Bernard Pirofsky

Intravenous immune globulin therapy in hypogammaglobulinemia: A review

An immune globulin preparation specifically modified for intravenous administration has been employed therapeutically in 30 patients with primary immunodeficiency disease. Our results of this long-term study are summarized within three major categories: (1) Levels of serum IgG produced and maintained after intravenously administered serum immune globulin infusions of 100 to 500 mg/kilo. The disappearance pattern of infused IgG is outlined and individual patient variations emphasized. (2) The therapeutic effects of intravenously administered serum immune globulin therapy are reported and related to dosages of intravenously administered serum immune globulin administered and serum levels of IgG maintained. (3) The incidence and nature of detrimental side effects are outlined, and methods to reduce this problem are indicated. It is recommended that patients with primary immunodeficiency be given from 150 to 200 mg/kilo intravenously administered serum immune globulin, every four weeks, as prophylactic therapy to reduce acute infectious complications. A method to establish an optimum therapy for a specific patient is presented.

Individual patient variations in the kinetics of intravenous immune globulin administration

Subjects with primary immunodeficiency received modified immune serum globulin (IGIV) intravenously at various dose levels in long-term therapeutic studies. Therapy was effective and essentially free from adverse reactions. Two pertinent observations were made relating to the attained levels of serum IgG. Over a dose range of 100-225 mg/kg, the serum IgG level directly reflects the dosage administered. Sequential analysis of serum levels of IgG demonstrated three patient populations in 14 subjects receiving 150 mg/kg. The largest group, nine patients, had progressive reduction of serum IgG values compatible with the half-life of the reagent, with a return to the original serum IgG level in four weeks. A second population of four patients had a slower reduction of serum IgG over the four-week period. IgG values were significantly elevated over baseline values at the time of the next due infusion. In one subject serum IgG values varied greatly with rapid drops and elevations unrelated to the infusion.

The prognostic and therapeutic implications of DNA:Anti-DNA immune complexes in systemic lupus erythematosus (SLE)

Serum samples serially obtained from 50 patients with systemic lupus erythematosus (SLE) were studied for antibody to deoxyribonucleic acid (DNA) and circulating DNA:anti-DNA complexes during the active and inactive phases of their disease. The patients were divided into four categories: Group I: six patients without clinical evidence of central nervous system (CNS) or renal involvement. Group II: three patients with CNS lupus. Group III: nine patients with normal urinalyses and glomerular filtration rates, but morphologic evidence of glomerular disease. Group IV: 32 patients with overt lupus nephritis. Elevated anti-DNA levels were observed in 16 of 18 patients (88 per cent) in groups I, II and III during active disease. This persisted in 14 (77 per cent) during remission. DNA:anti-DNA complexes were demonstrated in four of 18 (22 per cent) during active disease and disappeared in all but one patient with progressive disease. In 30 of the 32 patients (94 per cent) in group IV, DNA binding was increased during active disease; this persisted in 21 (70 per cent) despite remission. Complexes were observed in 25 of the patients in group IV (78 per cent) with active disease. In six of these patients, complexes have persisted; two have died, one has progressed to renal failure and the remaining three patients continue to manifest active disease. This study suggests that measurement of DNA:anti-DNA complexes provides a valuable additional index of disease activity and prognosis in SLE.

Prolonged interval high-dose intravenous immunoglobulin in patients with primary immunodeficiency states

Intravenous immunoglobulin can be a very effective form of treatment for patients with primary immunodeficiency states. Recommendations for intravenous dosing previously have been empirically derived. In order to determine the potential prolongation of intervals between infusions following the administration of 500 mg/kg of intravenous immunoglobulin, 11 patients were studied. This high-dose therapy was well tolerated and resulted in a modest prolongation of therapeutic IgG levels when compared with lower-dose 150 mg/kg regimens. Significant variability among individual patients was observed. Implications of this high-dose therapy are discussed.

Diet-Induced Systemic Lupus Erythematosus (SLE) in Primates

Ten adult, female cynomolgus macaques were randomly assigned to two equal groups: (1) semipurified diet (SPD); and (2) SPD with 45% ground alfalfa seed (AS). Both groups were studied at monthly intervals after 5 mo on their respective diets. Control animals had a mean hematocrit (Hct) of 43 +/- 2%, negative antiglobulin (AG), antinuclear antibody (ANA) and LE cell tests. Mean values for C3 and C4 were 309 +/- 47 mg/dl and 35 +/- 7 mg/dl, respectively. Mean serum binding to radiolabeled double stranded deoxyribonucleic acid (dsDNA) was 1.9 +/- 0.2%. Three of five animals fed AS developed signs of an SLE-like illness characterized by AG-positive anemia (lowest Hct 30%), positive ANA (highest titer greater than 1:15, 360; rim pattern) and elevated anti-dsDNA binding (highest 96%) with variable degrees of hypocomplementemia. One animal had granular deposition of immunoglobulin and complement at the dermal-epidermal junction of clinically normal skin the presence of immune complex-induced glomerulonephritis.

Intravenous immune globulins. A review of their uses in selected immunodeficiency and autoimmune diseases.

SummaryIntravenous immune globulin (IGIV) was introduced a decade ago as a therapy for primary immunodeficiency diseases. It proved to be a valuable therapeutic substance for this purpose and is now considered to be the treatment of choice. The intent was to supply ubiquitous anti-infectious agent antibodies through passive immunisation to replace deficient circulating antibody content. During such therapy, unexpected benefits were noted in thrombocytopenic patients. Since that time, the therapeutic indications for IGIV infusions have greatly increased, with a particular interest in infectious, haematological and autoimmune diseases. This review summarises the status of IGIV therapy in haematological diseases within the categories of primary immunodeficiency diseases, secondary immunodeficiency states and autoimmune syndromes.The majority of firm data have been gathered on the treatment of patients with primary immunodeficiency disease. These data are reviewed from the aspect of anticipated therapeutic response and side effects. Emphasis should be placed on the IgG circulating blood levels as there is a need for individualising therapy because of marked interindividual patient variation. The use of IGIV therapy in primary and secondary immunodeficiency states should consider the potential benefits to be attained in haematological malignancies and related complications which may be magnified by chemotherapy and radiation therapy. The mode of action of IGIV in autoimmune diseases, although not yet precisely determined, may involve establishing reticuloen- dothelial blockade or immunomodulation by supplying anti-idiotype antibodies.

Azathioprine in steroid-insensitive nephropathy

Twenty patients with steroid-insensitive glomerulonephritis were treated with azathioprine and prednisone in sustained low dosages. Serial parameters were measured to (1) assess functional response; (2) define any relationship between improvement in renal function and changes in the immune apparatus; (3) define criteria for patient selection; and (4) identify useful parameters to gauge therapeutic progress. Three patients had a complete remission, ten a partial remission, three slight improvement, and four continued to show deterioration despite treatment. Only one patient had septic complications. Functional response did not correlate with the degree of humoral or cellular immunosuppression. Azathioprine initially depressed immunoglobulin G (IgG) levels but after six months of therapy the levels of all immunoglobulins exceeded baseline values by nearly 50 per cent. Cellular immunity was never suppressed completely. Immunosuppression of humoral autoantibodies did not correlate with functional response. Renal histology, hyperalpha 2 -globulinemia and hypocomplementemia were the most reliable parameters in judging selection and probability of response in a patient with lupus glomerulonephritis. With other forms of glomerulonephritis, histopathologic criteria are not as well established and less useful. Hypocomplementemia and hyperalpha 2 -globulinemia, in the face of steroid unresponsiveness, were considered to be indications for antimetabolite therapy.

Clinical use of a new pH 4·25 intravenous immunoglobulin preparation (gamimune-N)

A multicentre, randomised, double-blinded, cross-over study was done to evaluate the clinical use and safety of a new immunoglobulin preparation for intravenous use (IVIgG). This reagent, IVIgG pH 4.25, was compared to a standard commercially available preparation IVIgG pH 6.8. Thirty-nine patients with primary immunodeficiency disease received a total of 232 infusions at a dose of 400 mg/kg every 4 weeks. Adverse effects from such infusions were transient and minimal. Clinically significant abnormalities did not occur. There were no statistically significant differences between the results for IVIgG pH 6.8 and for the new IVIgG pH 4.25 preparation. It was possible to infuse the new IVIgG pH 4.25 reagent at rates of 0.1 ml (5.0 mg)/kg/min without inducing vasomotor adverse effects.

Myasthenia gravis treated with purified antithymocyte antiserum

The therapeutic effect of goat anti-human thymocyte antiserum globulin (ATG) was assessed in 10 patients with myasthenia gravis. All subjects had far-advanced, debilitating disease poorly responsive to anticholinesterase therapy. Prolonged, low-dose ATG therapy was used, with 1.0 to 2.6 gm ATG protein administered intramuscularly over a 28-to 73-day period. Therapeutic responses of varying degrees were noted in 8 of 10 patients. Completion of a course of ATG treatment and discontinuation of the drug did not lead to acute relapse. Follow-up examinations for over 5 years have been maintained. A mean remission period of approximately 2 years was observed. This therapy deserves further evaluation; subjects with progressive myasthenia gravis despite prior thymectomy may represent ideal candidates.

The effect of oxisuran on human immunological responsiveness.

Immunological function was evaluated in 9 patients who received oxisuran at a dose range of 5–90 mg/kg, for periods of 5–40 weeks. Bone marrow cytotoxicity and lymphopenia did not occur. Established humoral immunological reactions were unaffected by oxisuran. Only 6 of 19 previously positive skin tests reverted to negative. Primary cellular immune reactivity was markedly suppressed. Allogenic skin graft survival was prolonged to a mean of 30.7 days and only 2 of 9 patients were successfully sensitized to dinitrochlorobenzene and Keyhole limpet hemocyanin, respectively. Both IgG and IgM responses to primary typhoid immunization were inhibited. In vitro peripheral blood lymphocyte activity in phytohemagglutinin and mixed lymphocyte culture tests remained normal. These data suggest that oxisuran interferes with the afferent limb of the immune system and may thereby be clinically useful in human transplantation.