Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin

M. Hundt, K. Manger1, T. Dörner2, B. Grimbacher3, P. Kalden3, A. Rascu1, D. Weber4, G. R. Burmester2, H. H. Peter3, J. R. Kalden1 and R. E. Schmidt

Department of Clinical Immunology, Hanover Medical School,
1 Department of Medicine III, University of Erlangen-Nürnberg,
2 Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin,
3 Department of Rheumatology and Clinical Immunology, University of Freiburg and
4 Grifols Deutschland GmbH, Langen, Germany

SIR, Intravenous immunoglobulin (IVIg) treatment has been approved by the Food and Drug Administration for immune-mediated thrombocytopenia, and Kawasaki's syndrome, and has been shown to be effective in other autoimmune diseases. For patients with systemic lupus erythematosus (SLE) there are no general valid guidelines of therapy applicable. IVIg has been demonstrated to enhance the catabolism of IgG, to block Fc{gamma} receptor-mediated mechanisms, and to inhibit Fas receptor-induced apoptosis [1, 2]. Furthermore, IVIg preparations contain anti-DNA idiotypic antibodies, which might influence the idiopathic network [3]. These mechanisms have been shown to be able to control the pathogenesis of SLE. Moreover, the efficacy of IVIg treatment has been demonstrated in case reports of patients with various manifestations of SLE, especially in those with thrombocytopenia and antiphospholipid antibody syndrome [4, 5]. However, prospective studies of the treatment of acute exacerbation of SLE with IVIg are rare. Therefore, we performed an uncontrolled multicentre trial.

Thirteen female patients fulfilling at least five American College of Rheumatology (ACR) criteria with an acute exacerbation of SLE were enrolled. The flare was defined as an increase in modified European Consensus Lupus Activity Measurement (mECLAM) by >= 4 points in comparison with a retrospective score covering the 3 months before the patient entered the study [6]. Patients with acute lupus nephritis were excluded because of reported worsening of renal function under IVIg treatment in some cases [7]. All patients received 0.4 g/kg body weight pasteurized IVIg once a day for 5 consecutive days. The mECLAM was determined retrospectively (not more than 3 months before acute exacerbation, score 0), at screening, at the end of treatment, and at weeks 1, 4 and 12 of the follow-up. Concomitant SLE therapy should not be changed during the study period. A decline of >= 3 points in mECLAM at week 4 after the end of the study treatment compared with the time of screening was defined as a full response.

The median retrospective mECLAM (score 0) before flare was 6 points (range 1–13) (Fig. 1Go). The median mECLAM at study entry (screening) was 12 points (range 6–20). The median increase in mECLAM was 7 points (range 4–11). After IVIg treatment, mECLAM had declined in 12 of 13 patients by >= 3 points at week 4 of follow-up (the primary endpoint of the study). The median reduction in disease activity was 7 points [range 1–12, P = 0.0002, 95% confidence interval (CI) 4.6–8.1; Wilcoxon signed rank test]. Although we aimed to keep concomitant therapy constant, the treatment was changed in six patients before week 4 of follow-up by a decision of the treating physician. The groups of patients with and without change in concomitant therapy did not differ significantly in severity of flare or in their course of disease activity (P > 0.3 at all time points, Mann–Whitney test).



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FIG. 1. Effect of IVIg treatment in SLE exacerbation. Time course of mECLAM in patients whose concomitant therapy was unchanged (closed circles, solid line) and changed (open circles, dashed line) before week 4 of follow-up. EOT, end of treatment.

 
The effects of IVIg treatment in the remaining seven patients for whom there was no alteration of concomitant SLE therapy were analysed further. The median reduction in mECLAM was 8 points (range 1–8, P = 0.0156, 95% CI 3.7–8.8; Wilcoxon signed rank test). Fatigue, myalgia and fever improved in all affected patients. Arthralgia or arthritis diminished in four of six patients. Clinical deterioration was rare (fatigue in one patient). The improvement in laboratory test results after IVIg treatment was less impressive. Erythrocytes and platelets increased in one patient with anaemia and thrombocytopenia. The erythrocyte sedimentation rate (ESR) decreased in two of three patients with an abnormal ESR. The DNA antibody titre improved in four of six patients. IVIg-related adverse effects during infusion phases were rare and mild. In addition, no worsening of renal function was observed during follow-up.

We have described the efficacy of high-dose IVIg treatment in 13 patients with acute exacerbation of SLE. Twelve of 13 patients (92%) were full responders (decrease in mECLAM by >= 3 points at week 4 of follow-up). In addition to the study treatment with IVIg, intensification of concomitant SLE therapy was given to six of 13 patients before week 4 of follow-up. Five (83%) of these six patients responded to IVIg treatment, measured by a decrease in mECLAM by >= 3 points: three showed a response at the end of the study treatment and two patients at week 1 of follow-up. Of the seven patients who were treated only by the addition of IVIg, six (86%) were full responders. If the six patients who received intensified concomitant SLE therapy before week 4 of follow-up are classified as non-responders, only six of 13 patients (46%) were full responders. These results agree with previous studies demonstrating positive effects of high-dose IVIg treatment in SLE [8, 9]. In our study, IVIg was very efficient in improving myalgia. In refractory dermatomyositis, a double-blind placebo-controlled study has demonstrated the effectiveness of IVIg treatment [10]. These results suggest that SLE patients with myalgia may represent a new subgroup who might benefit from IVIg treatment. Because we used only a single course of IVIg treatment, no statement about the efficacy of long-term therapy can be made. However, progressive clinical improvement has been demonstrated after monthly administration of IVIg [11]. Considering the risks and benefits of a 5-day, high-dose IVIg treatment in SLE exacerbations, we conclude that this regimen is safe and effective and may be used as an addition to conventional therapy.

Notes

Correspondence to: M. Hundt, Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Back

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