Page 746 - Clinical Immunology_ Principles and Practice ( PDFDrive )

718 Part SIX Systemic Immune Diseases

genetic markers, such as HLA-DRB1 SE, have not contributed that intensive treatment when combined with intensive control
dramatically to risk estimates. most convincingly influences outcome measures, including clinical
response, retention, functional status, and radiographic progres-
TREATMENT sion. The benefits of tight control have been substantiated in
many subsequent clinical trials as well as in “real life” clinical
Disease-Modifying Antirheumatic Drugs practice. 45,46
tHEraPEUtIC PrINCIPLES
Treatment Paradigms in RA Anticytokine Therapy
The introduction of targeted therapy to the clinic using biological
• Education and counseling through early involvement of a multidisciplinary agents (e.g., chimeric or fully humanized antibodies to ligands
team, including specialist nurse and other health care professionals; or receptors, soluble receptor fusion proteins, or recombinant
appropriate balance of rest and exercise during disease flares receptor antagonists) has transformed the treatment of RA. The
• Adequate nutrition (especially important with severe, active disease) prototype biological is TNF-α blockade. The rationale for
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• Comprehensive assessment of disease activity, especially during early
phase of disease to achieve rapid disease control inhibiting TNF-α bioactivity is based upon its pleiotropic effects
• Complete suppression of inflammation early in the disease, with tight on cell activation, cellular adhesion and migration, induction
control through regular and frequent reassessments focused around of cytokine and inflammatory gene mRNA and protein, neoan-
disease activity scores giogenesis, and the regulation of cartilage catabolic factors such
• Yearly imaging assessments, e.g., X-rays or high-resolution ultraso- as IL-1 and matrix metalloproteinases (Fig. 52.3). TNF-α and
nography of hands and feet to monitor radiographic progression other inflammatory cytokines such as IL-1, IL-6, IL-15, IL-17,
• Early use of DMARD/SAARDs and GM-CSF are expressed constitutively in inflamed synovial
• Early use of corticosteroids, including use of intraarticular joint injections
to suppress inflammation, and use of step-up combination therapy in tissue at mRNA and protein level. In many cases the expression
severe disease of their high-affinity cognate receptors is upregulated and the
• Appropriate use of biologicals, e.g., early use of anticytokine, T- or functional activity of the corresponding naturally occurring
B-cell–targeted therapies in severe disease inhibitors (e.g., soluble TNF-R or IL-1Ra) is reduced (although
• Early relief of pain with judicious use of NSAID or COX2 inhibitors levels of protein may be increased, reflecting an attempt at restoring
according to safety/risk profile homeostasis). As proof of principle, inhibition of cytokine activity,
• Monitoring for drug toxicity
• Effective contraception, where appropriate including TNF-α, IL-1, IL-6, IL-15, and IL-17, have all been
• Bone protection shown to have benefit in animal models of arthritis.
• Monitoring for risk factors of key comorbidities, including cardiovascular Chimeric anti-TNF monoclonal antibodies (infliximab) were
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disease first used to treat RA in open-label clinical trials in 1992.
• Prevention of infection through vaccination (preferably before instituting Humanized antibodies (adalimumab) and the soluble p75 TNF-R
immunosuppressive agents), e.g., against influenza, pneumococcus, IgG fusion protein (etanercept) were tested subsequently with
and herpes zoster
comparable therapeutic effects; golimumab and a construct
COX, cyclooxygenase; DMARD, disease-modifying antirheumatic comprising a PEGylated anti-TNF antibody Fab fragment
drugs; NSAID, nonsteroidal antiinflammatory drugs; SAARD, (certolizumab) are also licensed for use in patients with RA, as
slow-acting antirheumatic drugs. are a growing number of “biosimilar” TNF inhibitors. TNF-α
blockade leads to dramatic and rapid reductions in symptoms
(pain, stiffness, and fatigue) and signs (joint pain and swelling)
Over the past two decades there has been a dramatic paradigm of arthritis in a dose-dependent fashion, and in a significant
shift in the therapy of RA from control of symptoms to the proportion of patients (~60–70%) who have failed conventional
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control of the disease process and aggressive suppression of DMARDs. As a class, these biological agents can be used repeat-
inflammation. This shift has come about through a growing edly, and when used in combination with methotrexate, they
appreciation of the relationship between joint inflammation and are superior to either drug alone. The mechanism is not clear
joint destruction and also through the development of imaging but may be related to reductions in immunogenicity of the
technology that has documented evidence of erosive changes therapeutic antibody (the antidrug antibody [ADA] response),
within the first 6–12 months of disease. The impact of this effects on the half-life of the biological, or perhaps the combined
paradigm shift in therapeutic terms is striking. Traditional “go-low, immunological effects of anticytokine and anti-T-cell agents.
go-slow” regimens of the 1970s and 1980s included the initiation Radiographic progression may be attenuated, even in subsets of
of nonsteroidal antiinflammatory drugs (NSAIDs), followed by patients with poor clinical responses; in some patients radio-
implementation of DMARDs only after destructive disease became graphic scores improve, suggesting that healing of joint tissues
evident. Depending on the clinical response, sequential mono- may take place. TNF-α blockers when used early demonstrate
therapy was the norm. Although this strategy may still be superior remission rates. Some studies have shown that a sig-
appropriate for patients with mild disease, current practice now nificant proportion of patients remain in remission even after
dictates aggressive combination therapy (two or more conven- withdrawal of anti-TNF, providing evidence suggestive of immune
tional DMARDs) from the outset for patients with poor prognostic modulation. Regardless of the TNF inhibitor used, the contribu-
factors, with preference for the faster-acting DMARDs such as tion of TNF to host defense is further suggested by an approxi-
methotrexate, leflunomide, and sulfasalazine (onset 3–6 weeks) mately twofold increased risk, especially during the first 6 months,
over slower-acting agents such as hydroxychloroquine, gold, and of serious infections of the upper respiratory tract, skin, and
d-penicillamine (onset 3–6 months), but with the addition of joint as well as by a significantly increased risk of reactivation
oral or parenteral prednisolone. More recent data suggest that of latent tuberculosis. The global risk of malignancy, particularly
the specific choice of therapy may be less important than the lymphoma, which already is increased in the RA population as
strategy. For example, the TICORA and BeST studies both indicate a whole, does not appear to be increased with anti-TNF therapy,