Neuromuscular Disease
Table 1: (continued) Ref Age, MG Previous
Sex Type Treatments 45 11, F AChR+ S, P, I
20, F AChR+ S, A, M, P, C 24, F AChR+ S, A, I, P 29, F MuSK+ S, A, CA, I, P 34, F AChR+ S, A, Mx, M, I
MGFA CC Ab Titre
Immediately Before Before RTX RTX
IVa V
IIIb IVb IIIb
35, F AChR+ S, A, Mx, CA, I, P IVb 36, F AChR+ S, A, I 40, F MuSK+ S, M, I, P 46, F AChR+ S, A, I
V V V
52, F MuSK+ S, A, M, I, P Patient 9 Had a Malignant thymoma
A = azathioprine; Ab = antibodies; AChR+ = antiacetylcholine-receptor-antibody-positive; ASTC = allogenic stem cell transplantation; BL = standard dose of RTX for B lymphoma (375mg/m2, every week for four consecutive weeks); C = cyclophosphamide; CA = ciclosporine A; CSR = complete stable remission; D = died; I = intravenous immunoglobulins; Im = improved; MGFA CC = Myasthenia Gravis Foundation of America clinical classification;84
MGFA PS = Myasthenia Gravis Foundation of America post-intervention status;84
M = mycophenolate mofetil; MM = minimal manifestation; MuSK+ = antimuscle-specific tyrosine-kinase-antibody-positive; Mx = methotrexate; N = no; NR = not reported; P = plasma exchange; PR = pharmacological remission; RA = rheumatoid arthritis; RTX = rituximab; S = steroids (prednisone or prednisolone); U = unchanged; VGKC+ = antivoltage-gated potassium channel antibody-positive; W = worse; Y = yes.
the number of Treg cells, as has been reported in SLE67 and ITP.68
Second, by abrogating the antigen-presenting function of B cells, RTX could redirect this presenting function to other cells, such as DCs and/or monocytes/macrophages, which would then be able to stimulate different T cells with different functions. Finally, not only B cells express CD20 on their surface, but also a small proportion (2.4±1.5%) of T cells (CD20+ T cells) co-express this marker.69
CD20+
T cells are functionally characterised by constitutive cytokine production (interleukin [IL]-1 and TNF), suggesting that they are a terminally differentiated cell type with pro-inflammatory properties.60 These cells are also depleted by RTX.60
Factors Predictive of Response to Rituximab A potential cause of failure of RTX is a polymorphism of the Fcγ receptor III gene (substitution of a phenylalanine for a valine at position 158).70
lymphoma and SLE,71 Sjögren’s syndrome.72 in MG.
repeating the doses (such as during the standard B lymphoma regimen; personal observation). So, whether to prescribe 375mg/m2 four times or 1g twice may depend on the disease being treated and individual variations in response. The past history of the disease and its treatment may also influence response. Long-term refractory disease in patients who have received prior immunosuppressant drugs may be associated with the selection of particular memory B-cell clones (CD27+IgD- class-switched memory B cells) that could be more resistant to RTX. These memory B cells, which first reappear during B-cell reconstitution, seem to correlate with a poorer outcome in RA.75
Similarly, a higher number of anti-TNF agent
failures in RA seems to be associated with poorer clinical outcome after RTX.76
This is predictive of failure in the treatment of B-cell but not in chronic lymphocytic leukaemia70 This polymorphism has not been studied
or in
The quality of B-cell depletion seems to influence the response to RTX. In RA, a recent study (n=60)73
showed that rapid (at day 15 before
the second 1g RTX injection) and complete B-cell depletion measured using a highly sensitive flow cytometry assay (below 0.0001x109/l versus 0.05x109/L in conventional assays) was predictive of a better clinical outcome. Interestingly, patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete. It could be that patients who have difficulty achieving peripheral clearance may be more likely to have difficulty clearing other lymphoid organs and/or inflamed tissues, with a subsequent poorer response. B-cell depletion is more easily achieved in peripheral blood than in other compartments in non-human primates74
and also in humans.60 For MG patients this
effect, especially the degree of B-cell depletion within the thymus, can certainly influence the clinical response. The reason for this variability in depletion among patients is not well understood. It may be due to inter-individual pharmacological variations. For example, in the macaque monkey, greater B-cell depletion is achieved by increasing the first injection dose (mimicking the RA regimen) than
98
Moreover, the subtype of autoantibodies accompanying an autoimmune disease may influence RTX response. For example, in RA the presence of rheumatoid factors rather than anti-CCP antibodies was associated with better clinical response after RTX.76 Considering MG, in the 53 RTX-treated patients so far reported (see Table 1), 20 (38%) were anti-MuSK+, a much higher proportion than in the general MG population (10%). This may reflect observations that MuSK+ MG tends to be more severe and resistant to conventional immunnosuppressants than AChR+ MG,77
but in
addition, because of positive reporting bias, that RTX may be more effective in MuSK+ MG than AChR+ MG. Furthermore, five of the six MG patients whose antibodies reached undetectable levels after RTX were MuSK+ (see Table 1).
Finally, RTX is a chimaeric monoclonal antibody (i.e. murine antibody origin for a portion of the variable region and human origin for the remaining variable and constant regions), and human antichimaeric antibody (HACA) can be induced by RTX injection. The proportion of patients with HACA positivity was 9.2% after more than one cycle of RTX in RA.59
However, there was no clear evidence that the presence of HACA interfered with the safety or efficacy of additional courses of RTX, and HACA positivity does not appear to be a significant concern in determining whether a patient should receive additional RTX courses,59
at least in RA. In SLE, the proportion of patients developing HACA seems higher; in one trial of 24 patients EUROPEAN NEUROLOGICAL REVIEW IVb
NR NR NR NR NR NR NR NR NR NR
Initial Dose Other of RTX
BL BL BL BL BL BL BL BL BL BL
NR NR NR NR NR NR NR NR NR NR
Cycles of RTX (n)
Follow-up Duration
Post-(first) RTX (months)
NR NR NR NR NR NR NR NR NR NR
CSR CSR U
PR U
W
Im Im U
Im
NR NR NR NR NR NR NR NR NR NR
MGFA PS Ab Titre After RTX
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