Variability in Clinical and Biological Response to Rituximab in Autoimmune Diseases

An Opportunity for Personalized Therapy?

Venkat Reddy; Maria Leandro

Int J Clin Rheumatol. 2014;9(3):279-293.

Abstract and Introduction

Abstract

A better understanding of the variability in clinical response to B-cell-depletion therapy using rituximab in rheumatoid arthritis and systemic lupus erythematosus is important to optimize the use of this therapy and improve patient outcomes. To this end, we review current evidence on factors that affect pharmacokinetics and pharmacodynamics of rituximab, and the biological and clinical response to this drug. Also we briefly describe variability in B-cell depletion and reconstitution following rituximab treatment and summarize elements that have been shown to distinguish responders and nonresponders. Finally, we speculate on the prospects for exploiting the knowledge gained thus far in developing rituximab-based personalized therapy for rheumatoid arthritis and systemic lupus erythematosus.

Introduction

B-cell-depletion therapy (BCDT) using rituximab is licensed for the treatment of refractory rheumatoid arthritis (RA) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and is also routinely used in clinical practice to treat a range of autoimmune diseases including systemic lupus erythematosus (SLE). The list of unlicensed indications where rituximab is used has been increasing over the past decade. Although there exists robust evidence on the safety and efficacy of rituximab in RA considerable variability has also been noted in biological and clinical response between patients. However, what underlies this variability remains poorly understood. A better understanding of the factors and mechanism/s that determine the clinical response to rituximab could be exploited to improve the overall effectiveness of BCDT strategies. To this end, this review focuses on describing factors and mechanisms that may explain the variability in biological and/or clinical response to rituximab in RA and SLE.

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Table 1. Variability in biological and clinical response to rituximab.
Variability in parameters	Comments	Condition	Ref.
Degree of BCD and development of HACAs	The degree of depletion did not depend on the dose of rituximab used and the development of HACAs was associated with lower rituximab levels	SLE (n = 17)	[25]
Time to clinical relapse from B-cell repopulation varied from 0 to 17 months	Variability in depletion was noted between patients despite the same dose of rituximab	RA	[26]
The decrease of anti-dsDNA antibody levels from baseline	The extent of decrease in anti-dsDNA antibody levels was greater in responders	SLE (n = 16)	[27]
Duration of peripheral BCD (3–8 months)	One patient remained depleted at 4 years	SLE (n = 24)	[28]
Bone marrow B-cell lineage cells at 3 months after RTX	Variability was noted in the proportion of pro- and pre-B cells and there was a trend towards better response in patients with better depletion	RA (n = 6)	[29]
Degree of depletion	BCD (<5 cells) correlated with clinical response and inversely with HACAs	SLE (n = 18)	[30]
HACAs	No correlation between FcgRIIIa polymorphism and clinical response	SLE (n = 18)	[30]
Response to immunization with pneumovax	HACAs were higher in 3 patients treated with low-dose RTX (100 mg)	SLE (n = 18)	[30]
7 months after Rx with RTX	70% response (SLEDAI improved >2)	SLE (n = 18)	[30]
Degree of peripheral BCD	BCD defined as <5 cells/μl	SLE (n = 65)	[31]

BCD: B-cell depletion; HACA: Human antichimeric antibody; RA: Rheumatoid arthritis; RTX: Rituximab; SLE: Systemic lupus erythematosus; SLEDAI: Systemic lupus erythematosus disease activity index.

Table 2. Factors associated with poor response to rituximab in autoimmune disease.
Factor associated with poor response	Comments	Condition	Ref.
Good response correlated with a drop in CRP and autoantibodies	Reduction in autoantibodies would suggest that rituximab interupts the formation of autoantibody antibody secreting cells	RA	[26]
BM B-cell lineage cells at 3 months after RTX	Variability was noted in the proportion of pro- and pre-B cells and there was a trend towards better response in patients with better depletion	RA	[29]
Anti-ENA-positive patients were more likely to flare	Baseline autoantibody profiling may help predict response to rituximab in SLE	SLE	[43]
Incomplete depletion	Patients with incomplete B-cell depletion (<1 cell/μl) included all nonresponders	RA (n = 80)	[2]
Depletion of memory B cells in PB and BM (n = 8) at 3 months	Reduction of CD19⁺HLADR⁺ activated B cells. Insignificant reduction in BM B cells	RA (n = 11)	[59]
Nonresponders had a higher frequency of IgD⁺CD27⁺ MCs at the time of relapse	B-cell repopulation with a higher frequency of IgD⁺CD27⁺ MCs was associated with early relapse (no differences in subsets at baseline between Rs and NRs)	RA	[49]
BAFF levels (>1011 pg/ml), RF-negative and lymphocyte count >1875/ul		RA	[60]
FcRIIIa F158V polymorphism	High-affinity polymorphism associated with good response	RA (n = 177); and RA (n = 111)	[61,62]
FcRIIIa F158V polymorphism	High-affinity polymorphism associated with good response	SLE	[63]
No IFN type 1 signature	Genome-wide microarray in a small prospective RA cohort suggests IFN type 1 signature as a marker of nonresponse	RA (n = 14)	[64]
TTTT BLyS promoter haplotype in seropositive patients	The frequency of the promoter haplotype was comparable in both seropositive and seronegative patients, but good response to RTX was seen only in seropositive patients with the promoter haplotype. BLyS levels were not of predictive significance	RA (n = 152)	[65]
IgJ^hiFCRL5^lo, a combination biomarker of plasmablasts was associated with poor response	Pooled samples from RCTs	RA	[66]

BM: Bone marrow; ENA: Extractable nuclear antigens; MC: Memory cell; NR: Nonresponder; PB: Peripheral blood; R: Responder; RA: Rheumatoid arthritis; RCT: Randomized controlled trial; RF: Rheumatoid factor; RTX: Rituximab; SLE: Systemic lupus erythematosus.

Table 3. Parameters associated with clinical relapse.
Factor associated with early clinical relapse	Comments	Condition	Ref.
Relapse was preceded by B-cell repopulation and an increase in levels of autoantibodies	These findings suggest that relapse occurs after B-cell repopulation	RA (n = 22)	[26]
Higher numbers of IgD⁺CD27⁺ memory B cells at repopulation	Repopulation occurred mainly with naive cells whereas relapse was associated with memory B cells	RA (n = 24)	[44]
Higher numbers of IgD⁺CD27⁺ memory B cells at baseline and at the time of repopulation	Variability in the frequency of IgD⁺CD27⁺ memory B cells at baseline	RA (n = 17)	[49]
Anti-dsDNA antibody levels and B-cell numbers, B-cell phenotype were predictive factors for relapse	Relapse was associated with B cell markers and anti-ds DNA antibody levels	SLE (n = 67)	[51]