Page 728 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 51 Systemic Lupus Erythematosus 701

“Treat-to-target” recommendations in SLE from an international indications, whereas others are still in the developmental stages.
SLE task force include the following more specific guidelines: These therapies, in general, have more specific immunological
the treatment target should be remission of organ manifestations; targets than standard treatments. Although multiple agents have
factors such as pain that negatively influences health-related been tested in animal models of disease, we will focus only on
quality of life should be addressed; maintenance treatment should therapies that have been given to humans. Several of these agents
aim for the lowest glucocorticoid dose needed to control disease; have been recently evaluated in phase III clinical trials and have
and relevant therapies adjuvant to any immunomodulation should been unable to demonstrate superiority over treatment with
be considered to control comorbidity in SLE. 75 placebo or standard of care. Although imperfect trial design may
Some genetic factors predicting risk of toxicity or therapeutic account for some of these failures, the possibility remains that
benefit for individual agents have been identified. Polymorphisms these agents are not effective treatments for SLE and do not confer
of a key enzyme in the metabolism of azathioprine, thiopurine a substantial improvement over current standard-of-care therapies.
methyltransferase (TPMT), are common; 0.3% and 11% of Rituximab (anti-CD20 antibody), a B-cell–directed therapy
Caucasians are homozygous and heterozygous, respectively, for approved for use in rheumatoid arthritis, targeting all B cells
76
mutations associated with altered expression of TPMT. TPMT- except plasma cells, failed to demonstrate improved performance
deficient patients are especially susceptible to leukopenia and over standard of care in trials of patients with active SLE, or in
pancytopenia associated with azathioprine. Cyclophosphamide patients with active lupus nephritis added to a background therapy
is metabolized to its active form by cytochrome P450. Individuals of MMF and corticosteroids. Elevated BAFF levels are present
heterozygous or homozygous for a specific cytochrome P450 after B-cell depletion. These can exacerbate the impaired tolerance
polymorphism (CYP2C19*2) have a lower probability of develop- of SLE. Thus studies are ongoing to evaluate the efficacy of
ing premature ovarian failure, but they also show a poorer rituximab followed by belimumab. Abatacept (CTLA4-Ig), which
response to therapy. 77 is also approved for rheumatoid arthritis and blocks T-cell activa-
Although corticosteroids are the foundation of treatment, tion, was no better than placebo in trials of active lupus and of
exposure must be minimized to the greatest extent given their lupus nephritis, again added to background therapy of
multiple and frequent side effects, including hypertension, diabetes corticosteroids and MMF. A redesigned trial of abatacept for SLE
mellitus, increased susceptibility to infection, bone loss, and is now being conducted. Epratuzumab (anti-CD22 antibody)
weight gain (Chapter 86). Additional disease-modifying agents targeting all B cells failed a phase III clinical trial. TACI-Ig, which
that are also steroid-sparing include antimalarials (hydroxychlo- blocks both BAFF and APRIL, is undergoing clinical study, although
roquine), antimetabolites such as azathioprine (1–2.5 mg/kg per previous clinical trials were terminated prematurely because of
day), methotrexate (7.5–25 mg/week), leflunomide (10–20 mg/ infectious complications. Tocilizumab, an antibody to the IL-6
day), and mycophenolate mofetil ([MMF], 2–3 g/day), and receptor, a cytokine involved in B-cell survival and activation as
alkylating agents such as cyclophosphamide (monthly pulse well as in differentiation of Th17 and Tfh cells, which is approved
2
0.5–1.0 g/m ) (Chapter 87). When more conventional therapies for RA, demonstrated unacceptable toxicity in SLE. Other agents
have failed, anecdotal reports, case series, and open-label studies in earlier clinical development are inhibitors of intracellular B-cell
suggest the use of intravenous immunoglobulin (2 g/kg over signaling molecules designed to block B-cell activation; R406, a
2–5 days), thalidomide (50–100 mg/day), or cyclosporine (3–5 mg/ SYK inhibitor; and Janus tyrosine kinase (JAK) inhibitors. The
kg/day). Medications such as dapsone, danazol, and chlorambucil Jak inhibitors are being studied using topical administration for
may be efficacious in cutaneous disease, hematological disease, discoid lupus and oral administration for systemic disease.
and in severe refractory disease, respectively, but in general these Potential therapies aimed at DCs include vitamin D, which
medications are not commonly used due to their toxicity and blocks DC maturation and T-cell activation, and inhibitory
the introduction and availability of better-tolerated, efficacious oligodeoxynucleotides, which block TLR9 signaling and DC
agents. Belimumab, a monoclonal antibody directed against BAFF maturation. However, a study of vitamin D supplementation
(Chapter 89), was approved by the FDA for treatment of SLE designed to assess vitamin D inhibition of DC activation failed
in 2011 and represents a therapeutic option for patients with to demonstrate efficacy. Hydroxychloroquine, a standard agent
nonrenal, non-CNS active disease. for lupus, interferes with TLR7 and TLR9 signaling by preventing
A number of newer agents are on the horizon for treatment acidification of the endosomal compartment. A study of a novel
of SLE. Some are currently available but approved for other RNase is under way.

TABLE 51.4 treatments for Systemic Lupus Erythematosus Disease Manifestations
Low-Dose Corticosteroids High-Dose Corticosteroids
NSaIDs antimalarials † (<0.5 mg/kg per day) (>0.5 mg/kg per day) ‡ azathioprine MMF CtX
Constitutional + + + +
Musculoskeletal + + + + +
Mucocutaneous + +
Serositis + + + +
Hematological + + +
Renal + + + +
Central nervous system + +
Vasculitis + + + +
CTX, cyclophosphamide; MMF, mycophenolate mofetil; NSAIDs, nonsteroidal antiinflammatory drugs.
† Antimalarials should be given to all patients to sustain remission and reduce damage.
‡ High-dose corticosteroids are required for remission induction or an inadequate response to low-dose therapy.