Page 747 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 52 Rheumatoid Arthritis 719

although an increased risk of melanoma has been reported extent, JAK2; baricitinib blocks JAK1 and JAK2 to a similar extent.
through biologicals registries. The development of antinuclear Tofacitinib has been studied in head-to-head studies with
antibodies in 8–15% of patients, as well as rare cases of demyelin- methotrexate and with TNF inhibitors. In methotrexate-naïve
ation, points to effects that may be related to restoration of patients, tofacitinib was superior to methotrexate in reducing
autoimmune responses in predisposed subjects after TNF-α signs and symptoms of RA and in inhibiting the progression of
inhibition. structural joint damage. In patients taking background methotrex-
The clinical benefit of TNF-α blockade has prompted extensive ate therapy, tofacitinib was similar in efficacy to adalimumab.
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mechanism of action studies. Anti-TNF reduces the acute-phase JAK1- and JAK3-selective jakinibs are under evaluation. Inhibition
response, including IL-6 serum levels. Leukocyte trafficking is of another kinase, spleen tyrosine kinase (Syk) with R788
inhibited, as demonstrated through an early (within hours) and (fostamatinib), has also shown clinical efficacy in RA.
dramatic rise in lymphocyte counts through demargination, a
more prolonged and sustained exclusion of leukocytes based on Anti-T-Cell Therapy
reductions in cellularity of synovial tissue biopsies after treatment The contribution of costimulatory signals (“signal 2”) transduced
and suppression of markers of angiogenesis, including VEGF; through CD28 to priming and activation of naïve T cells and
TNF blockade promotes lymphangiogenesis and may facilitate amplification of cytokine gene expression and proliferative
cell egress from inflamed synovium. TNF-α blockade has also responses has provided a rationale for testing costimulatory
been shown to downregulate markers of cartilage and bone blockade in patients. This has been achieved using a nondepleting
destruction, including the collagenases MMP1 and 3, and to humanized IgG1-CTLA-4 fusion protein that prevents CD80
reduce the ratio of RANKL and OPG in serum, effects that might and CD86 (expressed on antigen-presenting cells) from engaging
explain in part the joint-preserving effects of anti-TNF in vivo. CD28 (but also CTLA-4) expressed on T cells. Initial studies
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Finally, there is additional evidence of anti-TNF-induced immune confirmed that the agent was safe and well tolerated. When
homeostasis, based on restoration of cell-mediated immune administered as an intravenous infusion on days 1, 14, and 28,
responses to recall antigens as well as mitogens, but also on an and then monthly thereafter at a 10-mg/kg dose in combination
+
increase in both the numbers and function of CD4 CD25 high with methotrexate, 60% of patients achieved a 20% improvement
Tregs and on increases in expression of the immunoregulatory in tender or swollen joint counts as well as 20% improvement
cytokine IL-10. 35,37 This effect could be explained in part by the in three of the other five ACR criteria (ACR20) compared with
effect of TNF blockade on restoring the expression of the Treg- 35.3% of controls; ACR50 responses were 36.5% versus 11.8%,
associated transcription factor FOXP3. respectively. CTLA-4-Ig (licensed as abatacept) has since been
The IL-1 receptor antagonist (IL-1Ra) is the only IL-1 inhibitor shown to inhibit radiographic progression and structural damage
currently licensed for use in RA. It has disease-suppressing effects by ~50%, and it is also effective in treating those patients who
in animal models of arthritis, with potent joint protection, but have had inadequate responses to TNF blockade as well as to
has proven less effective than anti-TNF in patients with RA. methotrexate. Abatacept can also be administered subcutaneously
Nevertheless, it has been used effectively to treat patients who on a weekly basis with efficacy comparable to that of the intra-
have failed TNF-α blockade, slowing radiographic progression, venous preparation. From an immunological standpoint the data
and may be efficacious in a subset of individuals with systemic are interesting in several respects. First, head-to-head studies
autoinflammatory syndrome–like features. Anti-IL-6R blockade indicate that the kinetics of response are remarkably similar to
(tocilizumab) is licensed for use in patients with established RA. those of anti-TNF. This likely reflects the significant number of
Evidence suggests that in early disease, tocilizumab as mono- costimulation-dependent T cells actively participating in the
therapy is as effective in suppressing signs and symptoms of RA ongoing inflammatory response. Clinical improvement may
as when it is combined with methotrexate. These effects are continue beyond 12 months. Second, recent data suggest that
mediated through blocking IL-6 actions on the immune response, inhibition of CD28 signals does reduce the number of Tregs, as
the acute-phase response, osteoclastogenesis, B-cell activation might have been predicted from mouse studies.
and immunoglobulin production, angiogenesis, and cell adhesion
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(reviewed in Kishimoto). Clinical responses are comparable Anti-B-Cell Therapy
to those observed with TNF blockade. Unlike in psoriasis, the Rituximab is a humanized monoclonal antibody that recognizes
effect of inhibiting IL-17 in RA (with humanized monoclonal human CD20, a 33- to 37-kDa membrane-associated phospho-
antibodies ixekizumab or secukinumab that block IL-17A) has protein expressed on pre-B, immature, and mature B cells but
been more modest, although there may exist a subset of RA not on plasma cells. It was initially developed, and then licensed,
patients in whom IL-17-driven inflammatory responses dominate. for the treatment of non-Hodgkin lymphoma. While CD20
A role for blocking GM-CSF is awaited. Blockade of cell adhesion ligation promotes B-cell activation, differentiation, and cell cycle
or chemokine function has proved disappointing in RA for reasons progression, the function of CD20 is still poorly understood.
that may lie in the redundancy of these complex systems. The therapeutic effects of anti-CD20 are related to B-cell deple-
Finally, the impact of using small molecule inhibitors of tion, which can vary between patients due to antibody-dependent
cytokine signals, transduced through receptors that utilize cell cytotoxicity, complement-mediated cell lysis, and/or triggering
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members of the Janus kinase (JAK) family of tyrosine kinases, of intracellular pathways for apoptotic cell death. 51
has been evaluated in some detail. These are interesting, immu- The initial open-label studies in RA patients combined
nologically important kinases, because gain-of-function mutants rituximab with cyclophosphamide and steroids, and so the precise
are associated with leukemia and lymphoma, whereas loss-of- contribution of rituximab to the clinical response was unclear.
function is associated with primary immunodeficiency. Jakinibs, A pivotal placebo-controlled trial of rituximab therapy random-
including tofacitinib and baricitinib, have been studied in phase ized 161 patients with RF-positive RA to compare the efficacy
III clinical trials of RA patients. Tofacitinib has high affinity for and safety of methotrexate alone (standard therapy) versus
JAK3 but is also able to partially inhibit JAK1 and, to a lesser methotrexate plus rituximab (1000 mg on days 1 and 15),