Rituximab for the Treatment of Graves’ Orbitopathy
Table 1: Clinical Characteristics of Patients with Graves’ Orbitopathy Treated with Rituximab Study
Number of Salvi et al., 2006–200732,34
El Fassi et al., 2 200742
Khanna et al., 6 201035
Patients Treated 9
RTX Dose
1 g twice with 2-week interval 375 mg/m2
1 g twice with 2-week interval
Silkiss et al., 201036
12
Mitchell et al., 6 201038
Krassas et al., 1 201040
Madaschi et al., 1 201039
Salvi et al., 201141
3
CAS Before CAS After Therapy Severity Therapy
4.7 5.5 5.5
(at 16 Weeks) 1.8
1.5 1.3
After RTX All patients
improved All patients
weekly improved for 4 weeks
All patients improved
1 g twice with 5.5 2-week interval
500 mg or 1 g 5.5 with 2-week interval 1 g twice with 2-week interval 1 g twice with 2-week interval Single dose of 100 mg
7 5 5.3 CAS = clinical activity scores; GO = Graves’ orbitopathy; RTX = rituximab. 1.9 2 7 0 1.6
All patients improved
2 (minor)
1 (major, i.e., cardiac death, likely unrelated to therapy) None
5 patients improved None 1 patient unchanged
Patient worsened Not reported Patient improved No
All patients improved
2 (major but transient)
No 1 (minor) No
Number of Patients with Side Effects
3 (minor)
GO Relapse No
No Not reported Yes No No
disease. IL-10 produced by B-cells has been shown to downregulate autoreactive immune mechanisms in collagen-induced arthritis14 inflammatory bowel disease.15
and psoriasis,18
Figure 1: The Multiple Functions of B Lymphocytes and As a consequence, B-cell elimination using
rituximab (RTX) was in fact associated with exacerbation of ulcerative colitis16,17
B-cell Depletion with Rituximab
RTX, a chimeric mouse–human monoclonal antibody targeting the CD20 antigen, has been used off-label in various autoimmune disorders, but is approved for clinical use only in non-Hodgkin’s lymphoma and for the treatment of moderate-to-severe rheumatoid arthritis (RA) in patients who do not respond to tumour necrosis factor (TNF) inhibitors. In mice, RTX depletes more than 95 % of mature B-cells in blood and primary lymphoid organs within two days of a single dose.
CD20 is a human B lymphocyte-specific antigen expressed on immature to mature B-cells as well as memory B-cells, but not on stem cells or B-cell precursors. Most importantly, CD20 is not expressed on antibody-producing plasma cells (see Figure 2).19
As a consequence,
therapeutic targeting of CD20+ cells removes B lymphocytes in all intermediate stages of B-cell maturation and, in addition, activated memory B-cells and short-lived plasma cells by depletion of their immediate precursors. Peripheral short-lived plasma cells return almost to baseline levels six to 10 months after treatment, at the time of B-cell repopulation. As therapy does not affect B-cell precursors or long-lived plasma cells residing in the bone marrow,20,21
of time, even without the contribution from memory cells.7,22
antibody production is maintained over a long period This is why
immunoglobulin (Ig) levels may not change throughout the period of peripheral B-cell depletion,23,24
even after multiple courses of treatment. In
humans, it is yet to be understood whether RTX is effective for the treatment of autoimmune diseases because of its direct B-cell depleting action or because it indirectly affects autoantibody production. Consequently, novel
US ENDOCRINOLOGY
biomarkers of its mechanism of action have to be sought. In particular, studies should address why response does not always correlate with complete B-cell depletion, as has been reported in some patients with RA.24,25
Pharmacokinetics
Variable half-lives (11–105 hours) may thus result from the different tumor burden, and also from the changes of CD20 expression in malignant B-cells consequent to repeated RTX administration.27
The majority of studies on RTX pharmacokinetics and pharmacodynamics have been performed in patients with B-cell lymphomas; they have shown that serum concentration of RTX directly correlated with response and inversely correlated with tumor mass.26
In RA, RTX half-life has been reported to be much 131 both being Th1-mediated autoimmune conditions. + - B-cell
T-cell
Cytokine production
IFN-γ IL-4 IL-6 IL-10 TGF-β
Dendritic cell
regulation
Antibody production
Antigen presentation Co-stimulation
Th1/Th2 cytokine balance IFN-γ = interferon-gamma; IL = interleukin; TGF-β = transforming growth factor-beta.
T-cell IL-10-
producing regulatory B-cells
Lymphoid tissue
organogenesis
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84