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Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patientsVol. 58, No. 1, January 2008, pp 308–317 2008, American College of Rheumatology Intravenous Immunoglobulins for Relapses of Systemic Vasculitides Associated With Antineutrophil Results of a Multicenter, Prospective, Open-Label Study of Twenty-Two Patients ´rie Martinez,1 Pascal Cohen,1 Christian Pagnoux,1 Ste Luc Mouthon,1 Laurent Sailler,1 Claire Delaunay,1 Alain Sadoun,2 and Loı¨c Guillevin,1 Objective. To evaluate at 9 months and 24 months
the time of relapse; immunosuppressants could be con-
the safety and efficacy of intravenous immunoglobulins
tinued but could not be reintroduced. At months 9 (end
(IVIGs) administered for 6 months to treat relapses of
point) and 24 (followup), the following information was
Wegener’s granulomatosis (WG) or microscopic polyan-
collected: complete or partial remission, relapse as
giitis (MPA) occurring either under treatment or during
assessed with the Birmingham Vasculitis Activity Score
the year following discontinuation of corticosteroids
(BVAS) 2005, and tolerance and safety of IVIG therapy.
Results. Twenty-two Caucasian patients (7 men
Methods. Patients received IVIGs (0.5 gm/kg/day
and 15 women) were studied: 19 had WG, and 3 had
for 4 days) as additional therapy administered monthly
MPA. Their median age was 53 years (range 19–75
for 6 months and were assessed every 3–6 months.
years), and their median duration of systemic vasculitis
Corticosteroids could be maintained or reintroduced at
was 27 months (range 7–109 months). Their median
BVAS 2005 score was 11 (range 3–25). At study entry, 21
ClinicalTrials.gov identifier: NCT00307658.
patients were ANCA positive, and 21 patients were
Presented in part at the 69th Annual Scientific Meeting of the American College of Rheumatology, San Diego, CA, November 2005.
taking steroids and/or immunosuppressants. All pa-
tients experiencing relapse were treated with the same
Laboratoire Franc¸ais du Fractionnement et des Biotechnologies, drug(s) plus IVIGs. All patients initially responded to
Courtaboeuf, France, provided the intravenous immunoglobulins(Tegeline) used in the study.
IVIG therapy. By month 9, 13 patients had complete
1Vale´rie Martinez, MD, PhD, Pascal Cohen, MD, Christian remission, 1 had partial remission, 7 had relapse, and 1
´phane Vinzio, MD, Alfred Mahr, MD, Luc Mou- thon, MD, PhD, Laurent Sailler, MD, Claire Delaunay, MD, Loı¨c had treatment failure. In 8 of the 14 patients who had
remission, the response persisted at month 24. Seven
´ Paris Descartes, Paris, France; 2Alain Sadoun, MD: patients experienced minor side effects.
Laboratoire Franc¸ais du Fractionnement et des Biotechnologies,Courtaboeuf, France. See Appendix A for members of the French Conclusion. IVIGs induced complete remissions
of relapsed ANCA-associated vasculitides in 13 of 22
Dr. Mouthon has received consulting fees (less than $10,000) from Laboratoire Franc¸ais du Fractionnement et des Biotechnologies.
patients at month 9. Because of the good safety and
Dr. Guillevin has received honoraria (less than $10,000 each) from tolerance profiles of IVIGs, these agents can be included
Actelion (Advisory Board), Wyeth, Roche, and Schering-Plough.
in a therapeutic strategy with other drugs used to treat
Address correspondence and reprint requests to Loı¨c Guil- levin, MD, Department of Internal Medicine, Ho relapses of WG or MPA.
ence Center for Rare Diseases (Vasculitis and Scleroderma), Assis-tance Publique Ho EA 4058, 27 Rue du Faubourg St. Jacques, 75679 Paris Cedex 14, Wegener’s granulomatosis (WG), microscopic France. E-mail: [email protected]
polyangiitis (MPA), and Churg-Strauss syndrome (CSS) Submitted for publication October 22, 2006; accepted in are small-vessel vasculitides that are frequently associ- INTRAVENOUS IMMUNOGLOBULINS FOR VASCULITIS RELAPSE ated with antineutrophil cytoplasmic autoantibodies PATIENTS AND METHODS
(ANCAs) (1). Corticosteroids in combination with im- Study design and patient population. This multicenter,
munosuppressants, such as oral or pulse cyclo- prospective, open-label study recruited patients from 20 phosphamide, are universally accepted as the standard French hospitals. The protocol was approved by the Institu- treatment for inducing remission, preventing relapses, and sometimes curing these diseases (2–4). However, Programme Hospitalier de Recherche Clinique. Study moni-toring was sponsored and funded by the Assistance Publique when therapy is reduced gradually and/or discontinued, ˆpitaux de Paris. Each patient gave written informed consent relapses are common and are responsible for substan- tially more drug-related morbidity and mortality. Al- Inclusion criteria were a previous diagnosis of WG, though cyclophosphamide can effectively manage re- MPA, or CSS based on disease manifestations that met thecriteria of the Chapel Hill Consensus Conference (14) and/or lapses, repeated cycles of cyclophosphamide are the American College of Rheumatology classification criteria associated with bone marrow suppression, myelodyspla- for WG (15) or CSS (16); factor(s) of poor prognosis at the sia, infection, infertility, and transitional-cell carcinoma time of first diagnosis of MPA or CSS (17); vasculitis relapse of the bladder, which may occur years after its initial use.
occurring during treatment or during the year following treat-ment discontinuation; and age Ͼ18 years.
Therefore, alternative therapies are needed to limit Patients were excluded for the following reasons: no treatment for Ͼ12 months; diagnosis of polyarteritis nodosa; Results of the European Vasculitis Study (EU- MPA or CSS without factor(s) of poor prognosis at baseline, as VAS) Trial showed that azathioprine maintenance ther- defined by the Five-Factors Score (17); recent extracapillaryglomerulonephritis or recent and active glomerulonephritis apy enabled the reduction of cyclophosphamide expo- with renal insufficiency (serum creatinine Ͼ300 moles/liter, sure without increasing the relapse rate over 18 months or 34 mg/dl); cancer, lymphoma, leukemia, or psychiatric (2). In addition, the safety and efficacy of agents in- disorders; age Ͻ18 years; or cutaneous vasculitis or vasculitis volved in the immune response, such as intravenous Patients with renal involvement resulting from chronic immunoglobulins (IVIGs), are being increasingly inves- extracapillary glomerulonephritis were eligible to participate.
tigated in vasculitis patients. For decades, IVIGs have However, at the time of relapse, we excluded renal flares with shown potent therapeutic efficacy in patients with rapid rises in serum creatinine levels for 2 reasons: immuno- ANCA-positive vasculitides (5–9). The effectiveness of globulins seemed unable to control severe renal failure andprevent renal deterioration, and immunoglobulins were inap- IVIGs alone (8,9) or as concomitant therapy has been propriate in this context because one of the side effects of high evaluated in several types of ANCA-associated vasculit- dose IVIG is impaired renal function.
ides, even though its mechanism(s) of action remains All patients received IVIGs (Tegeline; Laboratoire poorly understood (6,7,10,11). In small prospective stud- Franc¸ais du Fractionnement et des Biotechnologies, Courta-boeuf, France), which were infused at a dosage of 0.5 gm/kg/ ies on persistent ANCA-associated vasculitides, com- day for 4 consecutive days each month for 6 months. When plete or partial responses were obtained in 45–75% of relapse occurred during corticosteroid therapy, clinicians were the patients given IVIG alone or in combination with allowed to increase the oral or pulse prednisone dosage for other drugs (8,9,11–13). Moreover, IVIGs have an ex- 8–21 days provided that the dosage was tapered within 3 weeksto the dosage the patient was taking before relapse occurred.
cellent therapeutic/side-effects index. However, the Like other brands of IVIGs, Tegeline is derived from the blood place of IVIG in the treatment regimen of ANCA- of multiple donors. To prevent transmission of viral and prion associated vasculitides remains unclear because few infections, the product is prepared exclusively from selected trials have evaluated its indication as first- or second-line donors who have no family history of transmissible spongiformencephalopathy (TSE) and no potential exposure to the risk of treatment. The only placebo-controlled trial in patients contracting iatrogenic TSE through neurosurgery, transfusion, with persistent ANCA-associated vasculitides published or exposure to bovine spongiform encephalopathy– to date demonstrated regression of vasculitis at 3 months contaminated food in the UK. The isolation, purification, and preparation process consists of several steps that are able toinactivate/remove TSE infectivity, including ethanol precipita- The present study was designed to evaluate at 9 tion, filtration, 35-nm nanofiltration, and sterilizing filtration.
and 24 months of followup the efficacy and safety of Immunosuppressants being taken at the time of re- concomitant administration of IVIGs given monthly for lapse had to be maintained at the same dosage during IVIG 6 months to patients with relapses of ANCA-associated therapy and were then reduced, discontinued, or switched to amaintenance treatment if cyclophosphamide had been given.
vasculitides (WG, MPA, or CSS) occurring during ther- For patients who were off treatment at the time of relapse and apy with corticosteroids and/or immunosuppressants or study inclusion, short-term steroids were prescribed as de- during the year following their termination.
scribed above, but no immunosuppressants were prescribed.
The steroid dosage was freely decided by the treating physician Statistical analysis. Our working hypothesis was that
according to the disease severity, with the objective of return- monthly administration of concomitant high-dose IVIG as an ing the dosage to the pre-relapse levels within 3 weeks or to the immunomodulatory agent would attenuate disease activity minimal effective dosage. In addition, cotrimoxazole as pro- during relapses of ANCA-associated vasculitides. Given the phylaxis against Pneumocystis jiroveci pneumonia was manda- exploratory nature of this study, we aimed at including 40 tory in patients with CD4 cell counts Ͻ200/mm3, as well as in patients, with an intermediate analysis based on 20. End points patients with WG to prevent relapse (18).
were the numbers of complete remissions and partial remis- Clinical assessments. Patients’ medical records were
sions and the safety and efficacy of IVIGs. The objective was to reviewed at study entry (maximum of 5 days before the first have at least 20% of patients with complete remission or 50% IVIG infusion), at the time of infusion, monthly during the of patients with partial remission at month 9 of followup. If this 6-month IVIG treatment period, and at months 9, 12, 15, 18, goal was reached at the time of the intermediate analysis and 24 of followup. The following items were recorded on a corresponding to 20 patients included in the study, the inclu- preestablished report form: clinical symptoms; current ther- sion of additional patients would be stopped.
apy; C-reactive protein (CRP) level; serum creatinine level; Quantitative values are expressed as the mean Ϯ SD or glomerular filtration rate; Karnofsky Index of performance/ as the median and range. Qualitative values are given as the function; liver function test results; hemoglobin value; white number and percentage. Data were collected at the time of blood cell, neutrophil, lymphocyte, and platelet counts; hema- infusion, then monthly for 6 months, at month 9 (time of the turia, proteinuria; results of ANCA testing; and adverse effects intermediate statistical analysis), and at each followup visit secondary to IVIG infusion. All patients were tested for thereafter (at months 12, 15, 18 and 24). Data were analyzed with human immunodeficiency virus and hepatitis B and C viruses.
the StatView program (1992–1998; SAS Institute, Cary, NC).
The Birmingham Vasculitis Activity Score (BVAS) 2005, which was adapted from BVAS 2 (19,20), was used tospecifically evaluate vasculitis activity. This clinical index is Characteristics of the patients at study entry.
based on symptoms and signs in 10 categories (systemic signs; Twenty-four Caucasian patients were screened, and 22 skin; mucous membranes and eyes; ear, nose, and throat;chest; heart and vessels; gastrointestinal tract; kidney; nervous of them (7 men and 15 women) fulfilled the inclusion system; and others) divided into 60 predefined items. Each criteria: 19 had WG and 3 had MPA. Table 1 shows the item is weighted (range 1–9), and an item is scored if the patients’ characteristics at study inclusion, by type of investigator thinks it is present and caused by active vasculitis.
vasculitis. The median age of the 22 patients was 53 Higher scores indicate more active disease. For low-grade years (range 19–75 years), and the median duration of grumbling disease, but not new/worse signs, the BVAS 2005 their vasculitis symptoms before study inclusion was 27 Complete remission was defined as the disappearance months (range 7–109 months). Thirteen patients had of clinical and biologic signs of vasculitis, as reflected by a been smokers, and 6 had various allergies. The median BVAS 2005 score of zero. Partial remission was defined as BVAS 2005 score at study entry was 11 (range 3–25).
attenuation of clinical and biologic symptoms that were Before relapse of the vasculitis (prior to study present at the time of relapse, as reflected by Ն50% decrease inclusion), the median prednisone dosage was 4 mg/day in the BVAS 2005 score obtained at study entry. Vasculitis (range 0–10). At study inclusion, corresponding to the sequelae (lasting Ͼ3 months) could be present at the time ofevaluation and were not recorded as symptoms of disease first infusion of IVIG as concomitant therapy, 21 of the activity, but as persistent damage (e.g., persistent proteinuria 22 patients were taking corticosteroids (dosage range associated with the disappearance of hematuria, a stable serum 5–60 mg/day of prednisone in 19 patients and/or 1.2 creatinine level above the normal range, or persistent sinus- mg/kg/day to a maximum dosage of 1 gm/day of pulse itis). Worsening of symptoms was considered to represent methylprednisolone in 6 patients) and/or immunosup- relapse when new symptoms appeared after an initial complete pressants. One patient received a single pulse of cortico- remission or partial remission. Treatment failure was recordedwhen there were new symptoms or further deterioration of steroids at the time of the first IVIG infusion and then vasculitis symptoms that were present at trial entry.
received IVIGs alone. Patients were taking the following The Medical Outcomes Study Short Form 36 (SF-36) immunosuppressants: cyclophosphamide in 7 (intrave- health survey was completed at each assessment (21,22). The nous in 5 and oral in 2), azathioprine in 7, methotrexate SF-36 evaluates 8 dimensions of health status (general andmental health, physical and social functioning, physical and in 3, and mycophenolate mofetil in 1. Cotrimoxazole had emotional role, pain, and vitality), and it can be condensed into been prescribed for 12 WG patients to prevent relapse 2 scores, a physical component summary and a mental com- (800/160 mg of trimethoprim/sulfamethoxazole) (18) ponent summary. Scores for each dimension/summary range and for 1 MPA patient with severe lymphopenia to from 0 (worst) to 100 (best). A 5-point difference in the SF-36 prevent Pneumocystis jiroveci pneumonia (400/80 mg of score is considered clinically and socially relevant (23). Ad-verse events were graded according to predefined World trimethoprim/sulfamethoxazole). Cotrimoxazole was Health Organization criteria as mild, moderate, severe, or started before relapse occurred and before study inclu- INTRAVENOUS IMMUNOGLOBULINS FOR VASCULITIS RELAPSE Subsequent course (6–24 months). At the study end point at month 9, complete remission persisted in 13of the 16 patients who were in complete remission atmonth 6. Seventeen of the 22 study patients (77.3%)were in complete remission at month 24, and 2 patientswere still in partial remission. Between months 5 and 9of followup, 7 patients experienced a relapse despitetheir initial responses to IVIGs (5 had complete remis-sion and 2 had partial remission initially). Their therapywas modified at the discretion of the treating physician,and 5 achieved complete remission and 2 achievedpartial remission by the end of the study.
For the 13 patients in complete remission at month 9, the steroid dosage could be reduced in 9 ofthem and stopped in 4 of them. Moreover, dosages ofimmunosuppressants were lowered in 4 other patients.
Figure 1. Outcomes throughout 24 months of followup in patients
One patient received a corticosteroid pulse only with the with antineutrophil cytoplasmic antibody (ANCA)–associated vascu-litides treated with intravenous immunoglobulins (IVIG) as additional first IVIG infusion (at the time of relapse and therefore therapy. Twenty-two patients with ANCA-associated vasculitis, con- entry into the study); thereafter, no oral drugs were sisting of either Wegener’s granulomatosis (WG) or microscopic combined with IVIGs in this patient. His complete polyangiitis (MPA), were treated for 6 months with monthly infusions remission was maintained until month 18 of followup, of IVIGs. Assessments were performed at 6 months, 9 months (study end point; 3 months after cessation of IVIG infusions), and 24 months,and determinations of complete remission (CR) or partial remission Monthly IVIG therapy was reintroduced in 3 WG patients who were in complete remission at month 9.
The first patient relapsed at 10 months, and the treat-ment regimen was intensified with the use of cortico- All but 1 of the patients were ANCA-positive by steroids and various immunosuppressants, but there was indirect immunofluorescence analysis at the time of no clinical benefit. The second patient had vasculitis that vasculitis diagnosis and relapse: 2 had perinuclear was refractory to conventional therapy. Monthly IVIG ANCAs, 18 had cytoplasmic ANCAs, and 1 had ANCAs infusions were reintroduced in this patient, and a new of undetermined pattern. Enzyme-linked immunosor- complete remission was obtained until the end of fol- lowup. The third patient was in sustained complete myeloperoxidase-specific in 3 patients, proteinase remission as of the fourth IVIG infusion; IVIGs were 3–specific in 16 patients, and of undetermined specificity continued after the 6 planned cycles because of severe in 2 patients. All patients were seronegative for human hypogammaglobulinemia, but the dosage was lowered to immunodeficiency virus (HIV) and hepatitis B and C 1 gm/kg/day administered for 2 days each month.
viruses. Five patients had antibodies to hepatitis B Corticosteroid dosage. In the entire group of
surface antigen as a consequence of vaccination. All study patients, the median oral prednisone dosage pre- patients with granulomatous ear/nose/throat lesions also scribed at study inclusion was 20 mg/day (range 5–1,000), corresponding to the highest dosage during followup, Outcomes. Clinical outcomes in the 22 study
and was given in combination with pulse methylpred- patients at months 6, 9, and 24 of followup are shown in nisolone (n ϭ 6 patients) at that time. During followup, the median oral prednisone dosage was decreased to 15 Initial responses (0–6 months). One WG patient mg/day (range 0–60) by the second IVIG infusion (4 developed renal insufficiency after the first IVIG infu- weeks), 10 mg/day (range 0–70) by month 9, and 10 sion and was considered to have failed therapy. Twenty- one patients achieved remission between month 1 and In patients who achieved complete or partial month 5. After 6 months of IVIG therapy, complete remission, the median oral prednisone dosage at study remission occurred in 16 of the 22 patients (72.7%; 15 inclusion was 20 mg/day (range 5–500), corresponding to with WG and 1 with MPA), partial remission occurred in the highest dosage during followup. This dosage was 2 patients, and relapse occurred in 3.
gradually lowered during followup, to a median of 15 Characteristics of patients with Wegener’s granulomatosis (WG) or microscopic polyangiitis Duration of vasculitis since first symptoms, months Ear, nose, and throat involvement, no. (%) Birmingham Vasculitis Activity Score 2005 mg/day (range 0–30) by the second IVIG infusion, 8 3–25) at study inclusion to 0 (range 0–13) at month 9 and mg/day (range 0–12) by month 9, and 3.25 mg/day (range The mean physical component summary score on No difference in response rates according to the the SF-36 remained unchanged during followup, with a different organ manifestations was observed. Because mean Ϯ SD of 39.11 Ϯ 8.51 at study inclusion, 42.02 Ϯ IVIGs were able to induce complete remission in 13 of 11.74 at month 9, and 39.94 Ϯ 8.45 at month 24. The the 22 patients (59.1% [95% confidence interval 0.39– mental component summary score on the SF-36 im- 0.79]) and partial remission in 1 patient (4.5%) by month proved from study entry to month 9 and then remained 9, the objective of the study had been reached at the stable until month 24, with mean Ϯ SD values of 37.12 intermediate analysis, and study inclusions were there- Ϯ11.67, 43.27 Ϯ 10.00, and 43.82 Ϯ 9.91, respectively.
fore stopped according to the study protocol.
Compared with the values at study inclusion, some BVAS 2005 and SF-36 scores. As shown in Figure
scores were markedly improved at month 9: physical role 2, the median BVAS 2005 score dropped from 11 (range improved from a mean score of 26.25 to a score of 61.36, INTRAVENOUS IMMUNOGLOBULINS FOR VASCULITIS RELAPSE Figure 2. Changes in the Birmingham Vasculitis Activity Score (BVAS) 2003 (A and C) and the
C-reactive protein level (B and D) in patients with Wegener’s granulomatosis and microscopic
polyangiitis in whom complete remission (CA) or partial remission (PR) (A and B) or relapse (C
and D) occurred after or during 6 months of intravenous immunoglobulin infusions added to their
existing therapy. Data are presented as box plots. Boxes represent the 25th and 75th percentiles,
lines within the boxes represent the median, and lines outside the boxes represent the range.
pain improved from 47.05 to 63.50, emotional role IVIG therapy was maintained in all patients who expe- improved from 35.00 to 63.64, social functioning im- rienced an adverse event, and the infusion flow rate was proved from 51.88 to 62.50, vitality improved from 38.00 adapted to the individual patient’s tolerance level.
to 53.75, and health transition improved from 51.25 to Three infections developed in 2 patients during 58.33. No relationship was found between the BVAS followup. One patient developed a staphylococcal infec- 2005 scores at study inclusion and the scores for the tion in the arteriovenous fistula without septicemia. The other patient developed Kaposi’s sarcoma, which was Safety and adverse events. One patient devel-
related to prior immunosuppressive therapy, and a uri- oped renal insufficiency after the first IVIG infusion nary tract infection identified as Escherichia coli.
(considered to have failed therapy). This was recorded Evolution of ANCAs. Among the 13 patients who
as a serious adverse event. Moderate and transient were in complete remission at month 9 of study, 5 were adverse effects of IVIG treatment were reported in 7 of negative for ANCAs during followup (months 9–18), 6 the 22 patients (31.8%): 1 patient experienced nausea were positive for ANCAs, and data were missing for the and/or vomiting at each infusion, 1 patient experienced other 2 patients. After 24 months of followup, 4 of the 9 nausea only during the first infusion, and 5 patients had patients who were in complete or partial remission and headaches after the first infusion, which was associated underwent ANCA determinations at this time were with fever at only the first infusion in 1 of them, with ANCA-positive. The patient who was in partial remis- arthralgias at only infusion 4 in 1 of them, and with sion at month 9 remained ANCA-positive during fol- influenza-like symptoms at only infusion 2 in 1 of them.
lowup. Among the 7 patients who were experiencing a No severe or life-threatening events were reported.
relapse at month 9 of study, 2 remained ANCA-positive, 3 were ANCA-negative since month 2, and 1 was lished results, with 59.1% of the patients experiencing ANCA-negative at month 2 but became ANCA-positive complete remission, 4.5% experiencing treatment fail- ure, and 31.8% experiencing relapse at month 9 offollowup. Therapy with IVIGs added to conventionaltreatments was able to induce remission in patients who DISCUSSION
were already being treated and to facilitate a reduction Conventional treatment of ANCA-associated in the dosages of steroids and/or immunosuppressants.
vasculitides consists of corticosteroids, usually in combi- An increased steroid dosage was permitted for 3 weeks nation with immunosuppressants. Maintenance therapy to “kick-start” a response in our patients, all of whom typically consists of azathioprine or methotrexate, which were experiencing relapse of their vasculitis at study is prescribed for at least 12–18 months (2,24,25). Despite entry. The strategy of briefly increasing the steroid optimal treatment regimens, relapses occur in ϳ50% of dosage was to obtain rapid control of the disease while WG patients and in Ͻ50% of MPA patients after 5 years waiting for the effects of the IVIGs to begin, with the of followup (2–4,25–29). Depending on the maintenance requirement that the steroid dosages be returned to the agent prescribed, relapses have been reported in 33– pre-relapse or minimal effective dosage within 3 weeks.
52% of patients given azathioprine, methotrexate, le- We believe that the long-term results of IVIG treatment flunomide, or mycophenolate mofetil (30–34); hence, no were not attributable to the limited and temporary single drug seems to be better than the others.
increase in the steroid dosage. Followup of our study patients continued for 24 months, whereas in the obtained from pooled blood samples from Ͼ1,000 placebo-controlled study (11), followup continued for 12 healthy blood donors, and they exert their immuno- months. Although in several open-label studies, fol- modulatory effects on a wide range of autoimmune lowup continued for 4 weeks to 5 years, too few patients and/or systemic inflammatory diseases. IVIGs have been were included to draw definitive conclusions about the shown to be effective in the treatment of Kawasaki disease (35) and to prevent the development of coronary Our study is the first multicenter, prospective, aneurysms. They appear to be effective against ANCA- open-label trial designed to evaluate the long-term associated vasculitides (6–8). The efficacy of IVIGs effects of 6 courses of IVIG therapy in patients with prescribed alone (8,9) or as concomitant therapy has ANCA-associated vasculitides. IVIGs have a place in been evaluated in several types of ANCA-associated the therapeutic approach to relapsing or refractory vasculitides (2,10,36,37). Treatment with IVIGs alone or ANCA-associated vasculitides, but there were no previ- in combination with other drugs achieved responses in ously published data concerning the persistence of the 45–75% of patients with persistent ANCA-associated positive effect of IVIGs as additional therapy. Our study vasculitides included in small prospective studies (8,11– excluded patients with active crescentic glomerulone- phritis, which requires other treatments, such as high- The results of a placebo-controlled trial of IVIGs dose steroids, cyclophosphamide, and sometimes plasma in patients with relapsing ANCA-positive vasculitides exchanges. However, patients with preexisting glomeru- demonstrated better control of the vasculitis with IVIGs lonephritis that was controlled at the time of study entry after standard therapy (11). That study was designed to investigate the efficacy of a single course of IVIGs The safety profile of IVIGs was good, with only (2 gm/kg) administered to previously treated patients moderate and transient adverse reactions and a positive with persistent disease activity in whom intensification impact on the quality-of-life scores, as assessed with the of therapy was needed. Seventeen patients were ran- SF-36 health survey. Side effects of IVIG therapy in domized to receive IVIGs and 17 to receive placebo and patients with various autoimmune diseases as well as were followed up for 12 months: 14 of the 17 patients vasculitides have been reported to occur in 0–36% of given IVIGs and 6 of the 17 given placebo responded to patients; most were mild, transient, and completely treatment (11). That study opened the way for the use of reversible (5,8,36,38–40). These values are consistent IVIGs according to a single course of infusions protocol with the 31.8% rate of moderate side effects observed in (2 gm/day for 4 days) and showed reduced disease our patients. Our patients were tested serologically for activity for 3 months (11), which is consistent with the antibodies to HIV, hepatitis C virus, and hepatitis B surface antigen, none of which were detected. One The results of our study confirm previously pub- patient developed renal insufficiency after the first IVIG INTRAVENOUS IMMUNOGLOBULINS FOR VASCULITIS RELAPSE infusion, with rapid deterioration. Because of the pres- vasculitic lesions. It is pertinent that the ability of IVIGs ence of microscopic hematuria and proteinuria, we to produce lasting disease remissions has been associ- believe this was probably glomerulonephritis and was ated with decreased ANCA levels (6). Such mechanisms not caused by IVIG; however, it was recorded as a could be at work in the positive effects observed in our serious adverse event of IVIG therapy, since the treat- patients; however, antiidiotype antibodies to ANCA ment was considered to have played a partial role in the were not monitored. The evolution of ANCAs in our patients showed that the clinical response was not To date, no cases of variant Creutzfeldt-Jakob associated with the appearance or disappearance of disease related to a plasma-derived product have been ANCAs. Some patients who were in complete or partial reported, and the risk of transmission by these products remission became ANCA-negative, but some remained is considered to be very low. Indeed, specific precaution- ary measures in the preparation of plasma-derived prod- Our findings confirm that IVIGs are a safe, ucts have been adopted in France to prevent this risk.
well-tolerated, and effective concomitant treatment for The IVIG preparation used in the present study was relapses of WG and MPA. We believe that because of subjected to these precautionary measures in order to these qualities, IVIGs should be included in the thera- prevent the transmission of viral and prion infections, peutic approach to ANCA-associated systemic vasculit- and the donors had no family history of TSE and no ides. Our observations also indicate that relapses were potential exposure to the risk of contracting iatrogenic frequent after stopping IVIG infusions, suggesting that TSE through neurosurgery, transfusion, or exposure to they can temporarily hold the disease at bay, but main- bovine spongiform encephalopathy–contaminated food tenance therapy remains necessary after IVIGs are discontinued or IVIGs should be continued over the The good safety and tolerance profiles of IVIG long-term. Prospective studies are needed to evaluate could place them in the potential key role as the the indication(s) of IVIGs for use as steroid-sparing and treatment of choice for ANCA-associated vasculitides.
immunosuppressant-sparing therapy, which was only Unlike in other studies, we chose 9 months as the study partially demonstrated in our studies. Because relapses end point because we wanted to evaluate responses to frequently occur in patients with WG and MPA, other IVIGs not only immediately postinfusion, but also at 3 prospective trials are warranted to determine the opti- months after treatment cessation (i.e., 9 months after mal duration of IVIG administration and their use in initial infusion) as well as later (at 12 and 24 months) in place of, or in addition to, steroids and immunosuppres- order to assess their long-term impact, if any. Because IVIGs are an uncommon and expensive treatment, theirwidespread use is a concern. For this reason, we recom-mend treatment with IVIG infusions only in patients AUTHOR CONTRIBUTIONS
with refractory and/or relapsed ANCA-associated sys- Dr. Guillevin had full access to all of the data in the study and temic vasculitides, which represents only a limited num- takes responsibility for the integrity of the data and the accuracy of thedata analysis.
Study design. Pagnoux, Mouthon, Guillevin.
Different mechanisms of action have been pro- Acquisition of data. Martinez, Cohen, Pagnoux, Mahr, Mouthon,
posed to explain the beneficial effects of IVIGs on Delaunay, Sadoun, Guillevin.
Analysis and interpretation of data. Martinez, Vinzio, Sadoun, Guil-
autoimmune diseases, including modulation of Fc␥ re- ceptor expression on leukocytes and endothelial cells, Manuscript preparation. Martinez, Mouthon, Sailler, Guillevin.
interaction with complement proteins, modulation of Statistical analysis. Martinez, Vinzio, Mahr, Guillevin.
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Dr. Joaquín M. Jiménez Ferrer HUMA3022 (Manifestaciones culturales) La moral—como ya hemos señalado—se da en un doble plano: el normativo y el fáctico. Por un lado, encontramos en ella normas y principios que tienden a regular la conducta de los hombres, y, por otro, un conjunto de actos humanos que se ajustan a ellos, cumpliendo así su exigencia de realización. La esencia de la mora