Thyroid Disorders
Figure 2: Expression of the CD20 Antigen Throughout the Maturation Steps of B Lymphocytes as a Potential Therapeutic Target for Direct B-cell Depletion
RTX
IL-6 IL-10
CD20
Stem cell
pro- B cell
pre- B cell
CD20
Immature B cell
CD20
Transitional B cell
Mature B cell
CD20
Long lived Plasmacell
IgM IgG IgA
Memory B cell
Short lived plasmacell
Ig = immunoglobin; IL = interleukin; RTX = rituximab.
Table 2: Comparison of Rituximab versus Glucocorticoid Therapy for Graves’ Orbitopathy in Patients with Active Disease
Number of patients Time to reach CAS<3 Response rate (%)
Side effects (%)
CAS = clinical activity scores; RTX = rituximab. Source: Salvi et al., 2007.34
cascade may be responsible of acute reactions caused by RTX. These reactions may be present in about 10 % of patients at first infusion, they can be severe but reversible. Among major side effects, progressive multifocal leukoencephalopathy (PML) has rarely been reported in patients receiving RTX, especially those with systemic lupus erythematosus (SLE). It is important to point out that all these patients had previously been treated with other immunosuppressive therapies including cyclophosphamide, azathioprine and even steroids, oral prednisone or intravenous methylprednisone.30,31
Since
more than 40 % of cases of PML have been reported in patients with SLE who were only minimally immunosuppressed, SLE itself may be considered to predispose for PML.31
Effects of Rituximab in Graves’ Disease and Orbitopathy
Over the last five years, the potential efficacy of RTX in active GO has been sought and data derived from either case reports or uncontrolled studies have appeared in the literature. Altogether, the effects of RTX in patients with active GO have been studied in 40 patients (see Table 1) and, although the lack of inclusion of randomised and controlled patients in the studies suggests caution in generalising results, data reported show that RTX may significantly affect the inflammatory activity and the severity of GO.
The first evidence of efficacy of RTX in active GO was reported in one patient unresponsive to standard intravenous methylprednisolone therapy.32
She was euthyroid on methyl mecapto-imidazole (MMI) and 110
RTX 9
Activity Severity
4 weeks 100 88 33
Glucocorticoids 20
6 weeks 80 75 45
treated two women with active GO, also resistant to glucocorticoid therapy, with four weekly doses of RTX of 375 mg/m2. At eight months after treatment, the CAS had decreased from five and six to one and two, respectively, and soft tissue changes, eye motility and proptosis significantly improved in both patients. In both reports the anti-inflammatory effect of RTX was observed as early as four to six weeks after therapy and persisted without disease relapse and any additional therapy. Unfortunately, case reports cannot tell us whether the disease improvement is due specifically to the drug employed or to spontaneous evolution of the disease’s natural course towards inactivation. On the other hand, while patients from these reports were unresponsive to repeated cycles of infusions of high doses methylprednisolone, they did improve rapidly and in a stable and consistent way after only two doses of RTX, suggesting that the drug did impact the active phase of the disease.
had well-controlled type 1 diabetes. The clinical response was characterised by a consistent decrease of the clinical activity scores (CAS) (<3) and improvement of ocular motility, but not of hyperthyroidism. In fact, she had a surprisingly sudden relapse of hyperthyroidism, characterised by a dramatic surge of serum TSH receptor antibodies (TRAb) (>85 IU/L), while being B-cell depleted. She eventually underwent thyroidectomy. RTX induced peripheral B-cell depletion for up to six months after two intravenous doses of 1,000 mg and intra-orbital B and T cell depletion at 10 months (see below). El Fassi et al.33
Subsequently, Salvi et al.34 conducted an open study and treated with
1 g RTX twice, with a two-week interval, a group of nine patients with active GO, of whom two had mild GO with only lid signs, and compared with a group of 20 patients treated with the standard intravenous methylprednisolone therapy. All patients responded to RTX therapy compared to 80 % of those treated with steroids (see Table 2).
CAS values significantly decreased from 4.7 to 1.8 at the end of follow-up and more rapidly compared with steroids. Proptosis, eye muscle motility and signs of soft tissue inflammation also improved significantly in response to RTX. Relapse of active GO was not observed in patients treated with RTX, but occurred in 10 % of those treated with steroids, who also experienced adverse effects more frequently (45 % versus 33 % of patients) (see Table 2).
EUROPEAN ENDOCRINOLOGY
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