Combination Of Intravenous Immunoglobulin Research Articles

Clinical outcome in patients with chronic antibody-mediated rejection treated with and without rituximab and intravenous immunoglobulin combination therapy

We previously reported that rituximab (RTX) and intravenous immunoglobulin (IVIg) combination therapy (RIT) is effective in treating patients with chronic active antibody-mediated rejection (CAMR), and the proteinuria level can determine the response to RIT. However, the results were not compared to those of patients who did not receive RIT. Fifty-nine patients with CAMR were divided into 2 groups: an RIT treated group (n=25) and a historic control (HC) group who had not received RIT (n=29). The RIT group was treated with RTX (375mg/m2) and IVIg (0.4g/kg) for 4days. We compared the decline in glomerular filtration rate/month (ΔeGFR), RIT-related complications, and allograft survival rate in both groups. We also compared the allograft survival rate between patients with high proteinuria (spot urine protein/creatinine [PC] ratio >3.5g/g) and low proteinuria (PC ratio <3.5g/g). ΔeGFR was significantly decreased in the RIT group compared with the HC group after 6months (P<0.05). No serious complications were associated with RIT, and only one case of herpes zoster infection developed. The overall allograft survival rate in the RIT group was significantly higher than in the HC group. In both groups, patients with low proteinuria survived better than patients with heavy proteinuria (P<0.05). The allograft survival rate was greater in the high proteinuria RIT group than that in the HC group. RIT treatment is recommended for delaying the progression of CAMR without serious complications, and is not limited by the presence of heavy proteinuria.

Clinical outcomes of initial dexamethasone treatment combined with a single high dose of intravenous immunoglobulin for primary treatment of Kawasaki disease.

PurposeTo investigate the clinical effects of a single high dose intravenous immunoglobulin (IVIG) combined with initial dexamethasone as a primary treatment on Kawasaki disease (KD).Materials and MethodsBetween January 2008 and December 2010, we reviewed the medical records of 216 patients with complete KD patients that were admitted to a single medical center. 106 patients were treated with a single high dose of IVIG (2 g/kg) alone and 110 patients received IVIG and dexamethasone (0.3 mg/kg per day for three days).ResultsThe combined IVIG plus dexamethasone patient group had a significantly shorter febrile period and duration of hospital stay (1.4±0.7 days vs. 2.0±1.2 days, p<0.001; 5.8±1.7 days vs. 6.9±2.5 days, p<0.001, respectively) than the IVIG alone group. The combined IVIG plus dexamethasone group required IVIG retreatment significantly less than the IVIG only group (12.7% vs. 32%, p=0.003). After completion of the initial IVIG, C-reactive protein levels in the combined IVIG plus dexamethasone group were significantly lower than those in the IVIG only group (2.7±4.0 mg/dL vs. 4.6±8.7 mg/dL, p=0.03). In the combined IVIG plus dexamethasone group, the incidence of coronary artery lesions tended to be lower without worse outcomes at admission after initial infusion of IVIG and in follow-up at two months; however, the differences were not significant (8.2% vs. 11.3%, p=0.22; 0.9% vs. 2.8%, p=0.29).ConclusionInitial combined therapy with dexamethasone and a single high-dose of IVIG resulted in an improved clinical course, in particular a shorter febrile period, less IVIG retreatment, and shorter hospital stay without worse coronary outcomes.

Intravenous Immunoglobulin Therapy for Persistent Pemphigoid Gestationis with Steroid Induced Iatrogenic Cushing's Syndrome

Dear Editor: A 30-year-old woman developed pemphigoid gestationis (PG) after 20 weeks of gestation during her first pregnancy. Initially, she was treated with prednisone (10~30 mg/d), but she had a miscarriage in the 26th week of pregnancy. After the miscarriage, she was treated with prednisone (30~40 mg/d) and azathioprine (100 mg/d). However, her PG did not show clinical remission and new blisters continued to develop until the 12th post-partum week. Therefore, she was referred to our clinic for further treatment. She had erythematous patches, plaques and tense bullae on both the upper extremities and trunk (Fig. 1A). Histopathological examination of the skin samples showed the presence of subepidermal vesicles with perivascular lymphocytes and eosinophils (Fig. 2A, B). Direct immunofluorescence examination revealed positive, linear deposition of IgG and C3 in the basement membrane zone (Fig. 2C, D). Therefore, we confirmed the diagnosis of PG and started her on high-dose systemic corticosteroids; however, after receiving the treatment, she rapidly gained weight and developed moon face. Therefore, we performed a rapid adrenocorticotropic hormone stimulation test and measured her 24-hour urine cortisol level; on the basis of the test results, she was diagnosed with iatrogenic Cushing's syndrome. Therefore, she was started on prednisone (40~60 mg/d) and azathiprine (100 mg/d), but the symptoms persisted. After considering further treatment options, we decided to administer intravenous immunoglobulin (IVIG) therapy at a dose of 0.5 g kg-1 day-1 for 2 consecutive days. Fig. 1 (A) Large tense bullae and erythematous pruritic plaques on the arm. (B) Improved skin lesions with postinflammatory hyperpigmentation after intravenous immunoglobulin combination treatment. Fig. 2 (A) Subepidermal blister with superficial inflammatory infiltrate. (B) Superficial perivascular lymphohistiocytic infiltration, with moderate infiltration of eosinophils. Linear staining for (C) IgG, (D) C3 at the basement membrane zone. (A) H&E, ... After receiving the IVIG therapy, her skin lesions quickly subsided (Fig. 1B), so prednisone was tapered down to 10 mg/day. She was also administered a steroid at a low dose for 8 weeks for treating her Cushing's syndrome. At the follow-up after 3 months, no lesions were found on the patient. PG is a rare autoimmune-mediated blistering disease, usually occurring in the late pregnancy and immediate postpartum period. Many patients experience spontaneous resolution during the latter part of gestation only to experience a flare at the time of delivery. However, the persistence of disease activity for many years postpartum has been reported. Numerous immunosuppressive treatments have been reported for PG1. If the disease persists, treatment options are limited because they have potential side-effects, e.g. development of Cushing's syndrome, as seen in our patient. IVIG has been used to treat various autoimmune blistering diseases2. Many authors reported the use of IVIG for treating PG. The immunomodulatory actions of IVIG are mediated via several immune-mediated mechanisms, such as complement blockade and degradation, Fc receptor blockade and induction of immunomodulatory Fc receptors, inhibition of B cells, and alteration of T-cell function, cytokine modulation, and cellular migration3. IVIG therapy is relatively safe, and severe adverse events associated with the use of IVIG are rare. Headache and acute cutaneous reactions are the most common adverse effects of the therapy, while renal failure, thromboembolic events, and anaphylaxis have rarely been reported in association with IVIG therapy3. It is difficult to differentiate refractory PG from epidermolysis bullosa acquisita using only clinical, histological and direct immunofluorescence findings. Therefore, the findings of enzyme-linked immunosorbent assay and indirect immunofluorescence performed on sodium chloride-split skin are helpful in the differentiation4. We confirmed the diagnosis of PG in the case of our patient, as PG manifests itself during pregnancy, moreover, the patient achieved remission after one-cycle treatment2,3. PG is a rare disease and only 4 cases of PG treated with IVIG have been reported to date. We presented a case of persistent PG treated with IVIG combination therapy. IVIG should be considered as a therapeutic option in patients that fail to respond to conventional immunosuppressive treatment.

Current Issues in the Treatment of Chronic Antibody-Mediated Rejection in Kidney Transplantation

Circulating alloantibodies are found in a substantial number of renal allograft recipients, and can induce chronic allograft injury, which is represented microscopically as transplant glomerulopathy and diffuse C4d deposition in peritubular capillaries (PTCs). Development of these injuries is significantly correlated with late allograft loss, and in this regard, it was included as a new disease entity named chronic antibody-mediated rejection (cAMR) in the updated Banff 05 classification. Usually, the prognosis of cAMR is poor and conventional immunosuppressants mainly targeting T cell-mediated immunity cannot prevent or reverse it. Therefore, some researchers have suggested that therapies directed at the humoral response may be required for the treatment of cAMR. Recently, some reports have suggested that the combined use of rituximab and intravenous immunoglobulin (IVIg) therapy may be useful for the treatment of cAMR. Our previous study also showed that rituximab and IVIg combination therapy effectively delayed the progression of cAMR. We administered rituximab and IVIg combination therapy to 18 biopsy-proven cAMR patients and found that it significantly slowed the decline of the estimated glomerular filtration rate. However, this effect was limited in patients with heavy proteinuria, and dissipated in all patients by 1 year post-treatment. Recently, new drugs targeting the humoral immune system, such as bortezomib and eculizumab, have been tested for the treatment of cAMR. However, the studies still lack definitive data in terms of successful treatment of cAMR. We speculate that those therapies will compensate for the limitation of previous anti-humoral therapies for cAMR.

Research in Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN): a network of specialist TEN centres is needed to undertake effective clinical studies and therapeutic trials

ORIGINAL ARTICLE, p 1304 When a case of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) presents, a management plan must be instigated immediately. Along with discontinuation of the culprit drug, institution of optimal supportive care is mandatory. Specialist dermatology nursing, local treatment of skin and mucous membranes, fluid replacement, nutrition and analgesia are all essential to improve the chances of survival and minimize sequelae. However, dermatologists are also prompted to consider prescribing active therapy in an attempt to ‘switch off’ keratinocyte apoptosis and limit the extension of skin involvement. Over the past 15 years, intravenous immunoglobulin (IVIg) has been used to this end, and many papers have been published indicating efficacy. However, in 2012 Huang et al.1 published a systematic review and meta‐analysis of all studies using IVIg in the treatment of SJS/TEN and concluded that the evidence does not support unambiguous therapeutic benefit. In the current issue of the BJD, Lee et al.2 have presented the outcome of 64 patients with SJS/TEN treated with IVIg in one specialist centre. This is a retrospective analysis using SCORTEN (a validated severity‐of‐illness score) at presentation to predict patient mortality. All 64 patients received IVIg in combination with a standardized regimen of supportive care. Twenty of 64 patients (31%) died; the standardized mortality rate was 1·10 (95% confidence interval 0·62–1·58), indicating that, in keeping with the conclusions of Huang et al.,1 IVIg does not appear to confer a survival benefit in TEN and may in fact be harmful. In previous studies authors have argued that the benefit of IVIg is achieved using higher doses; in the study by Lee et al.2 there was no mortality difference between patients when stratified for high dosage (≥ 3 g kg−1) vs. low dosage (< 3 g kg−1). The study's conclusion was that IVIg does not produce a survival benefit in SJS/TEN. Despite the findings from the study of Lee et al., and the conclusions from the meta‐analysis by Huang et al., we suspect that many dermatologists will continue to prescribe IVIg.

Guilain-Barre' Syndrome (GBS) Post Adult Cord Blood Transplantation In a Patient With Chronic Lymphocytic Leukemia (CLL)

Immune mediated demyelinating disease after allogeneic stem cell transplantation is a rare entity with unclear etiology. Acute inflammatory demyelinating polyneuropathy (AIDP) has been reported post related and unrelated allogeneic stem cell transplantation but no such case has been reported post unrelated cord blood transplantation. We hereby present the first case of GBS post double umbilical cord blood transplantation (DUCBT).A 55 year old male with relapsed refractory CLL received DUCBT with two 5/6 matched cord units (antigen level HLA-A, HLA-B and allele level HLA-DRB1) with fludarabine, cytoxan and total body irradiation based reduced intensity conditioning regimen. Graft versus host disease (GVHD) prophylaxis was with cyclosporine and mycophenolate. Early post transplant course was complicated by grade 4 acute GVHD of the gut with a complete resolution with steroid therapy and successful taper of all immunosuppression by day 180. 7 months post transplantation, patient presented with skin rash and tingling in both feet that progressed rapidly to lower extremity paralysis over the course of 2 days. Physical exam showed macula-papular rash affecting his upper extremities, upper chest and back area. Neurologic exam was significant for motor weakness in lower extremities 2/5, plantar flexion and knee flexion 3/5. He had loss of deep tendon reflexes in both lower extremities (Achilles and Patellar) and upper extremities (biceps and triceps).Workup revealed normal blood counts, organ function, vitamin B12, folate, TSH level, free cortisol. Serum electrophoresis and immunfixation was also normal. Magnetic resonance imaging of the central nervous system showed mild neural foramina narrowing at the L4-L5 level. Serology for Lyme disease, Epstein Bar virus (EBV), syphilis, cytomegalo virus (CMV), Hepatitis, HIV, toxoplasma, enterovirus and human herpes virus 6 was negative. Blood tests for autoimmune markers including (anti-nuclear antibody)ANA, acetylcholine esterase and volted calcium channel antibodies were normal. A lumbar puncture was performed and showed a high protein level of 67mg/dl, 1 nucleated cell/mm3 and normal glucose level. Cerebrospinal fluid was negative for oligoclonal bands, West Nile virus, cryptosporidium, HHV6, herpes virus 1 and 2, gram stain and cultures. Nerve conduction studies and needle electormyegraphy was suggestive of acute demyelinating polyneuropathy.Based on the above workup, he was diagnosed with GBS and started on therapy with intravenous immunoglobulin at 0.5gm/kg for 4 days and prednisone 1mg/kg daily for the treatment of GVHD. Etiology of GBS was presumed to be related to GVHD as his workup was negative for campylobacter, HIV and CMV. He improved significantly over the next 4 weeks and became ambulatory without assistance but his weakness symptoms relapsed as his prednisone was tapered. Prednisone was increased again to 1mg/kg and sirolimus was started. Patient was successfully tapered of prednisone and remains fully ambulatory without assistance or evidence of GVHD on single agent sirolimus 13 months post DUCBT.This is the first case of autoimmune demyelinating polyneuropathy post DUCBT with association of GVHD that was managed successfully with a combination of intravenous immunoglobulins, steroids and sirolimus. Disclosures:No relevant conflicts of interest to declare.

FIRST USE OF ALEMTUZUMAB IN BALO CONCENTRIC SCLEROSIS: A CASE REPORT

We describe an unsuccessful treatment of Balo concentric sclerosis (BCS), review the current evidence directing therapy, and propose next steps for exploring this rare and commonly fatal condition.Case ReportA 52–year–old...

Combination of intravenous immunoglobulins and lenalidomide in the treatment of scleromyxedema

Combination of intravenous immunoglobulins and lenalidomide in the treatment of scleromyxedema

Defining the Benefits of Desensitization Therapy

Defining the Benefits of Desensitization Therapy

32. Contribution of far-field potentials on motor unit number estimation (MUNE)

and chronic inflammatory demyelinating polyneuropathy (CIDP). Case report: A 78-year-old man presented with a 2-week history of ataxia, progressive weakness, and numbness of both hands and feet. His weakness was such that he was unable to ambulate. He has a history of well-controlled diabetes and refractory Crohn’s disease treated with infliximab for 1 year. He had marked distal muscles and mild proximal muscles weakness. He was areflexic throughout and had loss of proprioception below his wrists and knees with preservation of pain sensation. Initial nerve conduction studies (NCSs) of the median, ulnar, peroneal, and tibial motor nerves showed markedly prolonged distal latencies, decreased amplitudes, temporal dispersion, and absent F waves. His sensory NCSs were unresponsive. It was concluded that his CIDP was secondary to infliximab after ruling out other causes. He received intravenous (IV) Solu-Medrol 1 g daily for 3 days and IV immunoglobulin (IVIg) for 5 days with marked improvement. NCSs 6 weeks later showed shortened latencies, shortened F waves, and increased amplitudes. Conclusion: Infliximab is a TNF-alpha inhibitor used in the treatment of Crohn’s disease. It has been rarely linked to MS and CIDP. In this report the patient achieved significant clinical and electrodiagnostic improvement with a combination of IVIg and Solu-Medrol treatment.

87. Pancreatic cancer presents with bilateral lumbar plexopathy

and chronic inflammatory demyelinating polyneuropathy (CIDP). Case report: A 78-year-old man presented with a 2-week history of ataxia, progressive weakness, and numbness of both hands and feet. His weakness was such that he was unable to ambulate. He has a history of well-controlled diabetes and refractory Crohn’s disease treated with infliximab for 1 year. He had marked distal muscles and mild proximal muscles weakness. He was areflexic throughout and had loss of proprioception below his wrists and knees with preservation of pain sensation. Initial nerve conduction studies (NCSs) of the median, ulnar, peroneal, and tibial motor nerves showed markedly prolonged distal latencies, decreased amplitudes, temporal dispersion, and absent F waves. His sensory NCSs were unresponsive. It was concluded that his CIDP was secondary to infliximab after ruling out other causes. He received intravenous (IV) Solu-Medrol 1 g daily for 3 days and IV immunoglobulin (IVIg) for 5 days with marked improvement. NCSs 6 weeks later showed shortened latencies, shortened F waves, and increased amplitudes. Conclusion: Infliximab is a TNF-alpha inhibitor used in the treatment of Crohn’s disease. It has been rarely linked to MS and CIDP. In this report the patient achieved significant clinical and electrodiagnostic improvement with a combination of IVIg and Solu-Medrol treatment.

High-dose Intravenous Immunoglobulin Treatment Increases Regulatory T Cells in Patients with Eosinophilic Granulomatosis with Polyangiitis

We studied the effects of intravenous immunoglobulin (IVIG) treatment on clinical symptoms and regulatory T (Treg) cell frequency in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Twenty-two EGPA patients with severe mononeuritis multiplex or cardiac dysfunction received IVIG therapy combined with conventional therapy (corticosteroid, immunosuppressants, or both). As a control, 24 EGPA patients without severe vasculitic symptoms were treated with conventional therapy. Before, during, and after treatment, we determined percentages of Treg cells and other relevant cells in patients' peripheral blood. The frequency of CD25+ among CD4+ T cells was lower at onset in the study group than in controls but increased significantly after IVIG treatment, relative to controls. The frequency of CD25+ among CD4+ T cells correlated with the frequency of FOXP3+ among CD4+ T cells and interleukin 10 produced by CD25+CD4+ T cells. The increase in Treg cells seen with the combination of IVIG and conventional therapy may promote remission in EGPA.

Single versus multiple dose intravenous immunoglobulin in combination with LED phototherapy in the treatment of ABO hemolytic disease in neonates

Intravenous immunoglobulin (IVIG) has been found to decrease hemolysis in neonatal jaundice due to blood group incompatibility, but a consensus on its usage has not been reached. We conducted a study to compare single versus multiple dose of IVIG in combination with light emitting diode (LED) phototherapy in patients with neonatal jaundice secondary to ABO blood incompatibility, and compared the efficacy of these treatments with that in a group of patients who received LED phototherapy solely. Thirty-nine term neonates with ABO blood group incompatibility were enrolled in the study. Group I received one dose of IVIG (1 g/kg) and LED phototherapy, and group II two doses of IVIG (1 g/kg) and LED phototherapy, whereas group III received LED phototherapy only. In group I, exchange transfusion was performed in one patient (6%) and in group II in one patient (10%). In the control group, none of the patients required exchange transfusion. Duration of LED phototherapy was 4.3 ± 0.7 days in group I + II (IVIG group), 3.9 ± 0.6 days in group III (P = 0.06). Lowest hematocrit level in group I + II was 35.0 ± 7.8 and group III was 38.9 ± 4.2, this was statistically significant (P = 0.034). IVIG therapy, single or multiple, did not affect exchange transfusion, need of erythrocyte transfusion and hospitalization time when used in combination with LED phototherapy in the treatment of ABO hemolytic jaundice in neonates.

Prediction of the fetal status in noninvasive management of alloimmune thrombocytopenia

AbstractFetal/neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia in the fetus and in an otherwise healthy newborn. To counter the consequences of severe fetal thrombocytopenia, antenatal therapies have been implemented. Predictive parameters for fetal severe thrombocytopenia are important for the development of noninvasive strategy and tailored intervention. We report here data concerning 239 pregnancies in 75 HPA-1bb women. Analysis of the index cases (diagnosis of fetal/neonatal alloimmune thrombocytopenia) did not show any significant correlation between the severity of the disease and the maternal genetic background (ABO blood group and HLA-DRB3 allele). Subsequent pregnancies were managed, and therapy effectiveness was evaluated. The highest mean newborn platelet count was observed for a combination of intravenous immunoglobulin and steroids (135 × 109/L; 54 newborns) compared with intravenous immunoglobulin alone (89 × 109/L; 27 newborns). The maternal anti-HPA-1a antibody concentration measured before any treatment and before 28 weeks of gestation was predictive of the fetal status. The weighted areas under curves of the maternal alloantibody concentrations were predictive of therapy response. To conclude, this large retrospective survey gives new insights on maternal predictive parameters for fetal status and therapy effectiveness allowing noninvasive strategies.

Analysis of prognostic factors and efficacy of plasmapheresis in the treatment of myasthenia crisis

To examine the prognostic factors and efficacy of myasthenia gravis (MG) in crisis on plasmapheresis and detect the reasons for ineffective plasmapheresis. The investigators analyzed a total of 69 MG patients in crisis on plasmapheresis by case control study. Gender, age at onset of myasthenic symptoms, duration between the onset of crisis and plasmapheresis, pre-therapeutic use of glucocorticoids, pulmonary infections, other complications, nutritional status, history of thymectomy in 48 hours before crisis, thymic pathology, combined intravenous immunoglobulin (IVIG) and total sessions of plasmapheresis were measured retrospectively. Univariate analysis showed that pulmonary infections (P = 0.000, OR = 29.250), history of thymectomy in 48 hours before crisis (P = 0.046, OR = 0.267), combined intravenous immunoglobulin (P = 0.003, OR = 0.136) and total sessions of plasmapheresis (P = 0.022, OR = 0.498) were all influencing factors of plasmapheresis. However the analysis of multivariate logistic regression revealed that pulmonary infections (P = 0.000, OR = 23.600) was an independent risk factor and combined intravenous immunoglobulin (P = 0.047, OR = 0.192) was an independent protection factor of plasmapheresis. Plasmapheresis is ineffective in MG crisis with pulmonary infections. Control of pulmonary infections and combined intravenous immunoglobulin can improve the response to plasmapheresis in patients with MG crisis.

Non-Invasive Management of Alloimmune Thrombocytopenia: Prediction of the Fetal Status.

AbstractAbstract 3690Fetal/neonatal alloimmune thrombocytopenia (F/NAIT) is the most common cause of severe thrombocytopenia in the fetus and the newborn in maternity wards. To counter the bleeding consequences of severe fetal thrombocytopenia, antenatal therapies have been implemented for subsequent pregnancies with incompatible fetuses. Predictive parameters for fetal severe thrombocytopenia are important for the development of non-invasive strategy and tailored intervention. We report here data concerning 67 HPA-1bb women with 81 managed pregnancies with IVIG. In 51% of the cases, the diagnosis of F/NAIT was made during the first gestation, following an intracranial haemorrhage (ICH) in 8 cases (12%). Severe thrombocytopenia was recorded for 88% of the newborn. Analysis of the index cases did not show any correlation between the severity of the disease and the maternal genetic background (ABO group and HLA-DRB3 allele). Subsequent pregnancies were managed and therapy effectiveness was evaluated. The highest mean newborn plt count was observed for a combination of intravenous immunoglobulin (IVIG) and corticoids (135.109/L; 54 newborn), in comparison with IVIG alone (89.109/L; 27 newborn). No ICH was recorded in these 2 groups. The maternal anti HPA-1a antibody concentration measured before any treatment and before 28 weeks of gestation was predictive of the fetal status: a high antibody concentration (≥28 International Units/mL) was correlated with a severe thrombocytopenia of the fetus (p=0.0016). Follow-up of the antibody concentrations during 34 pregnancies with antenatal management allowed demonstrating for the first time that the areas under curves (AUC) weighted by the weeks of gestation were a predictive parameter of therapy failure. The weighted AUC was significantly higher for women who delivered severely thrombocytopenic newborn than newborn with platelet count above 50.109/L (p=0.0107). To conclude, this large retrospective survey gives new insights on maternal predictive parameters for fetal status and therapy effectiveness allowing non-invasive strategies. Disclosures:No relevant conflicts of interest to declare.

Clinical applications of intravenous immunoglobulins (IVIg) – beyond immunodeficiencies and neurology

The clinical use of intravenous immunoglobulin (IVIg) has expanded beyond its traditional place in the treatment of patients with primary immunodeficiencies. Due to its multiple anti-inflammatory and immunomodulatory properties, IVIg is used successfully in a wide range of autoimmune and inflammatory conditions. Recognized autoimmune indications include idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, Guillain-Barré syndrome and other autoimmune neuropathies, myasthenia gravis, dermatomyositis and several rare diseases. Several other indications are currently under investigation and require additional studies to establish firmly the benefit of IVIg treatment. Increasing attention is being turned to the use of IVIg in combination with other agents, such as immunosuppressive agents or monoclonal antibodies. For example, recent studies suggest that combination therapy with IVIg and rituximab (an anti-CD20 monoclonal antibody) may be effective for treatment of autoimmune mucocutaneous blistering diseases (AMBDs), with sustained clinical remission. The combination of IVIg and rituximab has also been used in the setting of organ transplantation. Firstly, IVIg +/- rituximab has been administered to highly human leucocyte antigen (HLA)-sensitized patients to reduce anti-HLA antibody levels, thereby allowing transplantation in these patients. Secondly, IVIg in combination with rituximab is effective in the treatment of antibody-mediated rejection following transplantation. Treatment with polyclonal IVIg is a promising adjunctive therapy for severe sepsis and septic shock, but its use remains controversial and further study is needed before it can be recommended routinely. This review covers new developments in these fields and highlights the broad range of potential therapeutic areas in which IVIg may have a clinical impact.

Successful Treatment of Chronic Antibody-Mediated Rejection With IVIG and Rituximab in Pediatric Renal Transplant Recipients

Chronic antibody-mediated rejection (CAMR) of renal allografts has recently been recognized as a defined nosologic entity. The outcome of CAMR is poor; there is no established treatment protocol for this condition. We therefore initiated a pilot study on treatment of CAMR with an antihumoral regimen consisting of high-dose intravenous immunoglobulin (IVIG) and the chimeric anti-CD20 antibody rituximab. Six pediatric renal transplant recipients with CAMR received four weekly doses of IVIG (1 g/kg body weight per dose), followed by a single dose of rituximab (375 mg/m2 body surface area) 1 week after the last IVIG infusion. Renal allograft biopsies were evaluated using the Banff '05 classification. Human leukocyte antigen-specific antibodies were detected by panel-reactive lymphocytotoxicity and solid phase ELISA assays. Median glomerular filtration rate during 6 months before intervention dropped by 25 (range, 11-26) mL/min/1.73 m2 (P<0.05) and increased in response to antihumoral therapy by 21 (-14 to +30) 6 months (P<0.05) and by 19 (-14 to +23) mL/min/1.73 m2 12 months (P=0.063) after start of treatment. Glomerular filtration rate improved or stabilized in 4 patients; the two nonresponders had the highest degree of transplant glomerulopathy, the highest degree of C4d deposition in peritubular capillaries and pronounced interstitial inflammation. The treatment regimen was well tolerated. This pilot study demonstrates that CAMR in pediatric renal transplant recipients can be treated successfully and safely with a combination of IVIG and rituximab. This observation should encourage more extensive studies to evaluate this new treatment strategy.

Successful treatment in pulmonary alveolar proteinosis with the combination of intravenous immunoglobulin and pulse methylprednisolone

Successful treatment in pulmonary alveolar proteinosis with the combination of intravenous immunoglobulin and pulse methylprednisolone

Treatment of neurodegenerative CNS disease in Langerhans cell histiocytosis with a combination of intravenous immunoglobulin and chemotherapy

In rare cases, patients with Langerhans cell histiocytosis (LCH) develop neurodegenerative CNS disease (ND-CNS-LCH). Management of ND-CNS-LCH has not been established. We treated five pediatric patients with a combination of intravenous immunoglobulin (IVIG) and chemotherapy (steroid +/- vinblastine +/- 6-mercaptopurine +/- methotrexate). Prior to the therapy, three of the five patients had cerebellar ataxia while the remaining two had abnormal MRI findings without apparent neurological deficits. IVIG was given monthly or twice monthly at the dosage of 250-400 mg/kg/dose. The four patients administered more than 23 doses of IVIG and chemotherapy remained in a stable condition and did not show significant progression signs in neurological deficits or brain MRI findings during the 30-month follow-up period (median; range: 19+ to 38+) following the initiation of therapy for ND-CNS-LCH. The IVIG-containing treatment may be promising for ND-CNS-LCH; however, its effectiveness remains to be further tested in more patients as well as in a randomized trial.