renal function was found to be protective against relapse with a hazard ration of 0.3 compared to patients with a creatinine less than 120 μmol/litre after adjusting for the increased risk of death from poor renal function (95% CI 0.13 to 0.69; p = 0.003). A complete response rather than a partial response was also associated with a decreased hazard of relapse (hazard ratio 0.41, 95% CI 0.21 to 0.80; p = 0.009).

Figure 1 Kaplan–Meier estimate showing relapse free survival in 60 patients with refractory/relapsing anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV) treated with CAMPATH-1H who experienced an initial complete or partial remission.


A total of 31 patients died during the observation period with a median time to death of 106 months and a mortality rate of 0.09 per patient-year (fig 2). The cause of death was attributed to infection in six cases, vasculitic damage in four cases, a combination of infection and active disease in six cases, malignancy in three cases and vascular events (heart disease or stroke) in five cases. In seven cases the cause of death was unknown. In univariable analysis, age over 50 years, a requirement for the intensive care unit, renal involvement, dialysis dependency and the development of a post-treatment infection were significantly associated with an increased hazard of death while remission of disease was associated with a decreased hazard of death (fig 3). Of note, the majority of deaths in patients on dialysis or in the intensive care unit at the time of treatment occurred within 6 months of beginning treatment. In multivariable Cox regression analysis, dialysis dependency, post-treatment infection and age over 50 years were significantly associated with increased death and remission was associated with a reduced hazard of death (table 2).

Figure 2 Kaplan–Meier survival estimate for all patients with refractory/relapsing anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV) treated with CAMPATH-1H.
Figure 3 Kaplan–Meier survival estimates for patients with refractory/relapsing anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV) treated with CAMPATH-1H separated by important prognostic factors. A. Patients who achieved complete remission defined as no more than 10 mg/day prednisolone and the absence of clinical signs or symptoms (dashed line) and those that did not (solid line). B. Patients over age 50 (dashed line) compared to those under age 50 (solid line). C. Patients requiring either dialysis or to be in the intensive care unit at the time of treatment (dashed line) compared to those requiring neither (solid line).
Table 2 Cox proportional hazard model results for survival in patients treated with CAMPATH-1H

Adverse events

A total of 28 patients (39%) experienced 31 infections after treatment with CAMPATH-1H of which, 21 were considered severe infections. The median time to infection was 91 days after treatment with CAMPATH (interquartile range 34 to 279 days); 15 infections were bacterial, 2 were viral, 4 were fungal and in 10, no organism was identified but the clinical diagnosis was of an infective syndrome. The most common causative organism was Staphylococcus sp. accounting for 10 infections, while cytomegalovirus, Pneumocystis jirovecii and Aspergillus accounted for two infections each and Salmonella, Pseudomonas, Escherichia, Actinomyces and mixed anaerobes accounted for one infection each. Patients in the intensive care unit were 30% more likely to have a severe infection (95% CI 0.4 to 60%; p = 0.03) and patients with complete CD4 positive cell depletion were 27% more likely to have a severe infection (95% CI 8 to 46%; p = 0.02). None of the following predicted an increased risk for infections: prior cumulative prednisolone dose, prior cumulative cyclophosphamide dose, successful induction of remission, or renal failure.

Three patients were diagnosed with a malignancy within 1 year of treatment (two lung and one prostate cancer), one diagnosed with a pituitary adenoma 4 years after treatment and one with lymphoma 8 years after treatment. Additionally, one patient had a dysplastic colonic polyp removed 6 years after her CAMPATH-1H treatment. Eight patients (11%) developed Graves disease after a median of 3.5 years after treatment (range 0 to 9 years). No patients in our cohort developed ITP.


In all, 16 patients (23%) had an undetectable CD4 positive cell count before beginning treatment. With 3 months of CAMPATH-1H treatment, 40 patients (56%) had an undetectable CD4 positive cell count while an additional 13 (18%) had a count less than 10 cells/μl. The recovery of CD4 positive cells was slow. At 12 months post treatment, 58% continued to have CD4 positive lymphocyte counts less than 10 cells/μl (fig 4). Although the depletion of CD4 positive cells was thought to be of major importance in inducing remission, it was not significantly associated with the induction of remission or time to relapse. ANCA positivity was lost in 9 of 26 patients but also was not significantly associated with the induction of remission or time to relapse.

Figure 4 Box plot of CD4 positive cell counts at baseline, 3 months after treatment with CAMPATH-1H and 12 months after treatment with CAMPATH-1H in patients with anti-neutrophil cytoplasm antibody (ANCA) associated systemic vasculitis. Centre bars represent the median, upper and lower edges of the box represent the interquartile range the whiskers represent the range of 95% of patients and dots represent the outliers.


We describe the first long-term follow-up of the use of CAMPATH-1H for the induction of remission in a cohort of patients with refractory or relapsing AASV predominantly with a diagnosis of Wegener granulomatosis. Despite the refractory nature of the disease in the patients selected for treatment, CAMPATH-1H was able to induce a remission in 85% of patients with some enjoying a sustained remission for several years when other agents had failed. The benefits of treatment were, however, tempered by a high rate of relapse and serious infections, particularly in patients with more severe disease manifestations and more profound immunosuppression. Our experience suggests CAMPATH-1H may be useful for controlling refractory disease in patients who are not yet seriously ill.

Studies of refractory and relapsing AASV are uncommon making it difficult to compare our results to other studies. The nature of the cohort treated with CAMPATH-1H in this study must be carefully considered when assessing the balance between its efficacy and adverse event profile. Although the patients in our cohort had a higher 5-year mortality than other studies, our patients had previously failed other immunosuppressive medications including, in the majority of cases, high doses of oral cyclophosphamide. Many of the patients were moribund and CAMPATH-1H was offered as a salvage therapy for resistant, aggressive disease. The high mortality rate in this very ill group of patients with longstanding disease is, therefore, perhaps unsurprising.

CAMPATH-1H appears to induce remission in AASV that has been previously difficult to control with 85% of patients having a clinical response in this study. Multiple courses of CAMPATH-1H are often necessary to induce remission and the duration of remission varies. Biomarkers such as CD4 positive lymphocyte counts and ANCA titres do not appear to provide reliable indices for the amount of treatment needed to provide a durable remission although we had only limited data on the latter. Similar efficacy was seen in trials of anti-thymocyte globulin, a polyclonal immunoglobulin that also depletes lymphocytes.12 13 Success with anti-thymocyte globulin (ATG) is, however, tempered by a limited ability to re-dose patients due to the development of an antiglobulin response against the non-humanised, polyclonal antibody. Although anti-CAMPATH antibodies have been observed in studies of CAMPATH-1H used for multiple sclerosis, and they were not specifically measured in our study, there is little evidence that this is a significant response that impairs the efficacy of repeated dosing.10

Severe infections were common in our cohort and a cause of excess mortality. This observation has not been seen in other diseases treated with CAMPATH-1H and may relate to the high degree of morbidity in our patients at the time of treatment. Disease severity as well as prior therapy have been independently associated with increased risk for infections14 and accordingly, almost half of all severe infections in our patients were seen in those either being treated in the intensive care setting or already on dialysis. In other trials of patients with severe AASV, severe infections were seen in up to 27% of patients.15 Additionally, although other immunosuppressants were stopped, the depth of immunosuppression by CAMPATH-1H may be implicated in the development of severe infection as almost all severe infections occurred in patients with unmeasurably low CD4 positive lymphocyte counts. However, the majority of infective episodes were bacterial in nature and given CAMPATH-1H has little effect on neutrophils, this may simply be a reflection that more seriously ill patients were also more likely to have profound CD4 positive lymphopenia even before treatment. Again, severe disease and prior large doses of cyclophosphamide may account for some of the excess infections observed. In the absence of a suitable control group, it is difficult to make conclusions about the infective risk associated with CAMPATH-1H alone. It is notable that other patient groups treated with CAMPATH-1H in similar doses to our patients but with less vital organ involvement, did not develop as many infections as our patients.5 8 9

The occurrence of other adverse events, particularly thyroid disease and malignancy were also relatively common. Thyroid disease has become an increasingly recognised late complication of CAMPATH-1H.10 16 Studies in multiple sclerosis have found up to one third of patients treated with CAMPATH-1H develop anti-thymocyte antibodies.10 Given patients with vasculitis are at risk of developing thyroglobulin antibodies,17 it may have been expected that even more patients would develop clinically apparent thyroid disease after CAMPATH-1H. The risk of malignancy appears to be increased with the use of any immunosuppressant medication. Whether the malignancies diagnosed within 1 year of treatment with CAMPATH-1H are directly attributable to the study medication or existed undiagnosed or in a preclinical phase before treatment is unclear. Our patients did not appear to develop malignancies at a rate higher than other cohorts of patients with AASV.18 However, other studies have noted an association between solid malignancies and the use of biological therapies in AASV.19

In conclusion, CAMPATH-1H appears capable of inducing remission of refractory and relapsing AASV. Although the patients treated in our study had a high rate of adverse events and particularly severe infections, many were treated after accruing significant morbidity and in the face of an extremely poor pretreatment prognosis. Young patients with relapsing or refractory disease before suffering major vital organ damage may benefit from CAMPATH-1H. Carefully monitoring for infection and, in the long term, for thyroid disease and malignancy are required in all patients treated with CAMPATH-1H. A randomised control trial testing the efficacy of CAMPATH-1H is required before recommending CAMPATH-1H as a standard treatment for recalcitrant AASV.


CAMPATH-1H was provided by the Therapeutic Antibody Centre, Oxford, under the direction of Professor H Waldman and Dr G Hale who were instrumental in the development of this application and have provided helpful comments during the preparation of the manuscript.



  • Funding: MW is supported by fellowship grants from the Kidney Research Scientist Core Education Training Program, Alberta Heritage Foundation for Medical Research, and the Royal College of Physicians and Surgeons of Canada.

  • Competing interests: DJ has received research funding from Genzyme.

  • Ethics approval: Ethics approval was obtained.

  • All patients in this study received CAMPATH 1-H under the supervision of Professor C M Lockwood who pioneered this and other immunotherapies in vasculitis.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.