Page 850 - Clinical Immunology_ Principles and Practice ( PDFDrive )

822 Part SIX Systemic Immune Diseases

ON tHE HOrIZON consecutive days, therapy was continued with oral prednisone,
and daily doses were swiftly tapered. Compared with the control
• Medium and large arteries in humans sense danger signals through arm, patients who received three initial steroid pulses had lower
wall-embedded cells; changing the understanding of how the immune likelihoods of disease flare-ups. Particularly, once they reached
system interacts with the vascular system.
• The multilineage nature of vasculitic T cells, which display differential prednisone doses close to 10 mg/day, these patients could tolerate
therapeutic responsiveness, almost certainly will require more complex steroid withdrawal significantly better, and most were taking 5 mg/
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therapies, adapted to disease stage and immune status of the host. day prednisone at 36 weeks. The benefit from initial pulse therapy
• The immune system changes profoundly with age. Age-appropriate continued over subsequent months, suggesting the potential benefit
management of each patient and avoidance of overtreatment of older of intense immunosuppression during early disease.
adults are important. Several biological agents have been explored or are currently
• Current therapies in large-vessel vasculitis induce partial remission. undergoing testing in clinical trials. Tumor necrosis factor-α
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Appropriately designed studies are required to explore whether partial
remission is sufficient and whether the risk/benefit ratio is maintained (TNF-α) inhibitors may have a role in TA but had no steroid-
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if complete remission is attempted. sparing effect in GCA. Preliminary study results suggest that
targeting T-cell costimulation with abatacept may prevent disease
relapses in GCA. Ustekinumab, a monoclonal antibody (mAb)
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by an immune network distinct from that in untreated patients. targeting IL-12 and IL-23, was reported to have potential efficiency
It is currently not known whether this persistent smoldering in refractory GCA in a small open-label study. The IL-6 receptor
process needs to be treated and what the risk/benefit ratio is for blocker tocilizumab has been explicitly effective in reducing acute
the older patient population affected by GCA. Unchanged life phase reactants (CRP, ESR) and is being explored in GCA and
expectancy in GCA suggests adequacy of current management. TA and a phase 3 double-blind trial of tocilizumab given weekly
Whether intensification of immunosuppressive therapy or chronic or every other week demonstrated substantial steroid-sparing
maintenance therapy can prevent long-term complications, such effect over a one-year period. 12
as aortic aneurysm/dissection from GCA aortitis, and improve
the overall prognosis is unknown. The ultimate decision depends Maintenance Therapy
on the cost/benefit analysis comparing the risk from smoldering With a major shift in the pathogenic concept about LVVs,
disease with the risks imposed by long-standing immunosup- especially the realization that the disease process has two, partly
pression. In that context, it is important to remember the independent components (extravascular, vascular) and that
profound impact of the immune aging process, which leaves the vessel wall infiltrates persist chronically, the therapeutic needs
patient with an impaired immune system and amplifies the risk for maintenance therapy have become the dominant issue for
of immunosuppression. 39 the treating physician. Patients with PMR are often managed
successfully with low-dose corticosteroids (prednisone 5 mg daily)
Induction Therapy and typically are highly responsive to transient and very small
In newly diagnosed patients with GCA, TA, and PMR, the dose increases (1–2 mg prednisone/day). Long-term management
immunosuppressants of choice are corticosteroids. Patients with of patients with GCA and TA relies on low-dose corticosteroids
GCA are started on a daily prednisone dose of 40–60 mg (about as well unless there is objective evidence for progressive vascular
1 mg/kg body weight). In patients with PMR, a daily dose of wall inflammation. Unfortunately no reliable biomarkers can
20 mg prednisone is sufficient in almost all patients. The response separate the extravascular and vascular disease components, and
is usually dramatic, with improvements within 24–48 hours. no evidence that suppressing acute phase response in the periphery
The promptness of clinical improvement is so exceptional that will ultimately restrict transmural vasculitis has been presented.
it has been suggested as a diagnostic criterion for PMR. However, Methotrexate is considered to have mild-to-moderate steroid-
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the promptness of response may be limited to extravascular LVVs. sparing potential in GCA and PMR but is more frequently
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Myalgias, fever, malaise, and headaches improve swiftly, in parallel used in TA. When given to human artery–severe combined
with a fast reduction of acute-phase reactants (CRP, IL-6, ESR). immunodeficiency (SCID) chimeras, acetylsalicylic acid (aspirin)
Emerging data suggest that the vascular component is much has marked antiinflammatory activities, with suppression of IFN-γ
more resistant to immunosuppression and may require entirely in vascular lesions. Clinical trials are needed to test whether this
new therapeutic strategies. immunosuppressive action can translate into corticosteroid
Once the condition is stabilized, steroid tapering is guided sparing. Because arteries are the primary targets of LVVs, the use of
by close monitoring of the clinical presentation as well as labora- aspirin as an antiplatelet agent should be routinely recommended.
tory markers of inflammation. In general, steroids should be There is no evidence that immunosuppressants, such as
reduced by 10–20% every 2 weeks. Monthly monitoring of ESR azathioprine and cyclophosphamide, lower steroid needs, prevent
and CRP is mandatory to adjust therapy. Patients frequently vascular complications, or shorten the duration of steroid use.
return with signs or symptoms of recurrent disease as immu- Whether any of the biological agents described above has a place
nosuppression is lowered. Fortunately, disease exacerbations to effectively suppress vessel wall inflammation and change the
causing vision loss are infrequent. Disease flare-ups typically course of chronic disease is currently unknown.
present with PMR symptoms or nonspecific manifestations of An integral part of chronic immunosuppression with pred-
malaise and failure to thrive. In most patients, a transient small nisone is regular monitoring for diabetes and hypertension.
increase in the steroid dose reinstates disease control. Patients should be encouraged to increase physical activity, as
Much effort has been invested in identifying steroid-sparing steroid-induced myopathy occurs frequently. A major issue of
agents. In a small study, treatment with pulse corticosteroids chronic steroid treatment, particularly in older individuals, is
appeared to have long-term beneficial effects, reducing the overall the risk of excessive bone loss, possibly resulting from increased
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steroid requirement and the rate of disease flare-ups. After bone resorption and impaired bone formation. Several effective
pulses of 1000 mg methylprednisolone were administered for 3 and safe therapies for osteopenia/osteoporosis are available.