Intravenous Immunoglobulin Group Research Articles

PASSIVE IMMUNIZATION IN THE CLINICAL MANAGEMENT OF SECONDARY SPONTANEOUS RECURRENT MISCARRIAGE

Objective: To investigate whether intravenous immunoglobulin (IVIG) can improve the chance of livebirth in womenwith a history of recurrent spontaneous miscarriage (RM).Study design: Randomized, double-blind, placebo- controlled trial.Patients and interventions: Fifty four women with a history of secondary (RM) were randomly assigned to receivedoses of (IVIG) or placebo (Saline) starting as soon as pregnancy test was positive.Results: The live birth rate (LBR) was significantly higher in the IVIG group when compared with placebo-infusedgroup even after exclusion of cases of ectopic pregnancy and cases with low serum ~hCG and progesterone levels,

Myasthenic crisis: Clinical features, complications and mortality

Myasthenic crisis is a life-threatening complication of myasthenia gravis (MG) and when treated aggressively is associated with good outcome. Retrospective study of case records of patients with episodes of myasthenic crisis. Twenty-one (22%) of the 95 patients with MG (9 with thymoma), experienced 23 episodes of myasthenic crisis, 3 (33%) in patients with thymoma. The crisis episodes occurred within 2 years of disease onset in 11 (52%) patients. Infection was the most common primary precipitant of the crisis occurring in 65%. The median duration of the crisis episode was 11 days (7-39 days), and the median neurological intensive care unit stay was 15 days (range 9-47 days). Fifteen (65%) episodes were treated with small volume plasma exchange (PE) and 8 (35%) episodes received intravenous immunoglobulin (IVIg). The time taken for disease stabilization, the median number of days for extubation, was 8 days (range 7-12) in the PE group and 10 days (range 7-39) in the IVIg group. Disease stabilization could not be achieved in one patient in the IVIg group. Ventilator-associated pneumonia (VAP) was the commonest complication, seen in 30%. Two (8%) of the 23 episodes of crisis were fatal, one resulting from VAP and septicemia, and the other due to crisis itself. All the 19 patients who survived to discharge had complete resolution of admission symptoms. In patients with myasthenic crisis, both therapeutic options, PE and IVIg, are equally effective in disease stabilization. To achieve good outcomes all efforts should be directed at decreasing the duration of intubation and also aggressively treating the associated medical complications.

Interferon Beta-1a and Intravenous Immunoglobulin Treatment for Multiple Sclerosis in Iran

The aim of the study was to evaluate the efficacy and safety of interferon beta-1a (Avonex) and intravenous immunoglobulin (IVIG) in clinical practice for the treatment of relapsing-remitting multiple sclerosis. Avonex is the most common disease-modifying therapy used in Iran due to its ease of administration. IVIG is also frequently used due to its alleged effectiveness and fewer side effects. Eighty patients were selected and prospectively monitored according to a predefined protocol. They were then randomized to receive either weekly intramuscular injections of Avonex or 0.4 g/kg monthly IVIG in a single blind fashion and following an attack of exacerbation which was treated with steroids. Basal relapse rate and Expanded Disability Status Scale (EDSS) were similar in both groups of patients (p > 0.4). Seventy-two patients remained in the study. The annual relapse rate consistently decreased from 0.95 ± 0.41 to 0.60 ± 0.67 (∼32%, p < 0.001) for 34 patients treated with Avonex and from 1.05 ± 0.34 to 0.55 ± 0.46 for 38 patients in the IVIG group (∼47%, p < 0.001). EDSS decreased by 0.4 units in IVIG-treated patients (p < 0.001) and remained stable (0.2 < p < 0.3) in the Avonex arm. This study confirms the relative efficacy of both treatments with better safety profile for IVIG in the studied Iranian population. However, the results are very preliminary ones, due to limited numbers of patients and only 12 months of treatment.

Effect of immunotherapy in myelitis with atopic diathesis

Objective A recent nationwide survey of myelitis with atopic diathesis in Japan disclosed that the disease frequently shows a chronic persistent course. A neuropathological study of the spinal cord also revealed chronic active inflammation. Since the effects of various immunotherapies have not been studied extensively in this condition, we evaluated the efficacies of various immunotherapies in patients with myelitis with atopic diathesis. Patients and methods Forty-two treatments in 26 patients with myelitis with atopic diathesis were retrospectively analyzed. One of the following therapies was administered: (1) corticosteroids (CS) (pulse therapy followed by oral administration with gradual tapering); (2) intravenous immunoglobulin (IVIG) (400 mg/kg/day for 5 consecutive days); (3) plasma exchanges (PE); or (4) PE followed by IVIG or CS (PE+IVIG/CS). The therapeutic efficacies were evaluated by thorough neurological examination and laboratory tests including MRI, somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs). Results Objective neurological findings improved in 89% of the PE group and 90% of the PE+IVIG/CS group, compared with only 72% of the CS and 60% of the IVIG groups. Improvement determined by laboratory tests was seen in 57% of the PE and 57% of the PE+IVIG/CS groups, compared with only 15% of the CS and none of the IVIG groups. Thus, the improvement rate determined by laboratory tests was significantly greater for therapies including PE than for those without PE ( p=0.0187). Conclusions These data suggest that immunotherapy is effective in myelitis with atopic diathesis despite a chronic persistent course, and that PE is the most beneficial immunotherapy.

Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial

Several double-blind placebo-controlled trials of relapsing-remitting multiple sclerosis have shown beneficial effects of intravenous immunoglobulin (IVIG) on relapse rate and disability. The European Study on Intravenous Immunoglobulin in Multiple Sclerosis set out to test IVIG in the secondary progressive phase of the disease. 318 patients with clinically definite secondary progressive multiple sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (albumin 0.1%; n=159) for 27 months. After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months. The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the expanded disability status scale (EDSS). Analyses were by intention to treat. 19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses. IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups. No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T2-lesion load over time. The treatment was generally well tolerated, although deep venous thrombosis, pulmonary embolism, or both occurred in seven patients with risk factors for thromboembolism (IVIG six, placebo one). Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with secondary progressive multiple sclerosis.

Possible Effect of Intravenous Immunoglobulin Therapy for Unexplained Secondary Recurrent Miscarriage

Objective. To review the role of intravenous immunoglobulin (IVIG) in the prevention of recurrent miscarriage (RM). Methods. In a prospective controlled clinical tria], 40 women with a history of unexplained. RMwere treated with IVIG, according to a specific protocol and compared to another 40 women who had the same condition and treated with tender loving care and vitamins only. The birth of a child of more than 28 weeks gestation was considered a successful outcome. Results. The overall success rate was 60% in the IVIG group compared with 52.6% in the control group (P = 0.65). The success rates for women with primary RM were 56.3% for IVIG group and 68.8% for the control group (P = 0.72). The success rates for women with secondary RM were 62.5% and 41.7% respectively (P = 0.25). None of the previous results is statistically significant. Conclusion. Women with unexplained RM in general have a good prognosis. IVIG did not improve the prognosis significantly in the total group of patients compared with controls. However; further investigations are needed to explore whether the 21 % therapeutic benefit of IVIG in patients with secondary RM indicates that the treatment is efficient in this subset of patients.

Study 2: evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the National Institutes of Health IG02 trial

I ntravenous immunoglobulin (IVIG) has potential prophylactic applications in solid organ transplantation. To determine its ability to reduce anti– human leukocyte antigen (HLA) antibody levels and improve transplant potential for patients with endstage renal disease (ESRD), we evaluated IVIG versus placebo in a randomized, double-blinded, placebo-controlled clinical trial. Between 1997 and 2000, 12 US transplant centers entered 101 adult ESRD patients who were highly sensitized to HLA antigens (panel reactive antibody [PRA] levels 50% monthly 3) into the National Institutes of Health IG02 trial. Patients were randomized 1:1 (49 IVIG; 52 placebo) to receive IVIG (Gamimune N 10% SD; Bayer Corp, Clayton, NC; or placebo 0.1% albumin, Bayer Corp). Subjects received IVIG 2 g/kg (maximum dose 180 g) monthly 4 or an equivalent volume of placebo with additional infusions at 12 and 24 months after entry if they did not undergo transplantation. If transplantation was performed, additional infusions were given monthly 4. The primary objective of the study was to determine whether IVIG reduced the number of months on dialysis by improving transplantation rates in highly sensitized patients. Baseline PRA levels were similar in both groups (IVIG 81.2% 2.1% vs 83.8% 1.9%). However, IVIG significantly reduced PRA levels in study subjects over the 2-year study period compared with placebo (P .005). Eighteen (37%) IVIG and 9 (17%) placebo patients underwent transplantation (P .03). More frequent transplants were observed in the IVIG group regardless of transplant history (P .02; prior transplant, 34% vs 10%; no prior transplant, 43% vs 26%). The maximum likelihood estimate of annual transplant rate is 24% for the IVIG group and 12% for the placebo group. There was a significant difference in the penalized time on dialysis (P .04). Of the transplants, 22 of 27 were cadaver transplants (16 IVIG, 6 placebo). Thirteen rejection episodes were reported (12 IVIG vs 1 placebo) in 8 of 18 IVIG subjects and 1 of 9 placebo subjects. Seven graft failures occurred over the study period (3 IVIG, 4 placebo). The remaining patients with viable transplants had a mean serum creatinine level of 1.7 1.1 mg/dL (IVIG) at an average of 529 days after transplantation versus 1.3 0.4 mg/dL for placebo at an average of 607.4 days after transplantation. Adverse events were similar in both groups (23 IVIG, 24 placebo). Headache was the most common infusion-associated adverse event (P .005, IVIG 43% vs placebo 17%). Conclusion: We can conclude that IVIG is superior to placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized ESRD patients. Although more acute rejection episodes were seen in the IVIG treatment group, the 2-year allograft survival and mean serum creatinine levels were similar. Thus, IVIG treatment offers significant benefits to highly sensitized ESRD patients awaiting transplantation. Immunomodulatory reduction of anti-HLA antibodies can be achieved without immunosuppression and the attendant risks of infection seen with other therapies. From Kidney Transplantation & Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles, CA; and EMMES Corp., Rockville, MD. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.003

Intravenous Immunoglobulin in Acute Rheumatic Fever

Acute rheumatic fever (ARF) remains the leading cause of acquired heart disease in children worldwide. No therapeutic agent has been shown to alter the clinical outcome of the acute illness. Immunological mechanisms appear to be involved in the pathogenesis of ARF. Intravenous immunoglobulin (IVIG), a proven immunomodulator, may benefit cardiac conditions of an autoimmune nature. We investigated whether IVIG modified the natural history of ARF by reducing the extent and severity of carditis. This prospective, double-blind, randomized, placebo-controlled trial evaluated IVIG in patients with a first episode of rheumatic fever, stratifying patients by the presence and severity of carditis before randomization. Patients were randomly allocated to receive 1 g/kg IVIG on days 1 and 2 and 0.4 g/kg on days 14 and 28, or they received a placebo infusion. Clinical, laboratory, and echocardiographic evaluation was performed at 0, 2, 4, 6, 26, and 52 weeks. Fifty-nine patients were treated, of whom 39 had carditis (including 4 subclinical) and/or migratory polyarthritis (n=39). There was no difference between groups in the rate of normalization of the erythrocyte sedimentation rate or acute-phase proteins at the 6-week follow-up. On echocardiography, 59% in the IVIG group and 69% in the placebo group had carditis at baseline. There was no significant difference in the cardiac outcome, including the proportion of valves involved, or in the severity of valvar regurgitation at 1 year. At 1 year, 41% of the IVIG and 50% of the placebo group had carditis. IVIG did not alter the natural history of ARF, with no detectable difference in the clinical, laboratory, or echocardiographic parameters of the disease process during the subsequent 12 months.

Intravenous immunoglobulin therapy in multifocal motor neuropathy: A double-blind, placebo-controlled study

We conducted a double-blind, placebo-controlled, study of 19 patients fulfilling eligibility criteria for multifocal motor neuropathy with persistent conduction block. They were enrolled and divided into two groups: those who had never been treated previously with intravenous immunoglobulins (IVIg) (Group 1: 10 patients) and those who presented recurrent symptoms after previously successful treatment with IVIg (Group 2: nine patients). They were randomized prospectively to receive either IVIg or placebo at a dose of 500 mg/kg/day for 5 consecutive days, once a month for 3 months. At month 4, patients found to be responders remained on the same treatment for the 3 following months, while non-responders were switched to the alternative study drug for the 3 following months. Clinical assessment was conducted with the MRC score in 28 muscles and a self-evaluation scale (five daily motor activities scored from 0 to 5). In Group 1, nine patients completed the study, of whom initially four received IVIg and five placebo; four patients responded to IVIg (two at months 4 and 7, and a further two at month 7 after switching treatment at month 4), two patients responded to placebo at months 4 and 7, and three patients did not respond to either treatment. In Group 2, nine patients completed the study. Five patients first received IVIg and all responded at months 4 and 7. Four patients first received placebo and none responded at month 4; all were then switched to IVIg and three responded at month 7. When the 18 patients were considered together, seven out of the nine patients who received IVIg first were responders at month 4, compared with two of the nine patients who received placebo first, a difference that was statistically significant (P = 0.03). On the other hand, there was no significant difference in MRC score but a significant difference in the self-evaluation score, at month 4, between IVIg patients and placebo patients. Electrophysiological studies did not show significant differences at month 4 in motor parameters between IVIg patients and placebo patients. IgM anti-GM1 titres did not change significantly in patients treated with IVIg compared with those who received placebo, between baseline, month 4 and month 7. However, of five patients who had significantly high anti-GM1 titres (>3200) at baseline, four responded to IVIg. This trial confirms that IVIg is a promising therapeutic option for multifocal motor neuropathy.

A randomized clinical trial comparing intravenous immunoglobulin with high-dose intravenous methylprednisolone, with or without subsequent oral prednisone administration, in adults with previously untreated severe autoimmune thrombocytopenic purpura

To compare the response to intravenous immunoglobulin (IVIg) with the response to high-dose methylprednisolone (HDMP) in previously untreated adults with severe AITP and to determine if oral prednisone (PRDN) is required after IVIg or HDMP infusions. M ethods 116 adults, previously untreated, with platelet count ≤ 20 × 109/L were assigned by simultaneous double randomization to receive either IVIg (0·7 g/kg body weight per day) or HDMP (15 mg/kg body weight per day, total daily dose less than 1 g) from day 1 to day 3 (randomization A), and then to receive either PRDN, 1 mg/kg body weight per day, or a placebo (randomization B), from day 4 to day 21 in blinded manner. R esults Between day 1 and day 21, the number of days on which platelet counts were above 50 × 109/L and above 20 × 109/L was significantly higher among the 56 patients receiving IVIg than among the 60 patients receiving HDMP (P = 0·008 and P = 0·013, respectively), and the percentage of patients who had a platelet count exceeding 50 × 109/L on day 5 was also higher in the IVIg group. During the second treatment period, PRDN was more effective than the placebo on all short-term end points. Patients who received IVIg followed by PRDN had a significantly larger number of days with platelet counts > 50 × 109/L and > 20 × 109/L between day 1 and day 21 (P = 0·008 and P = 0·005, respectively) than patients treated with HDMP followed by PRDN. As regards the long-term response, the percentage of remitters was 40% overall and was not influenced by the treatment allocation in either randomization period (A or B). C onclusion IVIg followed by PRDN appears to be the more effective treatment in adults with severe AITP.

Intravenous immunoglobulin in children with Guillain-Barré syndrome

We report our experience with intravenous immunoglobulin (IVIG), plasmapheresis and supportive care in 13 patients with the Guillain-Barré syndrome. Seven of 13 patients received IVIG, 2 plasmapheresis and 4 supportive care. At 15th day after IVIG administration, all patients in this group had improved at least one disability grade. In the plasmapheresis group, 1 improved at 5th day after the procedure. Two of the 4 patients that received supportive care improved at 20th day of evaluation. In the IVIG group, the final scores were lower and had no relapses. These results suggest faster clinical improvement with IVIG when compared with supportive measures.

Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial

Objective: To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with repeated unexplained in vitro fertilization (IVF) failure. Design: Prospective, randomized, double blind, placebo-controlled clinical trial. Setting: A university-based and a free-standing IVF program. Patient(s): Fifty-one couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or replacement of cryopreserved embryos. Intervention(s): Eligible women underwent a standard IVF stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks later if a clinical pregnancy was confirmed by ultrasound. Main Outcome Measure(s): Live-birth rates. Result(s): Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group ( P=0.52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of 4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group ( P=0.59). Conclusion(s): In this randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome.

Immunoglobulin administration to fetuses with anemia due to alloimmunization to D

The purpose of this study was to examine fetal tolerance of high-dose intravenous immunoglobulin (IVIG), given directly at the time of intravascular transfusion, and its effects on fetal hemolysis and pregnancy outcome in the setting of alloimmunization to D. Thirteen consecutive D+ fetuses requiring transfusion for maternal alloimmunization received high-dose IVIG (1.0 g/kg) and red cell transfusions. Twenty-four previous, consecutive fetuses with maternal anti-D served as controls. The schedules for subsequent transfusions were the same in the two groups. High-dose IVIG was well tolerated by all fetuses. In the IVIG group, daily decreases in hematocrit were smaller than those in controls after the second administration of IVIG (mean hematocrit decrease, 0.72 percent/day vs. 1.45 percent/day; p = 0.007). No significant difference was found in the total number of fetal transfusions, the gestational age at delivery, the duration of neonatal intensive care, the number of neonates requiring postnatal transfusion therapy, and perinatal mortality. In this small pilot study, direct administration to fetuses of IVIG with red cell transfusions was well tolerated and appeared to have a beneficial effect on fetal hemolysis.

Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood

In children, exacerbations of tics and obsessive symptoms may occur after infection with group A beta-haemolytic streptococci. If post-streptococcal autoimmunity is the cause of the exacerbations, then children might respond to immunomodulatory treatments such as plasma exchange or intravenous immunoglobulin (IVIG). We studied whether plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms. Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function. 30 children entered the study and 29 completed the trial. Ten received plasma exchange, nine IVIG, and ten placebo. At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45%] and 13 [58%], respectively), anxiety (2.1 [31%] and 3.0 [47%] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33%] and 2.8 [35%] improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49%). Treatment gains were maintained at 1 year, with 14 (82%) of 17 children "much" or "very much" improved over baseline (seven of eight for plasma exchange, seven of nine for IVIG). Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.

Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.

Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage An alloimmune abnormality is believed to be the cause of recurrent miscarriage in couples in whom no other cause can be identified. Because of its immunosuppressive properties, intravenous immunoglobulin (IVIG) is used as a treatment for this disorder. The purpose of this study was to determine whether IVIG improves the chance of successful pregnancy in women with recurrent miscarriage by using individual patient data from efficacy trials. Detailed information on each patient enrolled in these trials was obtained to evaluate the efficacy of IVIG and investigate the effect of clinical variability on pregnancy outcome. Data from 125 patients in the IVIG group and 115 patients in the placebo group were available for analysis. Although the number of previous miscarriages and female age were both negative prognostic factors for successful outcome, there was no significant improvement in successful pregnancy or live birth rate with IVIG. Subgroup analyses indicated that timing of IVIG administration may be important. The results of the present study highlight the importance of stratification for known confounders, so that the role of IVIG can be evaluated in more detail. The collective evidence thus far indicates that IVIG does not have a therapeutic effect that is clinically meaningful.

Intravenous immunoglobulin in very severe childhood Guillain-Barré syndrome.

To evaluate intravenous immunoglobulin (IVIG) therapy in children with very severe Guilain-Barré syndrome (GBS) with reference to the need for respiratory support, ICU stay and long-term outcome, we studied 33 children with very severe GBS and quadriparesis and/or respiratory muscle weakness admitted to the Pediatric Intensive Care Unit (PICU) of PGIMER, Chandigarh. Cases (n = 22, IVIG group) were enrolled prospectively, and controls (n = 11), similar to cases in age and severity of illness, retrospectively. All children received similar supportive and respiratory care. In addition, cases were given IVIG (Sandoglobulin, Sandoz) 0.4 g/kg bodyweight per day for 5 days. The mean age, duration of symptoms prior to admission and severity of illness in the two groups were similar. In the IVIG group, onset of recovery of muscle power was significantly earlier (day 14.8 (6.8) of illness vs day 20.9 (8.6), p < 0.05) and the length of PICU stay significantly shorter (20.5 (13.0) days vs 50.5 (33.3) days, p < 0.01). Sixteen (72.7%) children in the IVIG group had improved by at least one functional grade after 1 month and 15 (68%) were walking independently after 3 months compared with two (18%) and four (36%) controls, respectively (p < 0.05). The number of children who needed endotracheal intubation and mechanical ventilation and the duration of mechanical ventilation was significantly less in the IVIG-treated group. We conclude that in very severe GBS in children IVIG therapy improves outcome to a remarkable extent, reduces the need for intubation and mechanical ventilation, shortens the length of stay in ICU, and promotes ambulation sooner.

Intravenous Immunoglobulins in Multiple Sclerosis: Results of the Austrian Immunoglobulin in Multiple Sclerosis (AIMS) Trial

Background: Multiple sclerosis (MS) is an autoimmune disorder characterized by inflammatory, demyelinating lesions in the central nervous system. Open studies and experimental evidence suggest beneficial effects of intravenous immunoglobulin (IVIG) by immunomodulating mechanisms and induction of remyelination. Patients and Methods:In this randomized, double-blind, placebo-controlled multicenter trial we tested the efficacy of monthly IVIG in 150 patients with relapsing MS. Primary outcome measures were the effect on clinical disability as measured by the Expanded Disability Status Scale (EDSS), and the proportion of patients with improved, stable or worsened clinical disability (change by ≧?1.0 EDSS point) in each treatment group. Secondary outcome measures included the annual relapse rate and the proportion of relapse-free patients. IVIG was given over 2 years in a monthly dosage of 0.15–0.2 g/kg body weight. Results:As shown by intent-to-treat analysis, the EDSS significantly decreased in the IVIG-treated patients (–0.23 ??0.89) and increased in the placebo-treated patients (+0.12 ??1.07). The difference between both groups was statistically significant (p = 0.008). In the IVIG group 31% of the patients showed improved, 51% stable, and 16% worsened clinical disability. In the placebo group this distribution was 14%, 63% and 23%, respectively (p = 0.041). Annual relapse rates were 0.52 ??0.85 in the IVIG and 1.26 ??2.2 in the placebo group (p = 0.0037). The proportion of relapse-free patients receiving IVIG was 53% vs. 36% of patients in the placebo group (p=0.03). Adverse events occurred in 4% of patients in the IVIG group and in 5% of patients receiving placebo and did not appear to be directly related to the medication. Conclusion:This study demonstrates that monthly IVIG at a dosage of 0.15–0.2 g/kg body weight improves clinical disability and reduces the frequency of relapses without major side effects in relapsing MS.

Neuropsychiatric assessment as a secondary outcome measure in a multiple sclerosis intravenous immunoglobulin L(IMg) trial

Multiple sclerosis (MS) patients often suffer from abnormalities of mood including euphoria, depression, anxiety, pathological laughing and crying (PLC), and psychoses. We assessed neuropsychological functions (NF) as secondary outcome measures in relapsing-remitting multiple sclerosis (RRMS) patients treated by intravenous immunoglobulin (IVIg). Forty RR-MS patients (mean age 34.5±2.4; M : F=8: 32) were randomized to receive either IVIg or placebo in a double-blind trial for 2 years. NF evaluation at baseline, 1 and 2 years included the Goldberg Anxiety and Depression scales, the Brief Psychiatric Rating Scale, the Hamilton Anxiety Scale, the Beck Depression Inventory, and the Mini-Mental State Examination. Baseline anxiety, depression and general psychopathology scores were similar for the IVIg and placebo groups. At 1 and 2 years, anxiety, depression and general psychopathology had decreased similarly in both groups compared with baseline. No significant cognitive changes were observed in either group. In the IVIg group PLC emerged in one patient and one patient developed clinically overt depression necessitating antidepressant treatment. In the placebo group, two patients developed a hypomanic episode, and PLC emerged in two patients. IVIg treatment is safe, according to psychiatric outcome measures, and these measures should be routinely used in RR-MS drug trials.

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Natural History of Selective Antibody Deficiency to Bacterial Polysaccharide Antigens in Children

Children diagnosed with selective antibody deficiency to bacterial polysaccharide antigens over the last 10 years were analyzed in a retrospective study to examine the clinical characteristics and natural history for children with this disease. A total of 120 children aged more than 2 years were diagnosed based on a history of recurrent infections and failure to respond to a majority of serotypes following Streptococcus pneumoniae immunizations. An infectious history included recurrent otitis media (91%), sinusitis (97%), pneumonia (57%), and invasive infection (5%). Immune evaluation revealed 11% with IgA deficiency, 19% with IgG-2 deficiency, and average response to only 35% of S. pneumoniae serotypes. A total of 34 of 120 patients received intravenous immunoglobulin (IVIG) because of recurrent infections despite prophylactic antibiotics. The IVIG group had a greater percentage of abnormal responses to immunization, 73% versus 61% of serotypes tested (p < 0.01). Repeat immune studies after a mean interval of 3.1 years showed 50% of patients developed normal responses. Children with selective antibody deficiency to polysaccharide antigens present with recurrent upper and lower respiratory tract infections, but rarely with invasive disease. Natural history indicates that most patients will normalize their antibody responses to bacterial polysaccharides by age 5 to 6 years, whereas in a subgroup the defect may be permanent.