Page 748 - Clinical Immunology_ Principles and Practice ( PDFDrive )

720 Part SIX Systemic Immune Diseases

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rituximab alone, or rituximab plus cyclophosphamide. All Please check your eBook at https://expertconsult.inkling.com/
groups received a 17-day course of steroids, which may facilitate for self-assessment questions. See inside cover for registration
B-cell depletion. Up to 43% of patients receiving the combination details.
of rituximab and methotrexate achieved 50% improvement in
clinical and laboratory parameters after 24 weeks (ACR50), and REFERENCES
this was at least as good as the rituximab/cyclophosphamide
combination (41% achieving ACR50) and superior to methotrex- 1. Snorrason E. Landre-Beauvais and his goutte asthénique primitive. Acta
Med Scand 1952;142:115.
ate (13%) or rituximab alone (33%). The overall incidence of 2. Harris ED. Rheumatoid arthritis; pathophysiology and implications for
infection was similar across treatment groups, but serious therapy. N Engl J Med 1990;322:1277.
infections were reported in rituximab-treated patients. Postmar- 3. Silman AJ, Hochberg MC. Epidemiology of rheumatic diseases. Oxford:
keting surveillance has documented progressive multifocal Oxford University Press; 1993.
leukoencephalopathy in a small number of patients. 4. Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid
Detailed analysis of this and subsequent studies in RA patients arthritis: an old concept with new developments. Nat Rev Rheumatol
indicate that the B-cell depletion, which may depend on FCGR3 2016;12:335.
genetic variants, is profound (<2%), with no major differences 5. van der Woude D, Houwing-Duistermaat JJ, Toes RE, et al. Quantitative
in infection rates between groups with the possible exception heritability of anti-citrullinated protein antibody-positive and
of lower respiratory tract infections. Repopulation occurs at a anti-citrullinated protein antibody-negative rheumatoid arthritis.
Arthritis Rheum 2009;60:916.
+
mean of 8 months after treatment, comprises immature IgD 6. Schönland SO, Lopez C, Widmann T, et al. Premature telomeric loss
+
−
+
CD38 CD27 CD5 B cells, and is associated with increased serum in rheumatoid arthritis is genetically determined and involves both
B cell–activating factor (BAFF) levels. Early relapse is associated myeloid and lymphoid cell lineages. Proc Natl Acad Sci U S A
+
with reconstitution of CD27 memory B cells. The effects on 2003;100(23):13471–6.
serum immunoglobulin levels are modest with levels remaining 7. Spector TD, Roman E, Silman AJ. The pill, parity, and rheumatoid
in the normal range, unless patients undergo repeated cycles of arthritis. Arthritis Rheum 1990;33:782.
B-cell depletion. Selective and rapid decreases in pathogenic IgM, 8. Karlson EW, Lee IM, Cook NR, et al. A retrospective cohort study of
IgG, and IgA RF (~60%) and IgG anti-CCPs autoantibodies cigarette smoking and risk of rheumatoid arthritis in female health
have been documented; these changes are more striking in professionals. Arthritis Rheum 1999;42:910.
rituximab responders. Antibody titers to tetanus toxoid or to 9. Scott IC, Seegobin SD, Steer S, et al. Predicting the risk of rheumatoid
pneumococcal capsular polysaccharides were only modestly arthritis and its age of onset through modelling genetic risk variants with
smoking. PLoS Genet 2013;9:e1003808.
affected (~25%). These changes are intriguing given that termi- 10. Padyukov L, Silva C, Stolt P, et al. A gene-environment interaction
nally differentiated plasma cells do not express CD20. One between smoking and shared epitope genes in HLA-DR provides a high
possibility is that germinal center and marginal zone B cells may risk of seropositive rheumatoid arthritis. Arthritis Rheum 2004;50:3085.
be resistant to anti-CD20. B-cell depletion is surprisingly well 11. Lundberg K, Wegner N, Yucel-Lindberg T, et al. Periodontitis in RA—the
tolerated; however, in contrast to other biological agents, it may citrullinated enolase connection. Nat Rev Rheumatol 2010;6:727.
induce long-lasting immunocompromise. 12. Wu HJ, Ivanov II, Darce J, et al. Gut-residing segmented filamentous
bacteria drive autoimmune arthritis via T helper 17 cells. Immunity
Future Prospects for Therapy 2010;32:815.
13. Zhang X, Zhang D, Jia H, et al. The oral and gut microbiomes are
There remain unmet needs in the treatment of RA. Principal
among these are the fact that until relatively recently, treatment perturbed in rheumatoid arthritis and partly normalized after treatment.
Nat Med 2015;21:895.
has been considered lifelong for the majority of patients, imposing 14. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An
greater risk of toxicity and, as the immune system senesces, approach to understanding the molecular genetics of susceptibility to
increased risk of infection or lymphoproliferative disease. There rheumatoid arthritis. Arthritis Rheum 1987;30:1205.
is little doubt that early treatment with tight control offers the 15. Raychaudhuri S, Sandor C, Stahl EA, et al. Five amino acids in three HLA
best outcomes. Indeed, several synthetic and biological DMARDs proteins explain most of the association between MHC and seropositive
are now being tested in at-risk subjects to establish whether they rheumatoid arthritis. Nat Genet 2012;44:291.
can delay or even prevent development of clinically apparent 16. Viatte S, Plant D, Han B, et al. Association of HLA-DRB1 haplotypes with
disease. A better appreciation of the profile of RA-specific rheumatoid arthritis severity, mortality, and treatment response. JAMA
autoantigens has prompted early- phase studies to establish the 2015;313:1645.
safety and tolerability of peptide immunotherapy delivered by 17. Huizinga TW, Amos CI, van der Helm-van Mil AH, et al. Refining the
complex rheumatoid arthritis phenotype based on specificity of the
autologous DCs. From an immunological perspective, there HLA-DRB1 shared epitope for antibodies to citrullinated proteins.
remains a pressing need to develop immunological tools or Arthritis Rheum 2005;52:3433.
immune biomarkers that can redefine disease subsets and measure 18. Scally SW, Petersen J, Law SC, et al. A molecular basis for the association
effector and regulatory cell subsets. This must be achieved with of the HLA-DRB1 locus, citrullination and rheumatoid arthritis. J Exp
technology that is readily accessible to routine clinical laboratories Med 2013;210:2569.
and that uses methods that will inform disease activity states at 19. Eyre S, Bowes J, Diogo D, et al. High-density genetic mapping identifies
a biological level. While such tools may provide better insights new susceptibility loci for rheumatoid arthritis. Nat Genet 2012;44:1336.
into disease pathogenesis, they can also be adapted to monitor 20. Burn GL, Svensson L, Sanchez-Blanco C, et al. Why is PTPN22 a good
the impact of therapeutic intervention, whether this turns out candidate susceptibility gene for autoimmune disease? FEBS Lett
2011;585:3689–98.
to be cell-based therapy or the application of novel immune 21. Rawlings DJ, Dai X, Buckner JH. J Immunol 2015;194(7):2977–84.
modulators. It is possible that similar approaches to developing doi:10.4049/jimmunol.1403034. Review. PMID: 25795788.
immune signatures could be used in the future to identify those 22. Manzo A, Bombardieri M, Humby F, et al. Secondary and ectopic lymphoid
+
ACPAs arthralgia patients who have a genetic predisposition to tissue responses in rheumatoid arthritis: from inflammation to
RA and are at highest risk of developing the disease. autoimmunity and tissue damage/remodeling. Immunol Rev 2010;233:267.