US Pharm. 2012;37(4):54-58.
Scleroderma, also referred to as systemic sclerosis
(SSc), is a multisystem autoimmune disorder of the connective tissue.
It consists mainly of immunologic and vascular changes, and is
characterized by fibrosis and degenerative changes in the skin and other
organs (e.g., heart, lungs, kidneys, gastrointestinal [GI] tract).
Severe esophageal dysfunction is the most common visceral complication,
while lung involvement (e.g., pulmonary fibrosis, interstitial lung
disease) is the leading cause of death.1-4
SSc has three main features: excessive collagen production
and deposition, vascular damage, and inflammation or autoimmunity. It
is classified into two subsets based on skin involvement: limited
cutaneous (lcSSc) and diffuse cutaneous (dcSSc).1-3 Raynaud’s
phenomenon is usually the first clinical manifestation of lcSSc and is
typically seen in the majority of SSc patients. It is defined as a
bilateral, episodic reaction of the fingers, toes, and/or nose caused by
arterial vasospams.5,6 In certain cases, Raynaud’s phenomenon may be present for years before fibrosis is apparent.4,7
Therefore, early identification and close monitoring of patients with
Raynaud’s phenomenon may provide valuable prognostic information to
The incidence of SSc is estimated to be 2.3 to 22.8 cases
per 1 million persons per year. It affects approximately 75,000 to
100,000 people in the United States.9,10 SSc is reported to
occur more commonly in women than in men (3:1 to 14:1, respectively), is
usually diagnosed between 30 and 50 years of age, and has been linked
to genetic predisposition as well as environmental exposure (e.g.,
industrial solvents).4,9 Although its etiology in unknown,
immunologic abnormalities, fibroblast activation, chronic inflammation,
and vascular damage are believed to be the main pathogenic elements of
SSc. Early microvascular damage, mononuclear cell infiltrates, and
fibrosis are generally followed by very densely packed collagen in the
dermis, loss of cells, and atrophy in later stages of the disease.4
In the majority of patients, anticentromere and antitopoisomerase-I
autoantibodies are detected, reflective of immunologic changes.6,11
In addition to genetic predisposition, it has also been hypothesized
that psychological or mechanical stress (e.g., surgery, trauma, or
injury) can also activate or exacerbate the pathogenic process of SSc.12
The criteria for SSc are the oldest of the rheumatic diseases.13
In 1980, the American Rheumatism Association presented the Preliminary
Clinical Criteria for Systemic Sclerosis, which consisted of proximal
scleroderma as the major criterion and sclerodactyly on the fingers
and/or toes, digital pitting scars or loss of substance of the digital
finger pads, and bibasilar pulmonary fibrosis as the minor criteria for
diagnosis. Diagnosis of SSc is fulfilled if a patient meets the major
criterion or two of the minor criteria. Over the years, these criteria
were found to lack specificity for the diagnosis of early SSc because
emphasis was placed on cutaneous manifestations, but not other vascular
or immunologic changes that may occur prior to the onset of Raynaud’s
phenomenon or other skin changes.10,13
In 2001, additional criteria were proposed for the classification of early SSc, known as limited SSc
(lSSc). In addition to immunologic testing, confirmed Raynaud’s
phenomenon, abnormal nailfold capillary patterns, and/or SSc-specific
autoantibodies were recommended for early diagnosis of lSSc. For lcSSc,
the presence of digital cutaneous changes is required in addition to the
criteria for lSSc. Skin sclerosis is generally confined to the hands,
forearms, face, and neck. The diagnosis of dcSSc requires the criteria
for lSSc plus the presence of proximal cutaneous changes. Patients with
dcSSc commonly have chest, abdomen, upper arm, and/or shoulder
involvement, and are also at greater risk for developing various disease
complications (e.g., organ damage) than those with lcSSC.6
Rheumatologists are key in the management of SSc. Their
expertise and experience will help in developing appropriate and
individualized treatment plans, which may be complex and challenging.
Patients with dcSSc and visceral organ involvement may be particularly
difficult to manage due to the numerous complications that can arise.
Currently, there are no FDA-approved therapies for SSc; however, the
goals of therapy are to prevent complications and reduce morbidity
associated with SSc. Select agents, which have shown benefit and/or
promise in the treatment of SSc patients, are reviewed below.
Glucocorticoids: Corticosteroids are
used in numerous autoimmune disorders for their immunosuppressant and
anti-inflammatory properties. Despite limited data, oral prednisone may
be prescribed for its systemic effects, while topical corticosteroids
(e.g., triamcinolone) may be used to help prevent progression and
improve scleroderma affecting the scalp and forehead. In most cases,
glucocorticoids are used for controlling pain caused by arthralgias or
myalgias (similar to nonsteroidal anti-inflammatory drugs [NSAIDs]).
However, these agents should be used for the shortest duration possible
to avoid long-term consequences such as osteoporosis, glucose
abnormalities, ocular disorders, and weight gain. In addition,
prednisone is associated with an increased risk of scleroderma renal
crisis, especially at higher doses (>40 mg/day). Therefore,
alternative analgesics, such as NSAIDs and acetaminophen, can be
administered as initial agents for arthralgias.14,15
Vitamin D Analogues: These compounds
have also shown promise in the treatment of SSc by affecting
keratinocyte differentiation and proliferation. Topical calcipotriene
ointment has been reported to be well tolerated and to yield improvement
in a small group of patients with localized SSc after 3 months of
treatment.16 Calcitriol also inhibits fibroblast
proliferation, collagen synthesis, and, potentially, T-lymphocyte
activation. Oral dosages of 0.5 to 0.75 mcg daily have been well
tolerated and seen to increase joint mobility and extensibility of the
skin after 3 to 7 months of treatment.17,18
Immunosuppressants: These drugs have also
been used in SSc with debatable benefits. Methotrexate, an antirheumatic
agent, may suppress the immune system in addition to inhibiting DNA
synthesis and cell reproduction in abnormal cells. Although it has been
studied and found effective in a number of autoimmune disorders, data
are limited regarding methotrexate use in SSc patients. In a few case
studies investigating the use of methotrexate with or without
concomitant corticosteroid therapy in a small sample of patients,
methotrexate was found to yield a significant benefit in resistant and
active localized SSc with no serious adverse reactions reported after 3
to 6 months of therapy.19,20 In one randomized,
placebo-controlled, double-blind study of 29 SSc patients in the
treatment group (who received weekly injections of methotrexate),
methotrexate demonstrated significant improvements in skin induration
and handgrip strength after a 6-month follow-up period.21
CBCs, platelet counts, liver function, blood urea nitrogen (BUN),
creatinine, and estimated glomerular filtration rate should be monitored
at baseline and throughout the duration of therapy.
Cyclosporine, another immunosuppressant agent, selectively
inhibits the release of interleukin (IL)-2 from activated T
lymphocytes; IL-2 is believed to be elevated in patients with early SSc.
In one open-label trial of 10 SSc patients, a decrease in skin
induration was noted; however, no improvement was seen in pulmonary or
cardiac involvement after a 48-week follow-up. Nephrotoxicity occurred
frequently, but was transient and seen primarily with the use of higher
doses of cyclosporine (>3 to 4 mg/kg/day).22 In addition
to carefully monitoring renal function, hypertension, and bone marrow
suppression, it is important to remember that cyclosporine can interact
with a number of other medications as well.
Antifibrotic Agents: Antifibrotics
are also used in SSc due to the extensive fibrosis and related
complications that may occur. D-penicillamine is a chelating agent
involved in the cross-linkages of collagen. In one retrospective study
with a mean follow-up period of 38 months, results showed various
benefits in early SSc patients including a considerable decrease in
degree and extent of skin thickness, significant reduction in the rate
of new visceral organ involvement, and significant increase in 5-year
cumulative survival rate.23 In a multicenter, double-blind,
randomized clinical trial conducted years later, investigators noted
that there were no statistical differences in skin induration, incidence
of renal crises, or survival rate between the high-dose (750-1,000
mg/day) and low-dose (125 mg every other day) D-penicillamine groups
after a 24-month follow-up period. In addition, the majority of adverse
events (including proteinuria) occurred in patients receiving the higher
doses of D-penicillamine. Therefore, it was concluded that there is no
therapeutic benefit for using more than 125 mg every other day for SSc.24
Colchicine may also have a role in SSc as a result of its
interference with collagen synthesis, fibroblast proliferation
reduction, enhancement of collagenase activity, and anti-inflammatory
properties. It is generally well tolerated and was found to improve skin
elasticity, mouth opening, and finger motility, and to reduce dysphagia
in a small, uncontrolled study.25 CBCs, liver function, and renal function should be monitored at baseline and periodically during treatment.
Potential Treatments: Other agents and
interventions that have limited data available but show promise in the
treatment of SSc and its manifestations include interferon gamma,
minocycline, psoralen UVA, losartan, telmisartan, prazosin,
mycophenolate mofetil, oral etretinate, etanercept, thalidomide,
imatinib mesylate, statins, and allogeneic bone marrow or stem cell
transplantation.15,26-37 All of these potential treatments,
as well as the aforementioned therapeutic agents, require additional
controlled clinical trials with larger sample sizes in order to better
evaluate the potential benefits and risks for each and utilize them
appropriately in the individualized care of patients with SSc.
A number of recommendations for SSc (based on clinical
data and expert opinion) have been published by the European League
Against Rheumatism (EULAR)/Scleroderma Trials and Research (EUSTAR)
group (TABLE 1). In regard to skin involvement, dihydropyridine
calcium channel blockers (usually oral nifedipine) are recommended as
first-line therapy for the reduction of severity and frequency of
SSc-related digital vasculopathy. These agents are vasodilators that
help to improve peripheral circulation and reduce vasospasms (i.e.,
Raynaud’s phenomenon). For severe Raynaud’s phenomenon or active digital
ulcers, patients with SSc should be given IV prostanoids (usually
iloprost) due to their prolongation of vasodilation, reduction of
platelet aggregation, and promotion of endothelial cell lining.
Bosentan, a dual endothelin receptor antagonist found to reduce the
frequency of new digital ulcers, is recommended in cases that fail
therapy with calcium channel blockers and/or prostanoids.13,15,34
In patients with lung involvement, specifically pulmonary
arterial hypertension (PAH), bosentan is strongly recommended as a
result of data that demonstrated the prevention of deterioration in
exercise capacity and improved survival in patients with SSc-associated
PAH. Sildenafil, a selective type 5 phosphodiesterase inhibitor, may
also be considered for SSc-associated PAH since data have demonstrated
significant improvement in hemodynamics, exercise capacity, and
functional class. In severe cases, IV epoprostenol may be used. This
agent is also a vasodilatory prostaglandin, which inhibits platelet
aggregation and has been reported to improve exercise capacity,
hemodynamics, severity of Raynaud’s phenomenon, and healing of digital
Methotrexate is recommended for SSc-associated skin
involvement owing to improvements in skin scores noted with its use.
Cyclophosphamide has also been reported to improve skin changes;
however, it should be considered for the treatment of SSc-associated
interstitial lung disease because of its effects on improving lung
function tests, dyspnea, and quality of life.13,15,34
For SSc-associated renal crisis, angiotensin-converting
enzyme (ACE) inhibitors are recommended for treatment. In addition to
their renoprotective effects, ACE inhibitors have demonstrated effective
blood pressure control in patients with SSc. However, prophylactic use
is not supported due to the potential for poorer outcomes in patients
who develop SSc renal crisis.13,15,34,35
In cases of SSc-associated GI issues, proton pump
inhibitors are recommended for the prevention of gastroesophageal
reflux, esophageal ulcers, and strictures. Prokinetic agents (e.g.,
octreotide, cisapride) may be considered for SSc patients with
symptomatic motility disturbances such as dysphagia. Experts also
suggest that the rotation of antibiotics may be useful in SSc patients
with malabsorption, which is secondary to bacterial overgrowth.36-38
In conjunction with appropriate rheumatologic
interventions, certain lifestyle modifications may help to alleviate
various signs and symptoms associated with SSc. Patients should be
cautioned about consuming large doses of vitamin C (>1,000 mg/day)
due to its potential to stimulate collagen formation and enhance its
deposition. Exercise and physical and/or occupational therapy are also
encouraged to maintain good mobility and minimize or delay contractures.
GI involvement may necessitate changes in diet such as incorporating
smaller frequent meals throughout the day rather than larger meals. In
addition, patients with SSc should be instructed to keep digital ulcers
dry and clean and to avoid dermal contact with any potentially corrosive
or abrasive substances. In addition, protecting fingers and toes from
trauma or cold temperatures, as well as maintaining a core body
temperature, may help prevent episodes of Raynaud’s phenomenon and
Role of the Pharmacist
The treatment of SSc and its complications is complex and
requires careful evaluation of the available literature. In
collaboration with physicians and other health care providers,
pharmacists must assess the risks and benefits of each therapeutic
option prior to formulating a treatment plan. All interventions should
be individualized and carefully monitored for adverse events. In
addition, potential drug interactions should always be reviewed and
taken into consideration when finalizing a treatment regimen.
Pharmacists are a valuable source of information and should provide
comprehensive counseling for patients with SSc.
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