**7. Refractory/relapsing disease**

Some patients have disease that proves to be refractory to the therapies used for induction and maintenance of remission as above. Typically, patients with lung and upper airway involve‐ ment, positive PR3-ANCA and severe renal involvement have more resistant disease [47-49]. Relapse is also frequent in AAV, with an overall risk of 38% at 5 years seen in a large cohort of 535 patients from 70 European trial sites between 1995 and 2002 [32]. The presence of positive PR3 ANCA, cardiac involvement and absence of severe renal disease at presentation was found to be a predictor of relapse in that group [9]. A variety of agents have been proposed to address these refractory cases.

mg/kg/day after 1 year) or mycophenolate mofetil if azathioprine wasn't tolerated. In patients with persistent disease despite the use of methotrexate, azathioprine, mycophenolate mofetil or T/S, infliximab (5 mg/kg) at 0, 2, 6 and 10 weeks was added. If remission was achieved infliximab was maintained every 6 weeks for 1 year. In both groups, 88% achieved remission (BVAS ≤1) within a mean of 6.4 weeks. During follow-up (mean 17 months), only 18% experienced a relapse of disease. Both groups were able to significantly reduce their gluco‐ corticoid dose from a mean of 24 mg/day to 9 mg/day at week 14. There were 2 deaths in the newly diagnosed and relapsing group and 21% had severe infections. A second study has also examined infliximab use (5 mg/kg at 0, 2, 6 and 10 weeks) in addition to standard therapy and found no effect [52]. At 1 year, time to achieve remission, remission rates, adverse events,

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Adalimumab was used as an adjunctive therapy in a single centre, open label, prospective, uncontrolled study of newly diagnosed patients with GPA or MPA with renal involvement [53]. Seventy-nine percent of patients achieved remission (BVAS = 0) within the first 14 weeks of the study, and the mean oral prednisolone dose decreased from 37 to 8 mg/day, demon‐

Smith et al [54] reported a retrospective study of maintenance therapy with Rituximab in 73 patients with refractory or relapsing GPA and MPA. Twenty-eight received treatment with a single dose of rituximab (1000 mg) at the time of relapse. Of these, 19 were subsequently retreated at 6 months intervals. Another 45 patients were treated with rituximab (1000 mg twice at an interval of 2 weeks) and then received treatment (1000 mg) every 6 months for 24 months with ongoing follow-up for an additional 24 months. Of the patients treated with a single 1000 mg dose at relapse, 73% relapsed within 24 months. The frequency of relapse was lower in patients who received retreatment at 6 months at only 11% (p<0.001), and in those treated with the higher initial dose and ongoing retreatment at 12% (p<0.001). At 48 months, relapses had occurred in 81% of the single dose group, compared to 26% and 39% in the group with retreatment and the higher initial dose and retreatment. The median time to first relapse was 12 months (range 5-76) in the group receiving the single dose, compared to 29 months (range 5-48) in the group receiving retreatment and 34.5 months (range 5-53) in the group with the higher initial dose and retreatment. Retreatment was associated with a reduction in relapse rates compared to single rituximab courses and allowed early withdrawal of immunosup‐ pression and glucocorticoid reduction or withdrawal. In this study B cell count and ANCA

IVIg consists of intact IgG molecules, representing all IgG subclasses, from the pooled plasma of donors [55]. Small amounts of IgM, IgA, HLA and cytokines are also present in the prepa‐ ration. As such, IVIg contains a broad range of immune antibodies against pathogens and foreign antigens. Proposed mechanisms of action include modulation of the expression and function of Fc receptors, interference with the activation of complement and the cytokine

damage index scores, and relapse rates were similar between groups.

strating potential efficacy but requiring further rigorous study.

positivity didn't correlate with the time of relapse.

**7.3. Intravenous immunoglobulin (IVIg)**

**7.2. Rituximab**

#### **7.1. Tumor necrosis factor inhibition**

#### *7.1.1. Etanercept*

The "Wegener's Granulomatosis Etanercept Trial" (WGET) was a randomized, double blind, placebo controlled trial of etanercept as an adjunct to conventional therapy in patients with GPA [18]. The study enrolled 181 patients from 8 centres in the United States. Patients had newly diagnosed or relapsing GPA with a BVAS/WG of ≥3 and either limited or severe manifestations of their disease. Etanercept at the dose of 25 mg twice weekly subcutaneously or placebo was used simultaneously at the time of randomization with conventional therapy (corticosteroids along with methotrexate for limited disease and oral cyclophosphamide followed by methotrexate for severe disease induction and azathioprine for maintenance) and maintained as the conventional drugs were tapered over time. Prednisone was tapered by a specific protocol to be completely discontinued within six months, assuming that no relapse occurred.

The primary outcome measure was sustained disease remission, defined as a BVAS/WG of 0, for at least six months. The median duration of treatment was 25 months for etanercept and 19 months for placebo and the mean duration of follow-up was 27 months in the overall cohort. Seventy percent of subjects in the etanercept group met the primary outcome, as compared with 75% in the control group (p=0.39). There was no significant difference between groups in the time to sustained remission. The overall rate of sustained remission throughout follow-up was only 49.4%. Disease flares during treatment were not significantly different between the etanercept and control groups (relative risk, 0.89 (95%CI 0.62 to 1.28; p=0.54). The major concern arising from this study however was in the development of adverse events. Moder‐ ately severe to fatal infections occurred in 49% of subjects and were equal between treatment groups, however six solid cancers were identified during the trial, and all occurred in the etanercept group (standardized incidence ratio of 3.12 (95%CI 1.15–6.80, p=0.014)). An additional 3 other patients were subsequently diagnosed with a solid malignancy within 6 months of completion of the trial [50]. This study clearly demonstrated that etanercept was not effective, and the use of etanercept in combination with cyclophosphamide is associated with an increased risk of malignancy.

#### *7.1.2. Infliximab and adalimumab*

Infliximab has been studied as an adjuvant therapy for induction of remission in new, relapsing and refractory disease. A prospective, open label, multicenter study in the United Kingdom evaluated 2 small groups of patients with active disease [51]. In the new presentation or relapse group, infliximab (5 mg/kg) was given at 0, 2, 6 and 10 weeks as an adjuvant therapy to oral cyclophosphamide (2mg/kg/day) for 14 weeks and prednisolone. Once remission was achieved the cyclophosphamide was replaced by azathioprine (2 mg/kg/day, reduced to 1.5 mg/kg/day after 1 year) or mycophenolate mofetil if azathioprine wasn't tolerated. In patients with persistent disease despite the use of methotrexate, azathioprine, mycophenolate mofetil or T/S, infliximab (5 mg/kg) at 0, 2, 6 and 10 weeks was added. If remission was achieved infliximab was maintained every 6 weeks for 1 year. In both groups, 88% achieved remission (BVAS ≤1) within a mean of 6.4 weeks. During follow-up (mean 17 months), only 18% experienced a relapse of disease. Both groups were able to significantly reduce their gluco‐ corticoid dose from a mean of 24 mg/day to 9 mg/day at week 14. There were 2 deaths in the newly diagnosed and relapsing group and 21% had severe infections. A second study has also examined infliximab use (5 mg/kg at 0, 2, 6 and 10 weeks) in addition to standard therapy and found no effect [52]. At 1 year, time to achieve remission, remission rates, adverse events, damage index scores, and relapse rates were similar between groups.

Adalimumab was used as an adjunctive therapy in a single centre, open label, prospective, uncontrolled study of newly diagnosed patients with GPA or MPA with renal involvement [53]. Seventy-nine percent of patients achieved remission (BVAS = 0) within the first 14 weeks of the study, and the mean oral prednisolone dose decreased from 37 to 8 mg/day, demon‐ strating potential efficacy but requiring further rigorous study.

#### **7.2. Rituximab**

PR3 ANCA, cardiac involvement and absence of severe renal disease at presentation was found to be a predictor of relapse in that group [9]. A variety of agents have been proposed to address

The "Wegener's Granulomatosis Etanercept Trial" (WGET) was a randomized, double blind, placebo controlled trial of etanercept as an adjunct to conventional therapy in patients with GPA [18]. The study enrolled 181 patients from 8 centres in the United States. Patients had newly diagnosed or relapsing GPA with a BVAS/WG of ≥3 and either limited or severe manifestations of their disease. Etanercept at the dose of 25 mg twice weekly subcutaneously or placebo was used simultaneously at the time of randomization with conventional therapy (corticosteroids along with methotrexate for limited disease and oral cyclophosphamide followed by methotrexate for severe disease induction and azathioprine for maintenance) and maintained as the conventional drugs were tapered over time. Prednisone was tapered by a specific protocol to be completely discontinued within six months, assuming that no relapse

The primary outcome measure was sustained disease remission, defined as a BVAS/WG of 0, for at least six months. The median duration of treatment was 25 months for etanercept and 19 months for placebo and the mean duration of follow-up was 27 months in the overall cohort. Seventy percent of subjects in the etanercept group met the primary outcome, as compared with 75% in the control group (p=0.39). There was no significant difference between groups in the time to sustained remission. The overall rate of sustained remission throughout follow-up was only 49.4%. Disease flares during treatment were not significantly different between the etanercept and control groups (relative risk, 0.89 (95%CI 0.62 to 1.28; p=0.54). The major concern arising from this study however was in the development of adverse events. Moder‐ ately severe to fatal infections occurred in 49% of subjects and were equal between treatment groups, however six solid cancers were identified during the trial, and all occurred in the etanercept group (standardized incidence ratio of 3.12 (95%CI 1.15–6.80, p=0.014)). An additional 3 other patients were subsequently diagnosed with a solid malignancy within 6 months of completion of the trial [50]. This study clearly demonstrated that etanercept was not effective, and the use of etanercept in combination with cyclophosphamide is associated

Infliximab has been studied as an adjuvant therapy for induction of remission in new, relapsing and refractory disease. A prospective, open label, multicenter study in the United Kingdom evaluated 2 small groups of patients with active disease [51]. In the new presentation or relapse group, infliximab (5 mg/kg) was given at 0, 2, 6 and 10 weeks as an adjuvant therapy to oral cyclophosphamide (2mg/kg/day) for 14 weeks and prednisolone. Once remission was achieved the cyclophosphamide was replaced by azathioprine (2 mg/kg/day, reduced to 1.5

these refractory cases.

*7.1.1. Etanercept*

occurred.

**7.1. Tumor necrosis factor inhibition**

202 Updates in the Diagnosis and Treatment of Vasculitis

with an increased risk of malignancy.

*7.1.2. Infliximab and adalimumab*

Smith et al [54] reported a retrospective study of maintenance therapy with Rituximab in 73 patients with refractory or relapsing GPA and MPA. Twenty-eight received treatment with a single dose of rituximab (1000 mg) at the time of relapse. Of these, 19 were subsequently retreated at 6 months intervals. Another 45 patients were treated with rituximab (1000 mg twice at an interval of 2 weeks) and then received treatment (1000 mg) every 6 months for 24 months with ongoing follow-up for an additional 24 months. Of the patients treated with a single 1000 mg dose at relapse, 73% relapsed within 24 months. The frequency of relapse was lower in patients who received retreatment at 6 months at only 11% (p<0.001), and in those treated with the higher initial dose and ongoing retreatment at 12% (p<0.001). At 48 months, relapses had occurred in 81% of the single dose group, compared to 26% and 39% in the group with retreatment and the higher initial dose and retreatment. The median time to first relapse was 12 months (range 5-76) in the group receiving the single dose, compared to 29 months (range 5-48) in the group receiving retreatment and 34.5 months (range 5-53) in the group with the higher initial dose and retreatment. Retreatment was associated with a reduction in relapse rates compared to single rituximab courses and allowed early withdrawal of immunosup‐ pression and glucocorticoid reduction or withdrawal. In this study B cell count and ANCA positivity didn't correlate with the time of relapse.

#### **7.3. Intravenous immunoglobulin (IVIg)**

IVIg consists of intact IgG molecules, representing all IgG subclasses, from the pooled plasma of donors [55]. Small amounts of IgM, IgA, HLA and cytokines are also present in the prepa‐ ration. As such, IVIg contains a broad range of immune antibodies against pathogens and foreign antigens. Proposed mechanisms of action include modulation of the expression and function of Fc receptors, interference with the activation of complement and the cytokine network, provision of antiidiotypic antibodies (idiotypes are located in the variable region of autoantibodies in autoimmune conditions), and effects on the activation, differentiation and effector functions of both T and B cells [55]. In vasculitis, IVIG may reverse monocyte and neutrophil activation, reduce autoantibody production or effect the autoreactive T cell function [56]. In vitro, incubation of ANCA vasculitis patient sera with IVIg inhibited ANCA activity [57] which provided evidence to proceed with clinical use of this agent.

complete remission at month 9, steroids were stopped in 4 and reduced in 9, with reductions in other immunosuppressants in 4 subjects. The median BVAS 2005 was 0 (range 0-13) at month 9 and 0 (range 0-12) at month 24. Moderate and transient effects of IVIg were reported including nausea, headaches, fever, arthralgias, and 1 patient developed renal insufficiency and was

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IVIg is a safe agent for use in particular clinical situations, such as pregnancy, those with a potential infection mimicking vasculitis, and for patients with refractory persistent disease despite traditional immunsuppressive agents. Adverse effects included headaches, rise in creatinine, aseptic meningitis, backache and fever/chills. Theoretical adverse effects include the transmission of blood-borne pathogens, although extensive screening of blood donors occurs. Randomized clinical trials are lacking, and the role in new-onset disease or specific ANCA vasculitis entities is unexplored. The current evidence base is considered poor given the open-label nature of the literature with a lack of a control arm data or control over

**7.4. 15-deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4,9,12-triazanona-**

DSG is a synthetic analogue of spergualin, a natural product of the bacterium *Bacillus latero‐ sporus,* which possesses immunosuppressive properties [67, 68]. DSG has effects on B cell differentiation, blocks kappa light-chain expression at the transcriptional level and acts on T effector cells. A pilot study of DSG (0.5 mg/kg daily subcutaneously to target a leukocyte nadir of 3000/μ, 6 cycles with 2 week recovery periods) was performed in 20 subjects with refractory WG or MPA [68]. Steroids were dosed at the discretion of the treating physician but no other immunosuppressives were allowed. The primary endpoint was remission (either complete remission with no signs of disease activity, or partial remission defined as no new activity but with minor persistent activity) after 6 cycles of DSG. Response was noted in 14 subjects (6 complete, 8 partial, with the mean BVAS improving from 11 (SD 5.8) to 4 (2.9) in responders, and a reduction of oral steroids from 30 mg per day to 7.5 mg/day. Response was maintained out to 6 months for 11/14 of the responders. Side effects were largely infectious in nature, with diarrhea, headache, bronchitis, and anemia also reported. In a further open label-study, 44 patients with refractory WG received DSG (0.5 mg/kg/day in six cycles of 21 days with 7 days between cycles) followed by azathioprine [69]. In this study, 20 patients achieved remission (BVAS of 0 for 2 months) and 22 achieved partial remission (BVAS <50% of entry score).

The humanized monoclonal antibody, anti-CD52 (alemtuzumab, CAMPATH-1H) depletes circulating lymphocytes and macrophages. It has shown a promising effect in patients with multiple sclerosis and Behçet's disease. It has been studied in a group of patients with relapsing and refractory GPA or MPA in one UK centre [70]. Patients were eligible to receive CAM‐ PATH-1H if they had multiple relapses or life threatening disease despite the standard of care. Prednisolone was continued at 10 mg/day but all other immunosuppressants were discontin‐ ued. CAMPATH-1H was administered intravenously on consecutive days at doses of 4, 10,

deemed a treatment failure.

concomitant treatments received in addition of IVIg.

**decane-10,1-3-dione; gusperimus)**

**7.5. Alemtuzumab (campath-1H)**

In the initial publication, 7 patients with long-standing ANCA vasculitis resistant to standard immunosuppressive therapy received IVIg at a dose of 0.4 g/kg/day for 5 days [58] with maintenance of steroids and cytotoxic drugs for at least 6 weeks following the infusions. All patients improved within 2 days to 3 weeks; 5 went into full remission, 1 had sustained improvement and 1 had a partial transient response within 8 weeks. Relapses occurred in 3 patients between 2 and 9 months after treatment, with no relapses documented in the others who were followed between 6 and 18 months. Other successful case reports, case series and open-label studies followed [59-64] describing positive treatment responses, however there is likely an element of publication bias and confounding due to the variety in disease presenta‐ tions, prior and concomitant immunosuppressive therapies received, variable steroid doses and the lack of a control arm for comparison. Jayne et al reported on a prospective doubleblind placebo-controlled multicentre randomized study targeting a reduction in the BVAS [65]. Patients had either GPA or MPA with active vasculitis despite 2 months of treatment with prednisolone and cyclophosphamide or azathioprine. The mean disease duration of subjects in this study was 52.5 months. Seventeen subjects were randomized to receive IVIg 0.4 g/kg/day for 5 days with no changes in immunosuppressive drugs for 3 months after the trial infusion, and 17 subjects were in the placebo arm. Patients were assessed 2 weeks following the infusion and then monthly until 12 months. A 50% reduction in the BVAS was observed in 14/17 of the IVIg group and 6/17 of the placebo group respectively (OR 8.56; 95%CI 1.74-42.2, p-0.015) and two subjects in the placebo group died within 3 months. The mean BVAS in the IVIg group at baseline was 6.1, with a BVAS reduction of 3.2 at 1 month and 4.1 at 3 months, compared to a baseline BVAS of 5.4 in the placebo group with reductions of 0.87 and 2.3 at 1 and 3 months. However, after 3 months there were no significant differences in the BVAS between groups or in the frequency of relapse (5/16 for IVIG and 4/15 for placebo), and no differences in the subsequent steroids or immunosuppressive doses in follow-up.

An open-label study enrolled 22 poor-prognosis patients experiencing a relapse of WG or MPA despite treatment or within 1 year of stopping corticosteroids and/or immunosuppressants (0.5 g/kg/day for 4 days) to monthly IVIg for 6 months [66]. Temporary increases in prednisone doses were allowed but other immunosuppressants had to be maintained during the 6 months of IVIg therapy but could then be reduced, discontinued or switched to maintenance agents if cyclophosphamide had been given. In this study, the mean disease duration was 27 months (range 7-109 months) and the median BVAS 2005 at study entry was 11 (range 3-25). All but 1 patient was receiving steroids and/or immunosuppressants. Between months 1 and 5, 21 subjects achieved remission, with complete remission in 73% at 6 months, partial remission in 9% and relapse in 14%. The effect seemed persistent, with 13/16 responders still in complete remission at 9 months, and with 12/16 in complete remission at month 24. In those achieving complete remission at month 9, steroids were stopped in 4 and reduced in 9, with reductions in other immunosuppressants in 4 subjects. The median BVAS 2005 was 0 (range 0-13) at month 9 and 0 (range 0-12) at month 24. Moderate and transient effects of IVIg were reported including nausea, headaches, fever, arthralgias, and 1 patient developed renal insufficiency and was deemed a treatment failure.

IVIg is a safe agent for use in particular clinical situations, such as pregnancy, those with a potential infection mimicking vasculitis, and for patients with refractory persistent disease despite traditional immunsuppressive agents. Adverse effects included headaches, rise in creatinine, aseptic meningitis, backache and fever/chills. Theoretical adverse effects include the transmission of blood-borne pathogens, although extensive screening of blood donors occurs. Randomized clinical trials are lacking, and the role in new-onset disease or specific ANCA vasculitis entities is unexplored. The current evidence base is considered poor given the open-label nature of the literature with a lack of a control arm data or control over concomitant treatments received in addition of IVIg.

#### **7.4. 15-deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,1-3-dione; gusperimus)**

DSG is a synthetic analogue of spergualin, a natural product of the bacterium *Bacillus latero‐ sporus,* which possesses immunosuppressive properties [67, 68]. DSG has effects on B cell differentiation, blocks kappa light-chain expression at the transcriptional level and acts on T effector cells. A pilot study of DSG (0.5 mg/kg daily subcutaneously to target a leukocyte nadir of 3000/μ, 6 cycles with 2 week recovery periods) was performed in 20 subjects with refractory WG or MPA [68]. Steroids were dosed at the discretion of the treating physician but no other immunosuppressives were allowed. The primary endpoint was remission (either complete remission with no signs of disease activity, or partial remission defined as no new activity but with minor persistent activity) after 6 cycles of DSG. Response was noted in 14 subjects (6 complete, 8 partial, with the mean BVAS improving from 11 (SD 5.8) to 4 (2.9) in responders, and a reduction of oral steroids from 30 mg per day to 7.5 mg/day. Response was maintained out to 6 months for 11/14 of the responders. Side effects were largely infectious in nature, with diarrhea, headache, bronchitis, and anemia also reported. In a further open label-study, 44 patients with refractory WG received DSG (0.5 mg/kg/day in six cycles of 21 days with 7 days between cycles) followed by azathioprine [69]. In this study, 20 patients achieved remission (BVAS of 0 for 2 months) and 22 achieved partial remission (BVAS <50% of entry score).

#### **7.5. Alemtuzumab (campath-1H)**

network, provision of antiidiotypic antibodies (idiotypes are located in the variable region of autoantibodies in autoimmune conditions), and effects on the activation, differentiation and effector functions of both T and B cells [55]. In vasculitis, IVIG may reverse monocyte and neutrophil activation, reduce autoantibody production or effect the autoreactive T cell function [56]. In vitro, incubation of ANCA vasculitis patient sera with IVIg inhibited ANCA activity

In the initial publication, 7 patients with long-standing ANCA vasculitis resistant to standard immunosuppressive therapy received IVIg at a dose of 0.4 g/kg/day for 5 days [58] with maintenance of steroids and cytotoxic drugs for at least 6 weeks following the infusions. All patients improved within 2 days to 3 weeks; 5 went into full remission, 1 had sustained improvement and 1 had a partial transient response within 8 weeks. Relapses occurred in 3 patients between 2 and 9 months after treatment, with no relapses documented in the others who were followed between 6 and 18 months. Other successful case reports, case series and open-label studies followed [59-64] describing positive treatment responses, however there is likely an element of publication bias and confounding due to the variety in disease presenta‐ tions, prior and concomitant immunosuppressive therapies received, variable steroid doses and the lack of a control arm for comparison. Jayne et al reported on a prospective doubleblind placebo-controlled multicentre randomized study targeting a reduction in the BVAS [65]. Patients had either GPA or MPA with active vasculitis despite 2 months of treatment with prednisolone and cyclophosphamide or azathioprine. The mean disease duration of subjects in this study was 52.5 months. Seventeen subjects were randomized to receive IVIg 0.4 g/kg/day for 5 days with no changes in immunosuppressive drugs for 3 months after the trial infusion, and 17 subjects were in the placebo arm. Patients were assessed 2 weeks following the infusion and then monthly until 12 months. A 50% reduction in the BVAS was observed in 14/17 of the IVIg group and 6/17 of the placebo group respectively (OR 8.56; 95%CI 1.74-42.2, p-0.015) and two subjects in the placebo group died within 3 months. The mean BVAS in the IVIg group at baseline was 6.1, with a BVAS reduction of 3.2 at 1 month and 4.1 at 3 months, compared to a baseline BVAS of 5.4 in the placebo group with reductions of 0.87 and 2.3 at 1 and 3 months. However, after 3 months there were no significant differences in the BVAS between groups or in the frequency of relapse (5/16 for IVIG and 4/15 for placebo), and no

differences in the subsequent steroids or immunosuppressive doses in follow-up.

An open-label study enrolled 22 poor-prognosis patients experiencing a relapse of WG or MPA despite treatment or within 1 year of stopping corticosteroids and/or immunosuppressants (0.5 g/kg/day for 4 days) to monthly IVIg for 6 months [66]. Temporary increases in prednisone doses were allowed but other immunosuppressants had to be maintained during the 6 months of IVIg therapy but could then be reduced, discontinued or switched to maintenance agents if cyclophosphamide had been given. In this study, the mean disease duration was 27 months (range 7-109 months) and the median BVAS 2005 at study entry was 11 (range 3-25). All but 1 patient was receiving steroids and/or immunosuppressants. Between months 1 and 5, 21 subjects achieved remission, with complete remission in 73% at 6 months, partial remission in 9% and relapse in 14%. The effect seemed persistent, with 13/16 responders still in complete remission at 9 months, and with 12/16 in complete remission at month 24. In those achieving

[57] which provided evidence to proceed with clinical use of this agent.

204 Updates in the Diagnosis and Treatment of Vasculitis

The humanized monoclonal antibody, anti-CD52 (alemtuzumab, CAMPATH-1H) depletes circulating lymphocytes and macrophages. It has shown a promising effect in patients with multiple sclerosis and Behçet's disease. It has been studied in a group of patients with relapsing and refractory GPA or MPA in one UK centre [70]. Patients were eligible to receive CAM‐ PATH-1H if they had multiple relapses or life threatening disease despite the standard of care. Prednisolone was continued at 10 mg/day but all other immunosuppressants were discontin‐ ued. CAMPATH-1H was administered intravenously on consecutive days at doses of 4, 10, 40, 40 and 40 mg, for a total dose of 134 mg. CAMPATH-1H was readministered for relapsing disease if the initial treatment was tolerated. A total of 71 patients were treated and followed for a mean of 5 years. Sixty-five percent of patients achieved clinical remission, and an additional 20% had a clinically significant improvement in disease activity but still required greater than 10 mg of prednisolone per day or an additional immunosuppressive agent to control disease activity. Almost all subjects relapsed after 9 months, with better renal function and the absence of neurologic involvement protective for relapse. Unfortunately, 44% of the cohort died during the follow-up period, 5 patients were diagnosed with malignancy, and 11% developed Graves disease. These adverse events may limit the use of alemtuzumab in practice to highly selected patients or those with disease refractory to all other agents.

**9. Treatment of eosinophilic granulomatosis with polyangiitis (Churg-**

Most of the studies in AAV include only a small number of patients with EGPA or exclude

A prospective, multicenter, randomized trial of patients newly diagnosed with EGPA and at least 1 poor prognosis factor (creatinine >140 μmol/l (1.58 mg/dl); proteinuria >1 gm/ day; or central nervous system, gastrointestinal, or myocardial involvement) was conduct‐ ed to determine the shortest immunosuppressant duration able to limit the occurrence of side effects and still induce and maintain disease remission by comparing glucocorticoids and 6 compared to 12 intravenous cyclophosphamide pulses [75]. All patients received 3 consecutive intravenous pulses of methylprednisolone (15 mg/kg) followed by oral prednisone (1 mg/kg/day) for 3 weeks followed by a tapering regime. Intravenous

and patients were randomized to receive either 6 or 12 cyclophosphamide pulses. The cumulative cyclophosphamide dose was twice as high in the 12-pulse group than in the

proportion of patients achieving complete remission, at 91% for the group receiving 6 pulses and 84% for the group receiving 12 pulses. Relapse frequency demonstrated a trend to significance at 74% for the group receiving 6-pulses compared to 62% in the 12-pulse group (p=0.07), and the mean time to first relapse was 268 days in the 12-pulse group compared to 222 days in the 6-pulse group, although this was not statistically different.

One study examined treatment efficacy of corticosteroids as first-line treatment of EGPA without poor prognosis factors, and the use of azathioprine compared to intravenous cyclophosphamide for treatment failure or relapse [76]. Subjects could receive 1 intrave‐ nous pulse of methylprednisolone (15 mg/kg) and then oral prednisone (1 mg/kg/day for 3 weeks) followed by a tapering regimen. If the prednisone could not be tapered below 20 mg, or if the patient experienced a relapse, they were randomized to azathioprine (2 mg/kg/day for 6 months) or 6 cyclophosphamide doses (0.6 g/m2 every 2 weeks for 1 month, then every 4 weeks). Ninety-three percent of subjects achieved remission, with a 1 year survival rate of 100% and 5 year survival rate of 97%. Of the subjects achieving remission, 37% relapsed, and 3% could not reduce their prednisone. A total of 19 sub‐ jects went onto randomization with 10 receiving cyclophosphamide and 9 receiving azathioprine. Fifty percent of the cyclophosphamide subjects achieved remission, com‐ pared to 78% of the azathioprine subjects. Low-dose corticosteroid therapy was required

) was given every 2 weeks for 1 month, then every 4 weeks,

). There was a non-significant difference in the

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them altogether. We will discuss trials performed specifically in EGPA.

**Strauss syndrome)**

**9.1. EGPA with poor prognosis**

cyclophosphamide (0.6 g/m2

6-pulse group (6.6 g/m2 versus 3.48 g/m2

**9.2. EGPA without poor prognosis factor**

Adverse events and deaths were equal between both groups.

in 79% of subjects long-term, primarily due to lung disease.

#### **7.6. Antithymocyte globulin (ATG)**

The SOLUTION protocol was an uncontrolled prospective open-label study of ATG in 15 subjects with refractory GPA [71]. ATG was given intravenously at a dose of 2.5 mg/kg for a mean of 2 doses. The authors describe partial remission in 9/15 subjects and complete remission in 4/15 with reduced prednisone requirements (mean 49 mg/day to 13 mg/day) and only experiencing relapse after 8 months. However, 2 patients died and 5 others developed severe infections.
