Page 782 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 55 Scleroderma–Systemic Sclerosis 753

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Evidence-based management of SSc is helpful while innova-
Emotional Aspects tive therapies are being further studied in clinical trials.
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SSc impacts every aspect of a patient’s life and is a disfiguring Scleroderma is a multifaceted disease that includes active autoim-
disease; therefore, it is not surprising that significant depression munity, vascular injury, and fibrosis and/or epithelial damage.
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is common among patients with SSc. Patients are frequently Thus the major targets for therapy include regulating the immune
distressed by their appearance and avoid social interaction. system, controlling tissue fibrosis, and protection or prevention
Chronic pain and lack of social support are major causes of of progressive vascular disease. The majority of therapeutic
depression; therefore, family education, emotional support, pain interventions for scleroderma attempt to modify the disease
control, and management of depressive symptoms are most process by immunomodulation in early active dcSSc because of
important. the evidence that the SSc is an autoimmune disease initiated
and/or propagated by an immune process. Drugs currently used
Treatment for dcSSc include methotrexate, cyclophosphamide, and myco-
phenolate mofetil. Targeting specific immune cells is now a novel
tHEraPEUtIC PrINCIPLES strategy that includes eliminating B cells with rituximab and
Treatment of Systemic Sclerosis suppressing activation of T cells with abatacept. In cases of severe
life-threatening disease in highly selected cases not responding
Organ-Specific therapy to low-dose immunosuppression, immunoablative therapy with
• Vasodilator therapy for Raynaud phenomenon high-dose cyclophosphamide alone or with radiation, followed
• Proton pump inhibitor for gastroesophageal reflux by stem cell rescue, may be considered. Studies to evaluate the
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• Angiotensin-converting enzyme (ACE) inhibitor for scleroderma renal safety and efficacy of stem cell therapies are in progress. Inhibit-
crisis ing proinflammatory and/or profibrotic cytokines or signaling
• Vasodilator therapy for pulmonary arterial hypertension pathways that may block tissue injury and fibrosis are being
• Antiinflammatory therapy for arthritis explored. These include antichemokines (CCR2) or inhibitors
• Immunosuppressive therapy for interstitial lung disease
of CTGFs, recombinant humanized mAb to block TGF-β1 activity,
Disease-Modifying agents modulation of interleukin-6 (IL-6) signaling, antagonists of the
• No ideal treatment available; immunomodulatory, antiinflammatory, bioactive phospholipid LPA, and small-molecule inhibitors, such
vasoactive, and antifibrotic agents are used and/or under study. as tyrosine kinase inhibitors or pirfenidone. It is recognized that
vascular disease also plays a fundamental role in the morbidity
and mortality seen in scleroderma. Novel drugs targeting vascular
To date, no drug or intervention has been proven to be effective disease, including endothelin receptor antagonists, agents that
and safe for modifying the overall disease course. Most successful enhance nitric oxide production, prostacyclin analogs, antiplatelet
SSc treatments are directed to the specific organ(s) involved. agents, and statins, are currently being used.
Therapy is focused on an organ-specific disease process (e.g.,
ACE inhibitor in SRC) or to aid a failing organ (e.g., proton ON tHE HOrIZON
pump inhibitors for GERD). Therefore it is important to carefully Novel Therapeutic Approaches to Systemic
characterize the patient’s clinical phenotype, specific organ Sclerosis (SSc) Management in Clinical Trials
involvement, and level of disease activity before deciding on
therapy. For example, a patient who has lcSSc but no evidence • Targeted therapies to block transforming growth factor-β (TGF-β)
of visceral organ involvement is likely to have a benign course • Development of antifibrotic agents, including new approaches to
that requires only symptomatic therapy (e.g., treatment of GERD blocking of fibrogenic pathways
and RP); use of systemic disease-modifying drugs would not be • Use of biological agents, including anticytokines, antichemokines, and
growth factor inhibitors
indicated. It is also important to distinguish disease activity from
severity or advanced cumulative organ damage. For example, a
patient with late-stage dcSSc with irreversible organ damage is Other Fibrosing Diseases
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unlikely to benefit from aggressive immunosuppressive or Several disorders can cause skin fibrosis and mimic SSc. SSc
antiinflammatory therapy. Intervention with currently available can be distinguished from these SSc-like fibrosing conditions
drugs should be initiated early, ideally during the edematous by its characteristic clinical, pathological, and laboratory features.
active inflammatory phase of the disease. It is during the early The most distinguishing clinical features of SSc include the
stage of the disease that immunosuppression and antiinflam- presence of RP, nailfold capillary changes, the characteristic
matory and antifibrotic agents have the greatest potential to distribution, and characteristic skin changes. The skin pattern
control disease progression. Clinical experience teaches that once in SSc is noted for severe finger, hand, and distal limb involvement
the edematous phase of the disease shifts to the more indolent and sparing of the skin of the back of the trunk. SSc-specific
fibrotic phase, current treatments are less likely to control the serum autoantibodies also help define the presence of the SSc
progression of disease and tissue damage. The primary outcome disease process.
measure in clinical trials that focused on aggressive skin disease Conditions that mimic SSC include localized forms of
has been the modified Rodnan skin score; in current studies, scleroderma (see Table 55.5), eosinophilic fasciitis, nephrogenic
however, composite scores that tally the burden of disease (activity systemic fibrosis, scleromyxedema (papular mucinosis), scler-
and severity) as well as patient reported distress are included. edema, graft-versus-host disease (GvHD), toxic oil syndrome,
Few well-designed controlled studies have been carried out for and eosinophilia–myalgia syndrome (Table 55.6). Eosinophilic
the treatment of early active disease; most reports are of anecdotal, fasciitis presents with induration of subcutaneous tissues, par-
uncontrolled experiences, complicated by investigator bias and ticularly in the proximal limbs, without RP or systemic organ
the highly variable natural course of SSc. involvement. A peripheral eosinophilia with radiological and