High Dose IVIG Therapy Research Articles

Multimodality Imaging Features of Orbital Necrobiotic Xantogranuloma: A Case Report and Literature Review

Background: Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans histiocytosis that primarily manifests as skin lesions and is often associated with hematologic disorders, particularly monoclonal gammopathy. The orbit is the most common site of extracutaneous involvement in NXG. Since its first description in 1980, the molecular pathology and dermatologic characteristics of NXG have been extensively studied. However, there is no comprehensive multimodality description of the imaging features of orbital NXG in the literature. This case report aimed to describe the imaging features of NXG and provide a brief overview of the imaging differentials. Patient presentation: A 16-year-old white young man was referred to our center for evaluation of a 6-year history of a slowly growing right orbital mass, which resulted in vision loss in his right eye. His medical history was notable for systemic juvenile rheumatoid arthritis (sJRA) and a gain-of-function (GOF) mutation in the IKAROS gene, which predisposed him to immune dysregulation. To further characterize the orbital lesion, orbital computed tomography (CT), magnetic Resonance Imaging (MRI), and Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging (FDG PET/MRI) were performed. A biopsy of the most hypermetabolic component of the infiltrative retro-orbital mass confirmed the diagnosis of NXG. He received high-dose immunosuppressive and IVIG therapy and bone marrow stem cell transplantation, which resulted in a slight reduction in the right orbital mass. Conclusion: This paper presents the first multimodality imaging features of orbital necrobiotic xanthogranuloma in an adolescent patient.

Eculizumab: A Review in Generalized Myasthenia Gravis

The humanized monoclonal antibody eculizumab (Soliris®) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan. It is the first complement inhibitor to be approved for use in these patients. In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab. Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks. Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.

Retrospective Analysis of the Nephrotoxic and Hemolytic Side Effects of Chronic High Dose IVIG Therapy in Neurologic Disorders (P1.128)

Retrospective Analysis of the Nephrotoxic and Hemolytic Side Effects of Chronic High Dose IVIG Therapy in Neurologic Disorders (P1.128)

Aseptic meningitis complicating immunoglobulin therapy in AIDP

Abstract Introduction A case of aseptic meningitis due to intravenous immunoglobulin is being reported. Aim To learn rare side effect of intravenous immunoglobulin. Case report Intravenous immunoglobulin is a safe therapy in many diseases. Side effects due to IVIG therapy usually are mild. Rarely can it lead to meningitis. We encountered aseptic meningitis in patient with acute inflammatory demyelinating polyneuropathy following IVIG. Results and discussion The incidence of drug-induced aseptic meningitis (DIAM) is unknown. Other drugs that have been associated with DIAM include NSAIDs, ranitidine, carbamazepine, vaccines against hepatitis B and mumps, immunoglobulin, and radiographic agents. Most of the reported cases had ITP as the primary disease or received high dose IVIG therapy. It has rarely been reported in patient with AIDP. Conclusions Recognition of aseptic meningitis as an adverse reaction following IVIG therapy is important as it may be treated effectively.

Selective Exclusion of High Titer Donor Plasma and Immunoadsorption Chromatography As Steps to Reduce Isoagglutinin Titers in IVIG

Hemolysis is a rare but potentially serious complication of high-dose IVIG therapy. Isoagglutinins originating in donor plasma are believed to play a major role in these reactions, but host factors are also important. We determined the effects of excluding plasma from donors with high isoagglutinin titers from the pools used to prepare IVIG, and of specific anti-A/B immunoaffinity chromatography (IAC), on the anti-A and anti-B titers of IVIG products prepared using the process for Privigen/Hizentra.

Catabolism of pemphigus foliaceus autoantibodies by high-dose IVIg therapy

High-dose intravenous immunoglobulin (HD-IVIg) has several distinguishing therapeutic characteristics. However, a certain number of pemphigus cases have been experienced, which did not respond to HD-IVIg. This is the first case report that the serum level of anti-desmoglein (Dsg)1 antibody rebounded, critically associated with IgG serum level. We describe a patient with pemphigus foliaceus (PF), unresponsive to oral prednisolone followed by pulse therapy and double-filtration plasmapheresis, in whom clinical remission was induced by 4 courses of HD-IVIg. Anti-Dsg1 antibody levels, serum IgG and disease activity were monitored. Anti-Dsg1 antibody titers rapidly decreased after IVIg treatment when total IgG levels were high; however, the serum level of anti-Dsg1 antibody rebounded as the total IgG level returned to normal. The levels of anti-Dsg1 antibody were decreased for an average of 13.7 days after treatment. The therapeutic effect of IVIg treatment was associated with an increased serum level of total IgG. IVIg therapy reduced the titers of autoantibody by accelerating the catabolism of immunoglobulin induced by high IgG serum levels. IVIg itself appears to accelerate IgG degradation rather than suppress IgG production. Sufficient suppression of antibody production is critical for successful treatment with IVIg.

Treatment of intractable pulmonary hemorrhage in two patients with childhood systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology with multisystem involvement. A number of pulmonary complications including pleuritis, pneumonitis, infectious pneumonia, and pulmonary hemorrhage, have been reported in patients with SLE. Pulmonary hemorrhage is a major life-threatening manifestation in children and adolescents with SLE. Mycophenolate mofetil is an immunosuppressive agent used in solid organ transplantation, and it may play an increasing role in autoimmune disease. In this report, we present two cases of childhood SLE with recurrent pulmonary hemorrhage, which were unresponsive to treatment with high-dose corticosteroids, cytotoxic therapy, IVIG, plasmaphoresis, and supportive therapy, but responded to IV mycophenolate mofetil. A multimodal therapy including mycophenolate mofetil was effective in treatment of these two children.

HIGH AND LOW DOSE IVIG THERAPY IN GUILLAIN-BARRE SYNDROME CHILDREN: A COMPARISON

Objective: Acute inflammatory demyelinating peripheral neuropathy (Guillain-Barre-Syndrome) is by far the most common cause of immune-medicated peripheral nervous system disease in children; with the near disappearance of poliomyelitis, GBS is responsible for the great majority of cases of acute flaccid paralysis. So far, in several controlled studies, corticosteroids, plasmapheresis and IVIG have been utilized in pediatric patients, afflicted with GBS. Regarding IVIG therapy, two methods have been used; the high dose (1 gr/kg/day for 2 days), and the low dose (400mg/kg/day for 5 days). Review of literature shows that a faster rate of recovery can be accomplished in patients who receive total dose of IVIG in 2 days as compared to the dose being given over 5 days. Materials & Methods: In this study we have compared these two types of treatment in an investigation, conducted in the Mofid Children Hospital on pediatric patients who had sudden onset of acute flaccid paralysis, and were diagnosed as having GBS. Based on histories, physical examination and electrodiagnosis, subjects were divided in two groups, the high dose IVIG treatment, 1gr/kg/day for 2 days (experimental group), and the low dose IVIG treatment, 400 mg/kg/day for 5 days (control group). Statistical analyses were then carried out using the appropriate software. Results: Result of this study showed a faster rate of recovery for patients in the high dose IVIG group; in this group duration of weakness of limbs was shorter and returning of DTR was faster than in controls. In fact, in this type of treatment, the relationship between high dose IVIG therapy and drug side effects was not significant. Conclusion: Base upon the finding in the present study, we conclude that the high dose IVIG therapy is superior to low dose, in view of faster duration of recovery and shorter hospital stay. Also we may infer that shorter hospital stay could be a factor in reducing of more nasocomial infection. In conclusion, we suggest using high dose IVIG treatment of choice in GBS. Keywords: Gulliain Barre Syndrome-High dose, Low dose IVIGcomparison of two types of treatment

High-Dose IVIG Therapy in a Child With Idiopathic Thrombocytopenic Purpura Associated With Mumps

High-Dose IVIG Therapy in a Child With Idiopathic Thrombocytopenic Purpura Associated With Mumps

Case report: exacerbation of hemolytic anemia requiring multiple incompatible RBC transfusions

Abstract RBC transfusions in a patient with a history of autoimmune hemolytic anemia (AIHA) can represent both a laboratory and a clinical challenge. The development of high-titer low-avidity antibodies and antibodies to high-frequency antigens may further impair the ability to identify compatible donor RBCs. Not infrequently, incompatible RBCs must be used and the desire to increase oxygen carrying capacity conflicts with the desire to avoid exacerbating the autoimmune hemolytic process with RBC transfusions. A 66-year-old Caucasian female with coronary artery disease and a history of refractory AIHA had recently developed anemia and required multiple RBC transfusions. The patient had maintained adequate RBC counts with erythropoietin and prednisone therapy for the previous 16 months. With the recent worsening of her hemolytic anemia, she had developed angina that was treated with RBC transfusions in an outpatient setting. However, her angina increased as her RBC counts decreased, leading to hospital admission for further management of her hemolytic anemia and angina. She subsequently required multiple incompatbile RBC transfusions despite increased prednisone therapy and did not improve until after coronary artery stent placement and high dose IVIG therapy. This case demonstrates the usefulness of early patient phenotyping in a case of accelerating hemolytic anemia to aid in donor RBC selection, the value of communicating with clinicians and the patient regarding the use of least-incompatible RBCs, and the importance of optimizing the patient’s clinical condition to avoid ischemia. In addition, it demonstrates the value of repeated attempts with IVIG treatment despite previous refractoriness to this treatment.

ANTI‐SULFATIDE IgM ANTIBODIES DETECTED IN A PATIENT DIAGNOSIS OF MOTOR NEURON DISEASE

D'Avino C., Del Corona A., Bacci A., Calabrese R., Siciliano G.Department of Neuroscience‐Clinical Neurology‐University of Pisa‐Italy Case report. The patient, a 66‐year‐old man with a 5‐year diagnosis of diabetes mellitus, in Sep. 2000 started complaining of language disturbances as rhinolalia. In Jan. 2001, because of generalized fatigue and difficulties in walking, he was hospitalized in Internal Medicine and a diagnosis of diabetic angiopathy and neuropathy was made. Since discharge patient clinical conditions gradually deteriorated and a neurological evaluation showed tongue atrophy, dysarthria, dysphagia, fasciculations in the four limbs, increased deep tendon reflexes with bilateral foot clonus and paraparetic spastic deambulation. He underwent spinal MRI that showed mild arthrosic abnormalities in cervical spinal cord and limb EMG that showed denervation spontaneous activity with neurogenic MUAP modifications, with normal sensory and motor conduction velocity. MEP showed bilateral pyramidal track involvement. A significantly increased anti‐sulphatide IgM antibodies titer (1:32,000) in the serum was detected. The diagnosis at discharge was “probable motor neuron disease” and the patient is under riluzole therapy at the moment. Discussion. Anti‐sulfatide IgM antibodies are currently associated with several subtypes of peripheral neuropathy. In most cases it is a chronic dysimmune sensory or sensorimotor neuropathy in which electrophysiological and morphological studies are usually con‐ sistent with a predominant demyelination frequently associated with prominent axonal loss. Although rare, an association between motor neuron disease and IgM anti‐sulfatide has been described in a recent paper by Latov and coworkers that reviewed electrophysiologic, morphologic and laboratory data of 25 patients with elevated antisulfatide antibodies. It seems interesting to follow‐up the clinical course of the patient, the response to therapy and its correlation to antibodies titer, while the opportunity of high dose IVIg therapy is under discussion at the moment.

Human intravenous immunoglobulin in primary and secondary antibody deficiencies.

IVIG is of value in patients with primary and secondary antibody deficiencies. High dose IVIG therapy is usually the treatment of choice for patients with primary antibody deficiency disease. Sufficient IVIG should be given to maintain IgG trough levels of > 500 mg/dl; this usually requires a dose of 400 to 500 mg/kg/month. Adverse side effects to IVIG has been described; the two most common serious side effects are hepatitis C and aseptic meningitis. New procedures to inactivate hepatitis C (and other viruses) are now in place. Aseptic meningitis is usually associated with high IVIG doses given rapidly to patients with autoimmune and inflammatory disease; its cause is not known. Subcutaneous infusions of IG or IVIG at weekly intervals has been shown to be clinically efficacious, well-tolerated and a less expensive alternative to monthly IVIG infusions. IVIG has been used with encouraging results in selected pediatric patients with HIV infection. The benefit is primarily in patients with CD4 counts > 200 cells/mm2 who receive no P. carinii pneumonia prophylaxis. IVIG may also be of value in preventing or ameliorating infection in other secondary antibody deficiencies including patients with malignancies; patients with protein-losing enteropathy and nephrotic syndrome; severely ill care patients with shock, trauma or surgery; premature infants and patients undergoing transplantation procedures; and severely burned patients. Guidelines for selecting patients for IVIG are offered.

Improvement of Histological and Immunological Change in Steroid and Immunosuppressive Drug-Resistant Lupus nephritis by High-Dose Intravenous Gamma Globulin

From July 1984 to December 1987, 9 patients with lupus nephritis did not respond to the administration of two courses of methylprednisolone pulse therapy and cyclophosphamide treatment for 56 days. Therefore, high-dose intravenous human gamma-globulin (IVIG) was administrated. Before IVIG therapy, renal biopsy showed class IV lupus nephritis in 5 cases, class V in 2 cases, and class IV with V in 2 cases. Immunofluorescence of the renal biopsy showed heavy IgG deposits along the glomerular capillary walls. These heavy glomerular IgG deposits were dissociated after in vitro incubation of the cryostat kidney sections with plasmin-treated, PEG-treated, sulfonated human gamma-globulin and a human Fc fragment, as evidenced by a dramatic decrease or even absence of fluorescent intensity. After high-dose IVIG treatment, 3 out of 5 cases of class IV lupus nephritis had a good response with decreased proteinuria and creatinine; serum C3, C4 levels and CH50 hemolytic activity also increased. The glomerular IgG deposits decreased in the follow-up biopsy. Pathologically, 2 of them transformed into class IIb. The capacity to synthesize immunoglobulin after pokeweed mitogen stimulation was reduced and the circulating immune complexes (CIC) lowered after high-dose IVIG treatment. In the others there was partial response. These clinical and immunological improvements after high-dose IVIG therapy are probably related to the modulation of macrophage-T cell function and enhancement of suppressor T cell function. The toxicity of high dose IVIG was minimal, but the cost is high, search for an optimal dosage is warranted.

Results of a prospective controlled two-dose crossover study with intravenous immunoglobulin and comparison (retrospective) with plasma treatment

Results of a two-dose (150 vs 500 mg/kg/month) crossover study with intravenous immunoglobulin (Endobulin, Immuno) (IVIG) carried out on 12 children with primary immunodeficiency syndromes over a period of 2 years are reported. Eight children had received human plasma (20 mg/kg/month) during the 2 years prior to the IVIG study. As these children had been thoroughly monitored during plasma treatment, a retrospective analysis of these data allowed for comparison with IVIG treatment. Children on low-dose IVIG therapy had significantly ( P < 0.01) fewer days with clinical illness, e.g., sinusitis, pneumonia, diarrhea, and arthritis, than did those receiving plasma treatment. High-dose IVIG therapy led to further significant clinical improvement. Lung function tests (MEF 25) improved significantly as well. The difference between high- and low-dose therapy with respect to the improvement in clinical symptoms (e.g., cold, fever, otitis) was more pronounced in children with severe clinical symptoms at the initiation of the study. Children with fewer symptoms did comparably well on high- and low-dose treatment, except for those with acute febrile illness, which was less frequent in children on high-dose IVIG. Regular monitoring of liver enzymes in the group of patients on IVIG therapy gave no indication of the transmission of viral hepatitis in the course of the 2-year IVIG treatment.

1003 SUCCESSFUL TREATMENT OF AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) IN COMMON VARIABLE IMMUNODEFICIENCY (CVID) WITH HIGH-DOSE INTRAVENOUS IMMUNE SLOBULIN (IVIS)

Standard therapy for AIHA with steroids, cytotoxic agents and/or splenectomy carries an even greater risk than in normals for patients with primary immunodeficiency. Because of the success of high dose IVIG therapy in immune thrombocytopenia, we treated a male with CVID and AIHA with large doses of a pH 4.0 IVIG preparation as a potentially effective means of therapy. A diagnosis of CVID (IgG 330, IgA 4, IgM 24 mg/dl) had been made at age 18 years following a history of chronic sinopulmonary disease and splenomegaly, and he was begun on I.M. gamma globulin at 100 mg/kg/mo at that time. He had no hematologic abnormalities until age 21 when he presented with acute AIHA (hgb 5.3 g/dl, haptoglobin <5 mg/dl and a 4 + positive direct Coombs). After 60 mg/d of prednisone for 2 months, his hgb rose to 12.8 and his haptoglobin to 50 mg/dl. However, his Coombs test remained 4 + positive for IgG antibody and his retic ct. was 9.7. Steroids were discontinued and therapy with 450 mg/kg IVIG was initiated and continued daily for 5 days; He was then given 100-200 mg/kg of IVIG at 4 week intervals. During this period, his hgb ranged from 12.5-14 g/dl and his retic ct. dropped to 0.5-2.3. After 7 months of IVIG therapy, his hgb is 12.6 g/dl, retic ct. 1.6%, haptoglobin 147 mg/dl and Coombs test negative. These observations provide strong support for the use of high dose IVIG in immunodeficient patients with AIHA. It is safe and a mere modification of standard replacement therapy for humoral immunodeficiency.

INHIBITION OF 125I-C3 UPTAKE ANH HEMOLYTIC COMPLEMENT ACTIVITY BY IV IgG

Recent studies suggest that IgG is a particularly good acceptor for nascent C3b. We used therapeutic immune serum globulin (ISG) preparations to determine if excess IgG would compete for deposition of C3b onto activators such as antibody sensitized sheep erythrocytes (EA) and decrease hemolytic activity. Both im and iv forms of ISG inhibited uptake of 125I-C3 onto EA with C6 or C8 deficient sera as sources of early complement components. 125I-C3 uptake was inhibited 50% at 10-20 mg/ml of im ISG and 20-30 mg/ml of iv ISG (Cutter). Similar concentrations of ISG also inhibited 125I-C3 uptake onto preformed EAC 14 with the deficient sera or with purified C2. IV and im ISG inhibited hemolytic activity of whole serum with EA and of purified C3 with EAC 14 and purified components, but the concentrations necessary for 50% inhibition of the hemolytic assays were much lower. These effects of IgG were specific since addition of human serum albumin at equivalent concentrations did not inhibit any of the assays. Using ISG fractionated by gel filtration, we verified that the inhibition of hemolytic activity was due to monomeric IgG rather than aggregates. These results suggest that inhibition of C3 uptake onto particles can occur at the elevated serum IgG levels achieved during high dose IVIG therapy. Diminished uptake of C3 onto sensizitzed platelets could contribute to the efficacy of high dose IVIG in ITP.