IVIg in Chronic, Refractory PM

Results and Long-term Followup of Intravenous Immunoglobulin Infusions in Chronic, Refractory Polymyositis: An Open Study With Thirty-Five Adult Patients

Cherin P, Pelletier S, Teixeira A, et al. Arthritis & Rheumatism. 2002;46(2):467-474 Cherin and colleagues [1] carried out an open, prospective study to evaluate the efficacy of intravenous immunoglobulin (IVIG) in subjects with polymyositis (PM) that was refractory to traditional treatments of corticosteroids and disease-modifying antirheumatic drugs (DMARDs).

Thirty-five adult white patients (20 women, 15 men; mean age, 43.5 years) with chronic, refractory PM were treated with high doses of IVIG after the patients had received the following traditional treatments:

prednisone (n = 35, mean dose 32 mg/day),
methotrexate (n = 24),
azathioprine (n = 13),
cyclophosphamide (n = 4),
cyclosporine (n = 7),
chlorambucil (n = 1),
plasmapheresis (n = 8),
lymphopheresis (n = 1),
and total body irradiation (n = 1).

There had been no changes in the patients' treatment in the 2 months before the initiation of IVIG therapy, and doses were not increased during IVIG treatment.

The patients received IVIG 1 g/kg/day for 2 consecutive days per month. The mean course of treatment was 4-6 months.

Clinical assessment involved the evaluation of proximal muscle power, muscle disability scale score, and esophageal disorders. In the short term, significant clinical improvement was noted in 25 (71.4%) of the 35 patients. Mean muscle power was estimated before and after IVIG therapy and was found to be significantly improved (P < .01). Mean creatine kinase levels during IVIG therapy decreased significantly before the fourth IVIG perfusion (P < .01).

Adverse effects, usually minor, were noted in 6 patients. This benefit allowed the initial prednisone dose to be reduced by more than 50% in all patients. The mean follow-up time for the 25 patients who responded favorably to IVIG treatment was 51.4 months. Twelve of these 25 patients remained in full remission after their initial course of IVIG, resulting in complete stoppage of medication in 5 patients or low doses of steroids in 7 patients. The condition of 6 patients remained improved and no other drugs were prescribed, but the patients remained dependent on IVIG infusions.

Seven of the 25 patients who responded well to IVIG treatment relapsed at an average of 17.1 months (range, 4-23 months) after the discontinuation of IVIG.

This article is important to rheumatologists for several reasons. First, the treatment for PM is usually corticosteroids and DMARDs, and these therapies are not always effective. This article extends the work on 20 PM patients initially reported by Cherin and colleagues[2] over a decade ago, when IVIG was considered a new therapy. They now present longer follow-up on patients initially refractory to corticosteroids and DMARDs (but responsive to IVIG) than has been reported in other series of patients. [3-5]

Second, the increased use of IVIG must be weighed against potential risks, and recent articles have described these current issues. [3-5]

Finally, the article presents a clinical correlate of new studies on the mechanism of action of IVIG on the immune system that can help us better decide on when and how to use IVIG. PM, dematomyositis (DM), and inclusion body myositis (IBM) are 3 distinct idiopathic inflammatory myopathies that are characterized by a common histologic endomysial inflammation and distinct immune-mediated mechanisms. [6,7]

In PM and IBM, sensitized CD8 cytotoxic T cells recognize muscle fibers that express class I major histocompatibility complex molecules. Muscle fiber necrosis occurs by a mechanism in which perforin and granzyme B are released.

DM differs from these 2 other diseases clinically because of the characteristic rash and the intramuscular microangiopathy, which is mediated by complement C5-C9 membrane attack complex, which leads to the destruction of endothelial cells, loss of capillaries, muscle ischemia, and muscle fiber necrosis and perifascicular atrophy. [8]

Despite their distinct characteristics, the treatment of PM and DM is similar. In contrast, in patients with IBM, no treatments have demonstrated consistent beneficial effects. [9]

Articles on viral safety of IVIG retrieved from MEDLINE using the search terms "gamma globulin," "intravenous," "adverse reaction," and "infection," and information from the manufacturers' literature and Food and Drug Administration package inserts have recently been reviewed by Ballow and colleagues.[10]

Although IVIG preparations are derived from pooled human plasma from a large number of donors, IVIG has had a good safety record and a low risk for transmitting viral infections such as HIV and hepatitis C, due to the preparation processes that inactivate lipid-enveloped and nonlipid-enveloped viruses.

Nevertheless, the European registries have recently expressed concern over the potential risks of hepatitis C and other diseases that may be transmitted because some plasma samples may contain these agents while being negative for the antibodies used for screening the donors. [10,11]

It is important to avoid IVIG use in patients who are IgA-deficient [11,12] due to increased risk of severe serum-sickness-type reactions as a result of anti-IgA in the recipients.

Transfusion reactions in one large series [12] included congestive heart failure, acute renal failure, and relatively frequent minor adverse effects such as vasomotor symptoms, headache, rash and fever suggestive of serum sickness, and pruritis.

Fifty-two patients (59%) had some adverse effect of IVIG infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath, which improved with reduced infusion rate or symptomatic medications.

Renal complications of high-dose IVIG are uncommon but important.[13] Infusion of IVIG preparations may cause osmotic-induced acute renal failure.[14]

Histopathology of renal tissue showed osmotically induced tubular injury (tubular vacuolization, tubulointerstitial infiltrate, and cryoglobulin deposits).[14] There appears to be no direct relationship between the development of acute renal failure and the type of IVIG.[13] However, underlying renal insufficiency increases the risk of renal failure. In view of the increasing use of IVIG preparations in medicine, it is imperative that clinicians be aware of this unusual form of renal injury.[15]

Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIG. These mechanisms include (1) interaction of the IgG Fc fragment with Fc receptors on leukocytes and endothelial cells; (2) interaction of infused IgG with complement proteins; (3) monocyte and lymphocyte modulation of synthesis and release of cytokines and cytokine antagonists; (4) modulation of cell proliferation and reparation; (5) neutralization of circulating autoantibodies; (6) selection of immune repertoires; and (7) interaction with other cell-surface molecules on T and B lymphocytes.[16]

Although IVIG inhibits T-cell proliferation and T-cell cytokine production, it is not clear whether these effects are directly dependent on effects of IVIG on T cells or via inhibition of antigen-presenting cell activity.

Bayry and colleagues[17] examined the effects of IVIG on differentiation, maturation, and function of dendritic cells. They showed that IVIG inhibits the differentiation and maturation of dendritic cells in vitro, and abrogates the capacity of mature dendritic cells to secrete IL-12 upon activation, while enhancing IL-10 production. IVIG-induced downregulation of costimulatory molecules associated with modulation of cytokine secretion resulted in inhibition of auto- and alloreactive T-cell activation and proliferation. This article extends another recent article, by Zhuang and coworkers,[18] that demonstrated that suppression of IL-4- and CD40-induced B-lymphocyte activation by IVIG was not mediated through the inhibitory IgG receptor FcgammaRIIb.[16]

In summary, IVIG is increasingly used in autoimmune and neurologic disease. It is effective and has a surprisingly good safety record, given its production from so many pooled plasma donors. Despite more than 50 years of use, information about its mechanism of action is still being clarified.

References

Cherin P, Pelletier S, Teixeira A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002;46:467-474.

Cherin P, Herson S, Wechsler B, et al. Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. Am J Med. 1991;91:162-168.

Brownell AK. Intravenous immune globulin for dermatomyositis. N Engl J Med. 1994;330:1392-1393.

Sakane T. Are intravenous immunoglobulin infusions beneficial in the treatment of inflammatory myopathies? Intern Med. 1996;35:598-599.

Cosi V, Piccolo G. IVIG in polymyositis and myasthenia gravis. Electroencephalogr Clin Neurophysiol Suppl. 1999;50:499-505.

Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med. 1991;325:1487-1498.

Dalakas MC. The molecular and cellular pathology of inflammatory muscle diseases. Curr Opin Pharmacol. 2001;1:300-306. Dalakas MC. Update on the use of intravenous immune globulin in the treatment of patients with inflammatory muscle disease. J Clin Immunol. 1995;15(6 suppl):70S-75S.

Vogel H. Inclusion body myositis--a review. Adv Anat Pathol. 1998;5:164-169.

Ballow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc (Wash). 2002;42:449-458.

Stangel M, Hartung HP, Marx P, Gold R. Side effects of high-dose intravenous immunoglobulins. Clin Neuropharmacol. 1997;20:385-393.

Brannagan TH III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology. 1996;47:674-677.

Ahsan N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIG therapy. J Nephrol. 1998;11:157-161. Hansen-Schmidt S, Silomon J, Keller F. Osmotic nephrosis due to high-dose immunoglobulin therapy containing sucrose (but not with glycine) in a patient with immunoglobulin A nephritis. Am J Kidney Dis. 1996;28:451-453.

Gupta N, Ahmed I, Nissel-Horowitz S, Patel D, Mehrotra B. Intravenous gammglobulin-associated acute renal failure. Am J Hematol. 2001;66:151-152.

Larroche C, Chanseaud Y, Garcia de la Pena-Lefebvre P, Mouthon L. Mechanisms of intravenous immunoglobulin action in the treatment of autoimmune disorders. BioDrugs. 2002;16:47-55. Bayry J, Lacroix-Desmazes S, Carbonneil C, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood. Published online August 29, 2002.

Zhuang Q, Bisotto S, Fixman ED, Mazer B. Suppression of IL-4- and CD40-induced B-lymphocyte activation by intravenous immunoglobulin is not mediated through the inhibitory IgG receptor FcgammaRIIb. J Allergy Clin Immunol. 2002;110:480-483.

Medscape Rheumatology 4(2), 2002. © 2002 Medscape