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Glatiramer acetate (GA)—formerly known as copolymer 1 or COP-1—has been shown to reduce the frequency of relapses and disease activity and burden as measured by MRI in patients with relapsing-remitting multiple sclerosis (RR-MS).1 The mechanism of action is thought to involve MHC-II blockade2and the induction of a Th2/Th3 cytokine response.3Peripheral blood mononuclear cells from patients with multiple sclerosis and healthy controls proliferate in reponse to GA in vitro.4 Therefore GA seems to have both immunostimulatory and immunomodulatory potential.
In our centre 27 patients with relapsing-remitting or relapsing-progressive multiple sclerosis were treated with 20 mg subcutaneous GA daily for 3 years as part of an open label multicentre study. Safety evaluation and expanded disability status scale (EDSS) rating were performed every 3 months and in the 3rd year every 6 months and when clinical relapses occurred. Relapses were defined according to Poser criteria and annual relapse rates were calculated for the 3 year study duration and a 2 year prestudy period. As two patients reported generalised tender swelling of lymph nodes spontaneously in temporal relation to the beginning of GA injections special attention was paid to the symptom and regular assessment of regional lymph nodes was performed in all patients. Only if patients reported symptoms such as tenderness or pain, was the diagnosis of lymphadenopathy made. All patients completed the full 3 years of the study. In one patient with generalised lymphadenopathy a lymph node biopsy was taken to rule out malignancy. As controls patients who were routinely treated with IFN-β injections at our multiple sclerosis outpatient clinic were also examined for lymphadenopathy.
In nine out of 27 patients lymphadenopathy occurred 1 to 15 months after initiating GA treatment and persisted for the study (treatment) duration. There were no significant differences between the groups with and without lymphadenopathy in their mean age, disease duration, EDSS scores, and annual relapse rates at the beginning of the study. The size of the lymph nodes ranged from 2 to 5 cm and lymphadenopathy was considered mild to moderate in eight patients and severe in one patient. In seven out of the nine patients lymphadenopathy was restricted to inguinal lymph nodes and in two patients it was generalised. Serological and haematological routine diagnostics of peripheral blood were normal. The lymph node biopsy in one patient with severe generalised lymphadenopathy showed strong immune stimulation with lymphofollicular hyperplasia but no atypical cells (thus ruling out malignancy). Lymphadenopathy did not necessitate the discontinuation of GA treatment. The examiners were reassured that all patients used a good (sterile) injection technique. In the control patients no lymphadenopathy was detected.
When analysing annual relapse rates, a significant reduction of the mean annual relapse rate was found under GA treatment. The annual relapse rate decreased from 1.8/year to 0.33/year and from 1.5/year to 0.54/year in the group of patients with and without lymphadenopathy respectively. When comparing annual relapse rate for both patient groups the difference did not reach significance (Mann-WhitneyU test, p=0.076) with a trend to a slightly favourable response in the group with lymphadenopathy. Although in the group with lymphadenopathy no patient showed an increase in relapse rate, three patients in the group without lymphadenopathy did. In both groups of patients no significant change in median EDSS over the 3 years of the study was noted (table 1).
The frequency of lymphadenopathy found in this study (nine out of 27 patients) is significantly higher than that reported in the postmarketing surveillance of GA (55 reports of lymphadenopathy out of about 30 000 reports of other adverse events). The lymphadenopathy in our study was mild to moderate, not accompanied by changes in routine laboratory indices, and persisted as long as the GA treatment was continued. In seven out of nine patients lymphadenopathy remained localised to the draining lymph nodes. Lymph node swelling receded and reappeared depending on injection site. Lymphadenopathy did not necessitate discontinuation of GA treatment. In one patient with generalised lymphadenopathy a biopsy was performed to rule out malignancy. The patient was then continued on GA without further problems and remained relapse free; GA injections were stopped 1 year after the end of the study, due to pregnancy, and lymphadenopathy resolved completely within 4 weeks.
Lymphadenopathy, if not due to malignancy, is a clinical sign of immune activation and has not yet been reported as an adverse event of GA treatment in the literature. The effect might be due to direct stimulation of T cells in vivo as GA has been shown to induce mRNA expression of IL-2 and T cell proliferation in vitro.4 In previous studies immunostimulatory cytokines such as IFN-γ or viral infections worsened the clinical course of multiple sclerosis whereas immunosuppression (for example, mitoxantrone, cyclophosphamide) was beneficial.5 It will be interesting to study further whether lymphadenopathy related to GA is associated with alteration of the clinical outcome measures of multiple sclerosis. The cohort of patients with lymphadenopathy did not show a significant difference in annual relapse rate or EDSS compared with patients without lymphadenopathy, but the small sample size per group should be taken into account. Glatiramer acetate induces clinical signs of immune stimulation (lymphadenopathy) in a subgroup of patients with multiple sclerosis that is not associated with clinical worsening. The finding is therefore interesting with regard to the potential mechanism of action of GA in vivo. Larger numbers of patients need to be examined to determine whether lymphadenopathy in patients under GA treatment is associated with distinct immunological markers—for example, MHC-II type or cytokine secretion pattern.
Patients examined in this study were enrolled in our centre as part of the German open label phase IIIb treatment study (protocol COP 1600) supported by TEVA and Aventis
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