Scleroderma

Scleroderma

1 Overview

Summary and Quick Facts

  • Scleroderma is an autoimmune-like condition that affects the skin and connective tissues. It primarily affects the skin and underlying tissues, but can affect internal organs throughout the body, in which case it is called systemic scleroderma.
  • In this protocol, learn about factors that may contribute to scleroderma and available treatment options. Also learn how targeting fibrosis with natural interventions may compliment medical treatments.
  • Supplements such as green tea and vitamin E have anti-fibrosis properties and may support connective tissue integrity.

What is Scleroderma?

The term “scleroderma” refers to a group of related conditions primarily characterized by similar manifestations. Fibrosis (excessive connective tissue formation, almost always resulting in hardening of the skin), vascular damage, and autoimmune responses are all common in scleroderma. The cause of scleroderma is not well understood, and there are no drugs to cure the underlying condition.

Scleroderma can either be localized or systemic. Systemic scleroderma, also called systemic sclerosis, is much more severe; it can cause damage to internal organs unlike the localized condition.

Several natural interventions such as epigallocatechin gallate (EGCG) from green tea and N-acetylcysteine may be helpful for addressing the driving factors behind the disease’s progression.

What are the Risk Factors for Scleroderma?

  • Genetic predisposition
  • Exposure to some industrial chemicals

Note: The exact cause of scleroderma is unknown.

What are the Signs and Symptoms of Scleroderma?

  • Skin changes, including hardening, swelling, and abnormal lightening or darkening
  • Raynaud’s phenomenon, in which cold temperature or stress causes vasoconstriction. The affected limb(s) or digit(s) usually turn white with lack of blood flow, then blue with poor oxygenation, and then red when blood flow resumes.
  • Systemic sclerosis can cause other symptoms involving internal organs—coughing due to lung involvement, arrhythmia due to heart involvement, digestive problems, or scleroderma renal crisis if kidneys are affected.

What are Conventional Medical Treatments for Scleroderma?

Note: There is no known cure for scleroderma. Conventional treatments generally are palliative and aim to alleviate symptoms and reduce complications.

  • Drugs to improve blood flow for Raynaud’s phenomenon
  • Immunomodulatory or suppressing drugs for skin or lung fibrosis
  • Antacids or drugs that reduce stomach acid for digestive problems
  • Dialysis or blood pressure lowering drugs for renal crisis

What are New Research Directions for Treating Scleroderma?

  • Studying epigenetic or other methods to reduce proliferation and/or activation of fibroblasts
  • Drugs that destroy immune B cells or inhibit their production

What Dietary and Lifestyle Changes Can Help Manage Scleroderma?

  • Avoid cold temperatures and emotional stress to reduce Raynaud’s phenomenon attacks.
  • Exercise to enhance blood circulation and improve endothelial function.
  • Eat plenty of fresh fruits and vegetables to avoid malnutrition and reduce oxidative stress.

What Natural Interventions Can Help Manage Scleroderma?

  • Gamma-linolenic acid (GLA). GLA, an omega-6 fatty acid found in evening primrose oil, can reduce episodes of Raynaud’s phenomenon. It also may diminish pain and improve skin texture in those with scleroderma.
  • S-adenosylmethionine (SAMe). SAMe has many uses, and in scleroderma patients it has been shown to improve skin quality.
  • N-acetylcysteine (NAC). NAC can reduce the severity of Raynaud’s phenomenon, diminish lung-related complications of scleroderma, and improve vascular function of the liver and kidneys.
  • Vitamin E. Vitamin E can be helpful in several autoimmune disorders, including scleroderma. Several symptoms of scleroderma have been reported to respond well to vitamin E.
  • Green tea. Green tea and one of its active constituents, epigallocatechin gallate (EGCG), have beneficial effects on the endothelium. Evidence suggests EGCG suppresses tissue fibrosis.
  • Gotu kola. Gotu kola is an herb that has many skin-healing properties. In one study, patients treated with gotu kola saw improvements in skin quality, vascular health, and general condition.
  • Other natural interventions such as curcumin, 4-aminobenzoic acid, vitamin D, and melatonin may be beneficial to patients with scleroderma.

2 Introduction

The term “scleroderma” encompasses a spectrum of complex and variable conditions primarily characterized by 3 major phenomenon: abnormal, excess formation of connective tissue (fibrosis), vascular alterations, and an autoimmune response (Gabrielli 2009; A.D.A.M. 2013; Derk 2003; Balbir-Gurman 2012; Varga 2008). Scleroderma spectrum disorders share the common feature of hardening or thickening of the skin, but other manifestations can vary greatly between patients. Although the cause of scleroderma is not understood, the hallmark of scleroderma is fibrosis, which is a process similar to the formation of scar tissue; fibrosis is primarily brought about by inflammation. No cure currently exists for scleroderma (Gabrielli 2008; Gomer 2008).

There are 2 primary types of scleroderma:

  • The less severe form is called localized scleroderma. It is limited to the skin and underlying muscles, joints, and sometimes bones; it does not affect internal organs. In some cases, localized scleroderma may resolve on its own (Mayo Clinic 2010; NIAMS 2012; Gabrielli 2009; Clemens 2003; Klein-Weigel 2011; Hawk 2001; Takehara 2005). There are about 27 new cases of localized scleroderma per million people per year (Peterson 1997).
  • The more widespread and severe form is called systemic scleroderma (also known as systemic sclerosis). This form is progressive and occurs throughout the body, affecting internal organs as well as the skin (Chatterjee 2010). It may affect the connective tissue of the lung, kidney, heart, and other organs, as well as blood vessels, muscles, and joints (Hawk 2001; Heinberg 2007). There are 2 subtypes of systemic sclerosis: limited cutaneous systemic sclerosis (historically known as CREST syndrome) and diffuse cutaneous systemic sclerosis (Jimenez 2012; Gabrielli 2009). Limited cutaneous systemic sclerosis typically affects the skin on limited areas of the body, such as the fingers, hands, or the face and is less likely to involve internal organs early in disease progression. Diffuse cutaneous systemic sclerosis, which may start suddenly and spread over much of the body, is associated with a poorer prognosis  (Hughes 2012). There are about 19 new cases of systemic sclerosis per million people per year (Jimenez 2012).

Conventional management strategies for scleroderma are limited to interventions that control specific symptoms; no drug has been developed that successfully treats the underlying cause(s) of scleroderma (Hinchcliff 2008). On the other hand, natural strategies may offer a means of directly targeting fibrosis, a destructive process that involves the formation of tough connective tissue through inflammatory pathways and is a central driving force behind scleroderma progression. Natural constituents like epigallocatechin gallate (EGCG) from green tea, N-acetylcysteine, and vitamin E may help preserve tissue integrity in scleroderma sufferers (Chang 2013; Rosato 2009b; Fiori 2009; de Souza 2009). Moreover, maintaining adequate blood levels of vitamin D may be an important consideration for individuals affected by scleroderma, since studies show it can directly modulate signaling pathways that contribute to fibrosis (Slominski 2013; Arnson 2011).

In this protocol you will learn about the different types of scleroderma and how they are diagnosed and treated. Future research directions will be explored, and a variety of scientifically studied natural interventions will be reviewed. Some important dietary and lifestyle considerations will be presented as well.

3 Development and Progression of Scleroderma

Scleroderma is primarily the consequence of 3 major factors: blood vessel damage, an autoimmune response, and fibrosis. In many ways, these factors create a vicious cycle, thus the disease is typically progressive; this is especially so for systemic sclerosis (Gabrielli 2008; Gomer 2008).

Blood Vessel Damage

Small blood vessels are especially prone to the damage and dysfunction caused by scleroderma. Vascular dysfunction is mostly the result of inflammation and fibrosis, which cause blood vessels to become “stiff” and disrupt their ability to expand and contract (Varga 2008). A major hallmark of vascular damage that occurs in scleroderma is endothelial dysfunction. The endothelium is the delicate innermost lining of blood vessels (Varga 2008; Deanfield 2005; Patel 2001; Gabrielli 2009). In severe cases of systemic sclerosis, dramatic vascular dysfunction can be life threatening (Hummers 2008).

In addition, scleroderma is associated with increased deposition of calcium in blood vessels. In one study, systemic sclerosis patients were found to have an 11-fold increased risk of moderate-to-severe calcification in the arteries that supply the heart (Mok 2011). Moreover, autopsy investigations of systemic sclerosis patients have found extensive calcification of small blood vessels that supply the brain (Heron 1998). 

Inflammation and Autoimmune Response

Inflammatory and autoimmune reactions also contribute to the tissue damage and dysfunction seen in scleroderma. Blood vessel alterations lead to an inflammatory response within the endothelium. In turn, damaged endothelial cells release inflammatory signaling molecules that recruit immune cells, in particular CD4+ helper T-cells, to the blood vessel walls. The presence of excessive inflammatory mediators serves to reinforce the continued deterioration of blood vessel integrity and subsequent generation of more inflammation and fibrosis. Autoimmunity also contributes to inflammatory damage of the blood vessels, though it is not known with certainty if an autoimmune response is the key initiating factor in scleroderma (Varga 2008; Castro 2010; Gabrielli 2009).

Fibrosis

Fibrosis describes the hardening or stiffening of tissues that are normally soft and malleable. It occurs as a result of over activation of specialized cells called fibroblasts, which produce collagen and the "glue" (called extracellular matrix) that holds tissues together. Connective tissue is made of collagen and other proteins, so when excessive collagen is produced via overactivation of fibroblasts, connective tissue can accumulate abnormally, thus contributing to tissue fibrosis. DNA damage and pro-inflammatory oxidative stress, which is increased in patients with scleroderma, is proposed to be a major driving force behind fibroblast overactivation (Gabrielli 2012; Avouac 2010).

Fibrosis is responsible for the most obvious symptom of scleroderma – hardening of the skin. However, fibrosis of organs and blood vessels can occur as well and this contributes to some of the systemic complications associated with scleroderma.

The Role of Oxidative Stress and Inflammation in Scleroderma

Accumulation of free radicals is thought to play a significant role in the development and progression of scleroderma, especially in tissue fibrosis. It has been suggested that perturbed balance between endogenous free radical formation and antioxidant defense mechanisms may be present in scleroderma, leading to excessive generation of reactive oxygen species (Gabrielli 2012). Indeed, increased oxidative DNA damage has been observed in scleroderma patients compared to healthy controls (Avouac 2010).

There are a few theories about how free radicals contribute to tissue fibrosis in scleroderma. First, free radicals may directly activate specialized cells called fibroblasts, which produce collagen and the extracellular matrix. Another theory suggests that, rather than directly activating fibroblasts, free radicals may make it much more difficult for excess connective tissue to be broken down and cleared by the body, leading to accumulation of fibrous tissue indirectly. Most likely, both of these mechanisms, and probably others yet to be discovered, are involved in the relationship between oxidative stress and tissue fibrosis in scleroderma (Gabrielli 2012).

Despite uncertainties surrounding the exact contribution of reactive oxygen species to scleroderma, scientists propose that therapy with antioxidants may effectively mitigate some of the fibrotic changes induced by oxidative stress. For example, evidence from animal and human studies suggests the antioxidant phytochemical epigallocatechin gallate (EGCG) found in green tea may guard against fibrotic changes (Dooley 2010, 2012).

Inflammation also plays a role in mediating the development of scleroderma. Particularly, the blood vessel damage characteristic of scleroderma is largely driven by inflammatory reactions. Inflammation may also contribute to tissue fibrosis (Barnes 2011).

The inflammatory mediator interleukin-6 (IL-6) has attracted significant interest from the research community as a potential therapeutic target in scleroderma treatment. Interestingly, fibroblasts isolated from skin lesions of individuals with systemic sclerosis express higher levels of IL-6 than fibroblasts from healthy individuals (Feghali 1992). Clinical trials are underway investigating the efficacy of IL-6 modulation in scleroderma treatment (Barnes 2011).

Additional evidence in support of an important role for inflammation in scleroderma comes from findings that components of the immune system called T-cells have been found at sites of fibrosis in an “activated” state. This means that these immune cells are recruited to the site of fibrosis and are actively promoting inflammatory reactions, including the generation of IL-6 (O'Reilly 2012). Moreover, the degree of skin thickening at sites of cutaneous fibrosis in scleroderma correlates with the number of T-cells that have infiltrated the tissue, suggesting an intimate relationship between fibrotic changes and the presence of inflammatory immune cells (Fleischmajer 1977). Treatment modalities targeting T-cells have shown some promise and are continually being evaluated (O'Reilly 2012).

4 Causes and Risk Factors

The exact cause of scleroderma is unknown. However, several factors are thought to influence risk, including environmental exposures and genetic susceptibility (ie, family history) (Castro 2010; Agarwal 2010a,b; Dieude 2011). For example, exposure to chemicals like polyvinyl chloride (used in the plastics industry), industrial solvents (such as paint thinners), and silica may trigger or exacerbate scleroderma (Barnes 2012; Varga 2008; Mora 2009; NIAMS 2010). Also, over 30 genes and gene regions are known to influence scleroderma susceptibility; most of these genes are related to the immune system (Mayes 2012).

5 Signs and Symptoms

The manifestations of scleroderma are variable and dependent upon the extent of systemic involvement. For example, localized scleroderma may affect only the fingers and cause moderate hardening of the skin, whereas severe systemic sclerosis can compromise internal organs such as the lungs and kidneys and be life threatening. Some of the more prominent features of scleroderma include:

Skin Changes

Skin manifestations of scleroderma include puffy and swollen fingers, hands, and toes, along with thickening and hardening of the skin, which can also affect the face and trunk. The areas of the skin affected often appear shiny and hair loss occurs in affected regions as well; skin may also appear abnormally light or dark. Tightening of the skin on the face can give a mask-like appearance. Sometimes, patients develop ulcers on their fingertips or toes, which can lead to scarring. In addition, small blood vessels just beneath the top layer of the skin may become dilated and more visually pronounced, called telangiectasias (Gaby 2006; Chatterjee 2010; A.D.A.M. 2013). 

Raynaud's Phenomenon

Raynaud's phenomenon is present in up to 95% of patients with scleroderma (Hinchcliff 2008; Simonini 2000; NIAMS 2010). Raynaud’s phenomenon is a complex vascular disorder in which blood vessels, particularly those in the fingers and toes, or rarely the tongue, nose, ears, lips, or nipples, overreact to cold temperature or emotional stress (Mayo Clinic 2011; Herrick 2012; Martínez 2011). The blood vessels constrict (ie, vasoconstriction), reducing blood flow to the affected extremity. This results in numbness while blood flow is reduced and tingling and/or pain as blood flow returns to the affected area (Herrick 2012; Martínez 2011). These attacks may last from minutes to hours, and the intensity of discomfort may vary from mild to severe (Malenfant 2011; NCBI 2011; Martínez 2011). In severe cases, prolonged oxygen deprivation can lead to tissue death in the affected extremities (Herrick 2012). More information is available in the Raynaud’s Phenomenon protocol.

Internal Organ Involvement

Systemic sclerosis can affect multiple internal organs. However, the disease does not progress in exactly the same way in all patients. Some significant manifestations include (Balbir-Gurman 2012):

  • Symptoms due to lung involvement include dry cough and shortness of breath (A.D.A.M. 2013). Cough is usually correlated with the degree of fibrosis in the lungs (Theodore 2012). Lung function tests are abnormal in as many as 80% of scleroderma patients (Jimenez 2012).
  • Heart and cardiovascular complications are caused by scarring and weakening of the heart muscle, and include myocarditis and arrhythmia (NIAMS 2012). In addition, patients with systemic sclerosis have significantly increased risk of atherosclerosis, heart attack, stroke, and peripheral vascular disease compared to healthy individuals (Man 2013; Au 2011). Thus, individuals with systemic sclerosis are also encouraged to review Life Extension’s Atherosclerosis and Cardiovascular Disease protocol.
  • A serious complication, when the kidneys are affected, is scleroderma renal crisis. This may lead to abrupt onset high blood pressure and progressive kidney failure (NIAMS 2012).
  • Digestive problems include difficulty swallowing, esophageal reflux, bloating, diarrhea, constipation, and fecal incontinence (A.D.A.M. 2013). 

6 Diagnosis and Conventional Treatment

Physicians may suspect scleroderma based on presentation of the characteristic signs and symptoms mentioned previously. Although there is no specific test for scleroderma, a diagnostic workup may include a detailed medical history, laboratory findings, and skin biopsy (NIAMS 2010; Nashel 2012; Khoo 2011).

Doctors may test for autoantibodies against topoisomerase (Scl-70), centromere-associated proteins, and nuclear antigens (ANA); this can aid in diagnosis but must be supported by other evidence (Grassegger 2008). Rheumatoid factor, another autoantibody, may be present in some patients as well. Abnormalities on routine lab tests may help identify involvement of specific organs (Ferri 2013). Elevated levels of the inflammatory marker C-reactive protein (CRP) have been associated with worse outcomes in some patients and may help influence treatment decisions (Muangchan 2012). Diagnosing scleroderma can be difficult due to the significant variability in disease presentation.

Scleroderma has no known cure. There are a variety of medications that can help palliate symptoms and reduce complications of scleroderma, but medications that modify the course of the disease are lacking (Kowal-Bielecka 2009; Opitz 2011; Baumhakel 2010; Gayraud 2007).

Treatments for Organ-Specific Complications of Scleroderma (Hinchcliff 2008)

Complication

Treatment

Raynaud's phenomenon

  • Drugs that can improve blood flow:
    • α – Adrenergic blockers
    • Angiotensin-II receptor blockers
    • Long-acting calcium channel blockers (dihydropyridines)
    • Pentoxifylline (Trental®)
  • Digital sympathectomy (surgery that interrupts the small nerves to the arteries feeding the finger)

Skin fibrosis

Immunomodulatory drugs (D-penicillamine [Cuprimine®], mycophenolate mofetil [Cellcept®], cyclophosphamide [Cytoxan®])

Gastroesophageal reflux disease (GERD)

  • Antacids
  • Drugs that reduce stomach acid:
    • Histamine H2 blockers
    • Proton pump inhibitors

Intestinal dysmotility and/or bacterial overgrowth

  • Antibiotics
  • Correction of nutritional deficiencies
  • Promotility agents

Pulmonary (lung) fibrosis or alveolitis

cyclophosphamide (Cytoxan®; an immune-suppressing drug)

Pulmonary arterial hypertension

  • Diuretics
  • Supplemental oxygen
  • Drugs that minimize blood vessel clots (Warfarin [Coumadin®])
  • Drugs that improve blood flow including:
    • Endothelin-1 receptor inhibitors (bosentan [Tracleer®])
    • Phosphodiesterase-5 inhibitors (sildenafil [Revatio®])
    • Prostacyclin analogues (epoprostenol [Flolan®], treprostinil [Remodulin®], iloprost [Ventavis®])

Scleroderma renal crisis

  • Dialysis
  • Blood pressure lowering drugs (eg, short-acting angiotensin-converting enzyme inhibitors)

Side effects of conventional treatment vary with medication, and may include fluid buildup in the feet, constipation and gastrointestinal disturbances, fatigue, flushing, allergic symptoms, gingivitis (inflammation of the gums), and erectile dysfunction. Steroids such as prednisone are frequently used for their anti-inflammatory action. However, steroids have significant side effects, including loss of bone density and weight gain.

7 Future Research Directions

Despite intensive study for several years, many questions about scleroderma remain unanswered. This is reflected by the fact that the mortality rate for scleroderma patients has not changed significantly over the past 40 years (Elhai 2012). However, as scientists continue to piece together the biologic framework of scleroderma, there is hope that therapeutics that target pathways leading to tissue fibrosis can be developed resulting in improved patient outcomes (Leask 2012).

Much of scleroderma research now focuses on developing ways to reduce the proliferation and/or activation of fibroblasts (Jungel 2011). Avenues being pursued include epigenetics and various methods of modifying growth and signaling pathways that lead to fibroblast activation (Gordon 2010). Unfortunately, some of these strategies have proved ineffective or only able to provide marginal benefits in clinical trials (Prey 2012).

One strategy that has shown some promise is suppression of the immune system with drugs that destroy B-cells or inhibit their production. Examples of drugs in this category include rituximab (Rituxan®) and mycophenolate mofetil (CellCept®). In preliminary trials, these interventions have shown some benefit (Le 2011; Mendoza 2012; Daoussis 2012). However, larger clinical trials are needed to more thoroughly assess the viability of this approach.

Other ongoing research efforts are evaluating immunosuppression followed by transplantation of autologous peripheral blood stem cells, and high-dose cyclophosphamide (NCT00114530; NCT00501995).

8 Dietary and Lifestyle Management Strategies

Several dietary and lifestyle considerations are relevant for people with scleroderma.

Since exposure to cold may trigger episodes of Raynaud’s phenomenon in scleroderma patients, taking steps to keep warm such as wearing gloves when venturing out in cold temperatures may be helpful (Maricq 1996; Herrick 1998; Ihler 2003).  More information is available in the Raynaud’s Phenomenon protocol.

Exercise enhances blood circulation, which may be beneficial for scleroderma that primarily affects hands and feet. It has also been shown to improve muscle strength and function as well as aerobic capacity in patients with systemic sclerosis (Pinto 2011; Semenova 1973). Exercise also improves endothelial function and lowers blood pressure, which may provide significant benefit to people with scleroderma, since blood vessel dysfunction is a hallmark of the disease (Tjonna 2011; Tinken 2008; Black 2008).

Scleroderma patients also often have poor nutritional status, with over 28% of the patients having a medium or high risk for malnutrition (Baron 2009; Krause 2010). Reduced levels of the antioxidants vitamin C, vitamin E, beta-carotene, and selenium have been reported among individuals with scleroderma and Raynaud's phenomenon (Simonini 2000). Because scleroderma is associated with increased oxidative stress, eating plenty of fresh fruit and vegetables is important (Gabrielli 2008; Sfrent-Cornateanu 2008).

9 Targeted Natural Interventions

Evening Primrose Oil and Gamma-linolenic acid (GLA)

GLA is an omega-6 fatty acid available from borage oil, evening primrose oil or black currant seed oil. It serves as a precursor for an anti-inflammatory signaling molecule called prostaglandin E1 (Gaby 2006).

In a randomized controlled trial, patients with Raynaud’s phenomenon (with or without scleroderma) were given 6 g of evening primrose oil per day or placebo for 8 weeks. After 6 weeks of treatment, the evening primrose oil group experienced significantly fewer episodes of Raynaud’s phenomenon than those in the placebo group. All of the scleroderma patients noticed improvement; the authors noted this was similar to their previous results using a prostaglandin E1 infusion (Belch 1985). Another study gave scleroderma patients 1 g evening primrose oil three times daily. After one year, patients experienced less pain in their hands and feet, healed ulcers, and improved skin texture (Strong 1985).

S-adenosylmethionine (SAMe)

Well known for its use in mood modulation, liver disease, and osteoarthritis, SAMe may also be of benefit in scleroderma (Bottiglieri 2002). One study found that intravenous administration of 600 mg SAMe per day for two months, followed by oral ingestion of 400 mg 3 times daily, significantly improved skin quality in patients with systemic sclerosis. After four months, 50% of patients in the study showed a significant improvement in skin texture; one patient even experienced improvement in walking abilities due to increased malleability of skin on the feet and ankles and 4 subjects displayed improved skin fold thickness, another marker of skin texture quality. In 3 patients who underwent skin biopsy, a significant reduction in skin thickness was observed (Oriente 1985).

N-acetylcysteine (NAC)

The antioxidant N-acetylcysteine (NAC) has shown promise in reducing the severity of Raynaud’s phenomenon in people with scleroderma. Several studies have shown that, in patients with Raynaud’s phenomenon as a result of systemic sclerosis, intravenous infusion of NAC effectively increases blood flow to the fingers due to its blood vessel dilating effect; it also reduces the severity and frequency of the episodes of Raynaud’s phenomenon (Salsano 2005; Sambo 2001; Rosato 2009c). NAC has also been shown to reduce lung-related complications of scleroderma (Failli 2002). An open-label trial in which 40 patients were administered intravenous NAC for 5 hours found that vascular function in the kidneys improved following NAC treatment in patients with systemic sclerosis whose disease was not severe (Rosato 2009b). Similarly, systemic sclerosis patients with limited disease severity showed improved markers of liver blood flow following the same intravenous NAC treatment (Rosato 2009a).

Vitamin E

Vitamin E has been shown to be useful in the management of a number of autoimmune diseases in which the skin is affected, including scleroderma (Ayres 1978). Various manifestations of scleroderma, including Raynaud’s phenomenon, were reported to respond well to vitamin E; the vitamin E doses to achieve these effects ranged between 200 and 1200 IU per day (Gaby 2006). Moreover, in some cases, vitamin E was also applied topically. For example, one study showed that topical application of vitamin E gel hastened healing of digital ulcers in systemic sclerosis patients (Fiori 2009).

In a clinical trial, vitamins C and E were combined with cyclophosphamide and compared to cyclophosphamide alone in patients with systemic sclerosis. The combination of the two antioxidant nutrients and cyclophosphamide led to less progressive skin thickening and a trend toward improved lung function compared to treatment with only cyclophosphamide (Ostojic 2011). A 24-week trial found that coadministration of the anti-inflammatory and vasodilating drug pentoxifylline with vitamin E reduced skin fibrosis in patients with systemic sclerosis (de Souza 2009).

Green Tea

Several studies have shown that green tea, and one of its main active constituents, epigallocatechin gallate (EGCG), has beneficial effects on the endothelium – the delicate inner lining of blood vessels, which is compromised in scleroderma (Shenouda 2007; Widlansky 2007; Alexopoulos 2008). Evidence also suggests that EGCG can suppress tissue fibrosis by inhibiting a signaling pathway that promotes excessive accumulation of collagen (Park 2008).

Experimental studies are strongly suggestive of the therapeutic potential of green tea EGCG in treating autoimmune diseases (Wu 2011). In addition, a laboratory study found that EGCG decreased collagen secretion by fibroblasts. The authors concluded that their results “suggest that the antioxidant, EGCG, can reduce ECM [extracellular matrix] production, the fibrotic marker CTGF [connective tissue growth factor] and inhibit contraction of dermal fibroblasts from SSc [systemic sclerosis] patients” (Dooley 2010). Numerous other studies have noted multiple antifibrotic actions of green tea constituents (Xiao 2013; Chang 2013; Tsai 2013; Cai 2013). While there is a need for future human clinical trials to confirm this, bearing in mind the well-documented cardiovascular effects of green tea and EGCG in humans, patients with scleroderma and other autoimmune diseases may benefit from supplementing with green tea EGCG (Wu 2011).

4-Aminobenzoic acid (PABA)

Sometimes referred to as a member of the B-vitamin family, PABA is a water-soluble organic compound that has been studied as far back as the 1940s as a remedy for scleroderma (Zarafonetis 1948). Case reports of the effects of PABA in scleroderma patients are dispersed throughout the scientific literature over the decades leading up to the 1980s, at which point more rigorous analyses were published (Meyers 1977; BMJ 1968; Gougerot 1951). Evidence from retrospective studies indicate PABA is associated with several benefits for scleroderma patients, including improved survival, skin softening, and better maintenance of lung function over time (Zarafonetis 1988a,b; Zarafonetis 1989). Unfortunately, in 1994, a double-blind, placebo-controlled trial failed to show that PABA was superior to placebo for treating skin manifestations of scleroderma (Clegg 1994). Despite the results of this study, case reports of benefits in skin conditions related to scleroderma continue to be published (Gruson 2005). Although the mechanism(s) by which PABA may modify scleroderma are unclear, one study showed that the compound was able to inhibit growth of fibroblasts derived from scleroderma patients (Priestley 1979). Additional studies are needed to evaluate PABA as a treatment for scleroderma.

Melatonin

Melatonin, also known as the "sleep hormone," is produced and secreted by the pineal gland during nighttime (Pandi-Perumal 2006). Melatonin is involved in sleep regulation, as well as in a number of other cyclical bodily activities.

Melatonin has several beneficial effects on the endothelium that are directly relevant for scleroderma: it scavenges free radicals, activates antioxidant defense enzymes, reduces blood pressure, and increases nitric oxide bioavailability (Scheer 2004; Rodella 2013). Its ability to protect against endothelial damage, blood vessel constriction, platelet aggregation, and the accumulation of excessive amounts of white blood cells in tissues (leukocyte infiltration) might explain the beneficial effects of supplementation that were described in patients with scleroderma (Rodella 2013). In a study that included 5 patients, supplementation of melatonin in combination with vitamin E and ACTH, a hormone secreted by the anterior pituitary gland and important for the health of the neuroimmunoendocrine system, achieved a partial response in all patients after one month of treatment, and disease progression was stopped in all five patients when the treatment was continued further (Todisco 2006). A laboratory study investigated the effect of melatonin on human skin fibroblasts (connective tissue cells), and reported that it caused an over 80% inhibition of the growth and multiplication of fibroblasts derived from the skin of healthy individuals and scleroderma patients (Carossino 1996).

Gotu kola (Centella asiatica)

Gotu kola (Centella asiatica) is an herb found in most tropical and subtropical countries, including India, South Africa, Madagascar, and Eastern Europe (Gohil 2010). Gotu kola alleviates microcirculatory problems and may help inflammatory skin conditions, such as lupus, varicose ulcers, eczema, atopic dermatitis, and psoriasis (Belcaro 2011; Gohil 2010). In addition to being an anti-inflammatory, gotu kola is also an antioxidant that can help control oxidative stress associated with inflammation and/or infections (Belcaro 2011; Gohil 2010). It also aids wound healing and is used for scar management (Maquart 1999; Bonte 1994; Widgerow 2000; Paocharoen 2010; Belcaro 2011).

Gotu kola has been used for localized and systemic scleroderma with positive results. After 6 months of supplementation in oral form with 30 mg/day (10 mg, three times a day), a study on 12 patients with systemic sclerosis showed a decrease of vascular disorders, hard lesions, hyperpigmentation, and improvement in the patients’ general condition. A beneficial response was also obtained with local application of gotu kola ointment on finger ulcers, and the therapy was well tolerated (Guseva 1998).

Curcumin

Curcumin is a major component of the spice turmeric. Turmeric has been used in Ayurvedic medicine to treat a wide range of conditions, and practitioners of alternative medicine often recommend curcumin as a treatment for inflammatory and autoimmune diseases (Aggarwal 2009,2011; Jurenka 2009). Moreover, curcumin has been shown in the last two decades to have potent immunomodulatory, neuroprotective, and anti-cancer effects (Jagetia 2007; Zhou 2011; Sharma 2005; Cole 2007; Jurenka 2009). Because scleroderma is a disease that involves exaggerated collagen deposition and excessive growth (proliferation) of fibroblasts, curcumin may be able to provide a therapeutic benefit through its ability to suppress the proliferation of fibroblasts (Tourkina 2004; Punithavathi 2003; Smith 2010). Laboratory studies reveal that curcumin suppresses transforming growth factor beta (TGF-β), a profibrotic signaling molecule implicated in the development of scleroderma (Song 2011). Another study found that curcumin caused cell death (apoptosis) in scleroderma lung fibroblasts but not in normal lung fibroblasts. The authors concluded “these observations suggest that curcumin may have therapeutic value in treating scleroderma…” (Tourkina 2004).

Vitamin D

Vitamin D is a precursor to the hormone calcitriol, which exerts a vast array of actions throughout the body. Calcitriol plays an especially prominent role in modulation of the immune system (Panichi 2003). Moreover, associations have been made between low blood levels of vitamin D and autoimmune and inflammatory disorders, including scleroderma (Agmon-Levin 2012; Vacca 2011).

In one study, scleroderma patients were more likely to be deficient in vitamin D compared to healthy control subjects. In addition, scleroderma patients with higher vitamin D levels had less extensive skin involvement than those with low levels. Higher vitamin D concentrations were associated with less skin fibrosis as well (Arnson 2011). These findings are in line with experimental evidence that suggests calcitriol and related vitamin D metabolites can modulate growth factor signaling, thereby reducing the propensity of fibroblasts to promote fibrosis (Slominski 2013).

Other clinical trials and case reports have shown that direct administration of calcitriol results in symptomatic improvement in scleroderma patients. In one small trial conducted on three patients with localized scleroderma, calcitriol administration for 7 months improved skin tightness and joint mobility (Hulshof 1994). Another trial showed oral calcitriol treatment considerably improved skin lesions in 5 of 7 children with scleroderma (Elst 1999). Similarly, in a trial conducted on 11 scleroderma patients, calcitriol treatment for up to 3 years was associated with significant improvements compared to baseline (Humbert 1993).

These findings give credence to the notion that maintenance of adequate vitamin D blood levels should be a priority for scleroderma patients. Life Extension suggests that most adults target an optimal 25-hydroxyvitamin D level of 50 – 80 ng/mL.

References

A.D.A.M. Medical Encyclopedia. PubMed Health web page. Scleroderma. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001465/. Copyright © 2013.

Agarwal SK, Reveille JD. The genetics of scleroderma (systemic sclerosis). Curr Opin Rheumatol. Mar 2010a;22(2):133-138.

Agarwal SK. The genetics of systemic sclerosis. Discovery medicine. Aug 2010b;10(51):134-143.

Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The international journal of biochemistry & cell biology. Jan 2009;41(1):40-59.

Aggarwal BB, Prasad S, Reuter S, Kannappan R, Yadev VR, Park B, . . . Sung B. Identification of novel anti-inflammatory agents from Ayurvedic medicine for prevention of chronic diseases: "reverse pharmacology" and "bedside to bench" approach. Current drug targets. Oct 2011;12(11):1595-1653.

Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in Systemic and Organ-Specific Autoimmune Diseases. Clinical reviews in allergy & immunology. Dec 14 2012.

Alexopoulos N, Vlachopoulos C, Aznaouridis K, Baou K, Vasiliadou C, Pietri P, . . . Stefanadis C. The acute effect of green tea consumption on endothelial function in healthy individuals. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. Jun 2008;15(3):300-305.

Arnson Y, Amital H, Agmon-Levin N, Alon D, Sanchez-Castanon M, Lopez-Hoyos M, . . . Shoenfeld Y. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature. Autoimmunity reviews. Jun 2011;10(8):490-494.

Au K, Singh MK, Bodukam V, Bae S, Maranian P, Ogawa R, . . . Khanna D. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis and rheumatism. Jul 2011;63(7):2078-2090.

Avouac J, Borderie D, Ekindjian OG, Kahan A, Allanore Y. High DNA oxidative damage in systemic sclerosis. The Journal of rheumatology. Dec 2010;37(12):2540-2547.

Ayres S, Jr., Mihan R. Is vitamin E involved in the autoimmune mechanism? Cutis; cutaneous medicine for the practitioner. Mar 1978;21(3):321-325.

Balbir-Gurman A, Braun-Moscovici Y. Scleroderma - new aspects in pathogenesis and treatment. Best practice & research. Clinical rheumatology. Feb 2012;26(1):13-24.

Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. Mar 2012;24(2):165-170.

Barnes TC, Anderson ME, Moots RJ. The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. International journal of rheumatology. 2011;2011:721608.

Baron M, Hudson M, Steele R. Malnutrition is common in systemic sclerosis: results from the Canadian scleroderma research group database. The Journal of rheumatology. Dec 2009;36(12):2737-2743.

Baumhakel M, Bohm M. Recent achievements in the management of Raynaud's phenomenon. Vascular health and risk management. 2010;6:207-214.

Belcaro G, Maquart FX, Scoccianti M, Dugall M, Hosoi M, Cesarone MR, . . . Feragalli B. TECA (Titrated Extract of Centella Asiatica): new microcirculatory, biomolecular, and vascular application in preventive and clinical medicine. A status paper. Panminerva medica. Sep 2011;53(3 Suppl 1):105-118.

Belch JJ, Shaw B, O'Dowd A, Saniabadi A, Leiberman P, Sturrock RD, Forbes CD. Evening primrose oil (Efamol) in the treatment of Raynaud's phenomenon: a double blind study. Thrombosis and haemostasis. Aug 30 1985;54(2):490-494.

Black MA, Green DJ, Cable NT. Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels. The Journal of physiology. Jul 15 2008;586(14):3511-3524.

BMJ. Potassium para-aminobenzoate (Potaba) in scleroderma. Drug and therapeutics bulletin. Jun 7 1968;6(12):47-48.

Bonte F, Dumas M, Chaudagne C, Meybeck A. Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis. Planta medica. Apr 1994;60(2):133-135.

Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule. The American journal of clinical nutrition. Nov 2002;76(5):1151S-1157S.

Cai Y, Yu SS, Chen TT, Gao S, Geng B, Yu Y, . . . Liu PQ. EGCG inhibits CTGF expression via blocking NF-kappaB activation in cardiac fibroblast. Phytomedicine : international journal of phytotherapy and phytopharmacology. Jan 15 2013;20(2):106-113.

Carossino AM, Lombardi A, Matucci-Cerinic M, Pignone A, Cagnoni M. Effect of melatonin on normal and sclerodermic skin fibroblast proliferation. Clinical and experimental rheumatology. Sep-Oct 1996;14(5):493-498.

Castro SV, Jimenez SA. Biomarkers in systemic sclerosis. Biomarkers in medicine. Feb 2010;4(1):133-147.

Chang JZ, Yang WH, Deng YT, Chen HM, Kuo MY. EGCG blocks TGFbeta1-induced CCN2 by suppressing JNK and p38 in buccal fibroblasts. Clinical oral investigations. Mar 2013;17(2):455-461.

Chatterjee S. Systemic Scleroderma. Cleveland Clinic web page. Available at: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/systemic-sclerosis/. August 1, 2010.

Clegg DO, Reading JC, Mayes MD, Seibold JR, Harris C, Wigley FM, . . . et al. Comparison of aminobenzoate potassium and placebo in the treatment of scleroderma. The Journal of rheumatology. Jan 1994;21(1):105-110.

Clemens PJ, Furst DE. Systemic Sclerosis Lippincott Williams & Wilkins; 2003.

ClinicalTrials.gov. NCT00114530. Available at: http://clinicaltrials.gov/ct2/show/NCT00114530?term=scot+trial&rank=1 Accessed: 6/7/2013.

ClinicalTrials.gov. NCT00501995. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00501995?term=high+dose+cyclophosphamide&rank=2 Accessed 6/7/2013.

Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Advances in experimental medicine and biology. 2007;595:197-212.

Daoussis D, Tsamandas AC, Liossis SN, Antonopoulos I, Karatza E, Yiannopoulos G, Andonopoulos AP. B-cell depletion therapy in patients with diffuse systemic sclerosis associates with a significant decrease in PDGFR expression and activation in spindle-like cells in the skin. Arthritis research & therapy. 2012;14(3):R145.

de Souza RB, Macedo AR, Kuruma KA, Macedo PA, Borges CT. Pentoxyphylline in association with vitamin E reduces cutaneous fibrosis in systemic sclerosis. Clinical rheumatology. Oct 2009;28(10):1207-1212.

Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, . . . Webb DJ. Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. Journal of hypertension. Jan 2005;23(1):7-17.

Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmunity reviews. Jun 2003;2(4):181-191.

Dieude P, Boileau C, Allanore Y. Immunogenetics of systemic sclerosis. Autoimmunity reviews. Mar 2011;10(5):282-290.

Dooley A, Bruckdorfer KR, Abraham DJ. Modulation of fibrosis in systemic sclerosis by nitric oxide and antioxidants. Cardiology research and practice. 2012;2012:521958.

Dooley A, Shi-Wen X, Aden N, Tranah T, Desai N, Denton CP, . . . Bruckdorfer R. Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate. Rheumatology. Nov 2010;49(11):2024-2036.

Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology. Jun 2012;51(6):1017-1026.

Elst EF, Van Suijlekom-Smit LW, Oranje AP. Treatment of linear scleroderma with oral 1,25-dihydroxyvitamin D3 (calcitriol) in seven children. Pediatric dermatology. Jan-Feb 1999;16(1):53-58.

Failli P, Palmieri L, D'Alfonso C, Giovannelli L, Generini S, Rosso AD, . . . Matucci-Cerinic M. Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis. Nitric oxide : biology and chemistry / official journal of the Nitric Oxide Society. Dec 2002;7(4):277-282.

Feghali CA, Bost KL, Boulware DW, Levy LS. Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. The Journal of rheumatology. Aug 1992;19(8):1207-1211.

Ferri FR. Ferri's Clinical Advisor 2013. Scleroderma. Available at: https://www.clinicalkey.com/#!/ContentPlayerCtrl/doPlayContent/3-s2.0-B9780323083737000285/{"scope":"all","query":"scleroderma ferri"}. Accessed: 6/7/2013.

Fiori G, Galluccio F, Braschi F, Amanzi L, Miniati I, Conforti ML, . . . Matucci-Cerinic M. Vitamin E gel reduces time of healing of digital ulcers in systemic sclerosis. Clinical and experimental rheumatology. May-Jun 2009;27(3 Suppl 54):51-54.

Fleischmajer R, Perlish JS, Reeves JR. Cellular infiltrates in scleroderma skin. Arthritis and rheumatism. May 1977;20(4):975-984.

Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. The New England journal of medicine. May 7 2009;360(19):1989-2003.

Gabrielli A, Svegliati S, Moroncini G, Amico D. New insights into the role of oxidative stress in scleroderma fibrosis. The open rheumatology journal. 2012;6:87-95.

Gabrielli A, Svegliati S, Moroncini G, Avvedimento EV. Pathogenic autoantibodies in systemic sclerosis. Current opinion in immunology. Dec 2007;19(6):640-645.

Gabrielli A, Svegliati S, Moroncini G, Pomponio G, Santillo M, Avvedimento EV. Oxidative stress and the pathogenesis of scleroderma: the Murrell's hypothesis revisited. Seminars in immunopathology. Jul 2008;30(3):329-337.

Gaby AR. Natural remedies for scleroderma. Alternative medicine review : a journal of clinical therapeutic. Sep 2006;11(3):188-195.

Gayraud M. Raynaud's phenomenon. Joint, bone, spine : revue du rhumatisme. Jan 2007;74(1):e1-8.

Gohil KJ, Patel JA, Gajjar AK. Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all. Indian journal of pharmaceutical sciences. Sep 2010;72(5):546-556.

Gomer RH. Circulating progenitor cells and scleroderma. Current rheumatology reports. Jul 2008;10(3):183-188.

Gordon JK, Spiera RF. Targeting tyrosine kinases: a novel therapeutic strategy for systemic sclerosis. Current opinion in rheumatology. Nov 2010;22(6):690-695.

Gougerot H, Hewitt J. [Scleroderma en plaques; combined action of p-aminobenzoic acid and alpha tocopherol]. Bulletin de la Societe francaise de dermatologie et de syphiligraphie. Jan-Feb 1951;58(1):42-43.

Grassegger A, Pohla-Gubo G, Frauscher M, Hintner H. Autoantibodies in systemic sclerosis (scleroderma): clues for clinical evaluation, prognosis and pathogenesis. Wiener medizinische Wochenschrift. 2008;158(1-2):19-28.

Gruson LM, Franks A, Jr. Scleredema and diabetic sclerodactyly. Dermatology online journal. 2005;11(4):3.

Guseva NG, Starovoitova MN, Mach ES. [Madecassol treatment of systemic and localized scleroderma]. Terapevticheskii arkhiv. 1998;70(5):58-61.

Hawk A and English III JC. Localized and Systemic Scleroderma. Seminars in Cutaneous Medicine and Surgery. 2001;20(1):27-37.

Heinberg LJ, Kudal I, White B, et al. Assessing Body Image in Patients with Systemic Sclerosis (Scleroderma): Validation of the Adapted Satisfaction With Appearance Scale. Body Image. 2007;4(1):79-86.

Heron E, Fornes P, Rance A, Emmerich J, Bayle O, Fiessinger JN. Brain involvement in scleroderma: two autopsy cases. Stroke; a journal of cerebral circulation. Mar 1998;29(3):719-721.

Herrick AL, Clark S. Quantifying digital vascular disease in patients with primary Raynaud's phenomenon and systemic sclerosis. Annals of the rheumatic diseases. Feb 1998;57(2):70-78.

Herrick AL. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nature reviews. Rheumatology. Aug 2012;8(8):469-479.

Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. American family physician. Oct 15 2008;78(8):961-968.

Hughes M, Herrick A. Systemic sclerosis. British journal of hospital medicine. Sep 2012;73(9):509-510, 511-506.

Hulshof MM, Pavel S, Breedveld FC, Dijkmans BA, Vermeer BJ. Oral calcitriol as a new therapeutic modality for generalized morphea. Archives of dermatology. Oct 1994;130(10):1290-1293.

Humbert P, Dupond JL, Agache P, Laurent R, Rochefort A, Drobacheff C, . . . Aubin F. Treatment of scleroderma with oral 1,25-dihydroxyvitamin D3: evaluation of skin involvement using non-invasive techniques. Results of an open prospective trial. Acta dermato-venereologica. Dec 1993;73(6):449-451.

Hummers LK. Biomarkers of vascular disease in scleroderma. Rheumatology. 2008;47:21-22.

Ihler G, Chami-Stemmann H. 7-oxo-DHEA and Raynaud's phenomenon. Medical hypotheses. Mar 2003;60(3):391-397.

Jagetia GC, Aggarwal BB. "Spicing up" of the immune system by curcumin. Journal of clinical immunology. Jan 2007;27(1):19-35.

Jimenez SA, Diamond HS. Medscape reference. Scleroderma. Available at: http://emedicine.medscape.com/article/331864-overview Accessed 6/3/2013. 2012.

Jimenez SA. and Diamond HS. 2012. Medscape reference. Scleroderma. Available at: http://emedicine.medscape.com/article/331864-overview Accessed 6/3/2013. [Online].

Jungel A, Distler JH, Gay S, Distler O. Epigenetic modifications: novel therapeutic strategies for systemic sclerosis? Expert review of clinical immunology. Jul 2011;7(4):475-480.

Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Alternative medicine review : a journal of clinical therapeutic. Jun 2009;14(2):141-153.

Khoo JJ, Pratt EJ. Phaeochromocytoma mimicking scleroderma. International journal of endocrinology. 2011;2011:917453.

Klein-Weigel P, Opitz C, Riemekasten G. Systemic sclerosis - a systematic overview: part 1 - disease characteristics and classification, pathophysiologic concepts, and recommendations for diagnosis and surveillance. VASA. Zeitschrift fur Gefasskrankheiten. Jan 2011;40(1):6-19.

Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, . . . Matucci-Cerinic M. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Annals of the rheumatic diseases. May 2009;68(5):620-628.

Krause L, Becker MO, Brueckner CS, Bellinghausen CJ, Becker C, Schneider U, . . . Riemekasten G. Nutritional status as marker for disease activity and severity predicting mortality in patients with systemic sclerosis. Annals of the rheumatic diseases. Nov 2010;69(11):1951-1957.

Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Annals of the rheumatic diseases. Jun 2011;70(6):1104-1107.

Leask A. Egr-ly awaiting a "personalized medicine" approach to treat scleroderma. Journal of cell communication and signaling. Jun 2012;6(2):111-113.

Malenfant D, Summers K, Seney S, et al. Results of a Pilot Randomized Placebo-Controlled Trial in Primary and Secondary Raynaud's Phenomenon with St. John's Wort: Detecting Changes in Angiogenic Cytokines When Raynaud’s phenomenon Improves. ISRN Rheumatol. 2011;2011:580704.

Man A, Zhu Y, Zhang Y, Dubreuil M, Rho YH, Peloquin C, . . . Choi HK. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Annals of the rheumatic diseases. Jul 2013;72(7):1188-1193.

Maquart FX, Chastang F, Simeon A, Birembaut P, Gillery P, Wegrowski Y. Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds. European journal of dermatology : EJD. Jun 1999;9(4):289-296.

Maricq HR, Weinrich MC, Valter I, Palesch YY, Maricq JG. Digital vascular responses to cooling in subjects with cold sensitivity, primary Raynaud's phenomenon, or scleroderma spectrum disorders. The Journal of rheumatology. Dec 1996;23(12):2068-2078.

Martínez JD. Raynaud phenomenon - First Consult. 2011; https://www.clinicalkey.com/#!/ContentPlayerCtrl/doPlayContent/21-s2.0-1014243/{"scope":"all","query":"raynaud"}. Accessed 3/26/2013.

Mayes MD. The genetics of scleroderma: looking into the postgenomic era. Current opinion in rheumatology. Nov 2012;24(6):677-684.

Mayo Clinic. Raynaud's Disease: Treatments and Drugs. 2011; http://www.mayoclinic.com/health/raynauds-disease/. Accessed December 21, 2012.

Mayo Clinic. Scleroderma. Treatments and Drugs. Available at: http://www.mayoclinic.com/health/scleroderma/DS00362/DSECTION=treatments-and-drugs. Last updataed 10/16/2010. Accessed: 6/5/2013.

Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. The Journal of rheumatology. Jun 2012;39(6):1241-1247.

Meyers D. Treatment of scleroderma. The Medical journal of Australia. Jun 11 1977;1(24):887.

Mok MY, Lau CS, Chiu SS, Tso AW, Lo Y, Law LS, . . . Lam KS. Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition. Arthritis and rheumatism. May 2011;63(5):1387-1395.

Mora GF. Systemic sclerosis: environmental factors. The Journal of rheumatology. Nov 2009;36(11):2383-2396.

Muangchan C, Harding S, Khimdas S, Bonner A, Baron M, Pope J. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis care & research. Sep 2012;64(9):1405-1414.

Nashel J, Steen V. Scleroderma mimics. Current rheumatology reports. Feb 2012;14(1):39-46.

NCBI 2011. Raynaud's Phenomenon. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001449/. Last reviewed June 2011.

NIAMS. Scleroderma. 2012.

NIAMS. What Is Scleroderma? Fast Facts: An Easy-to-Read Series of Publications for the Public. Website: http://www.niams.nih.gov/health_info/Scleroderma/scleroderma_ff.asp Accessed 01/12/2013. 2010.

Opitz C, Klein-Weigel PF, Riemekasten G. Systemic sclerosis - a systematic overview: part 2 - immunosuppression, treatment of SSc-associated vasculopathy, and treatment of pulmonary arterial hypertension. VASA. Zeitschrift fur Gefasskrankheiten. Jan 2011;40(1):20-30.

O'Reilly S, Hugle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology. Sep 2012;51(9):1540-1549.

Oriente P, Scarpa R, Biondi C, Riccio A, Farinaro C, Del Puente A. Progressive systemic sclerosis and S-adenosylmethionine. Clinical rheumatology. Sep 1985;4(3):360-361.

Ostojic P, Damjanov N. Effects of micronutrient antioxidants (alpha-tocopherol and ascorbic acid) on skin thickening and lung function in patients with early diffuse systemic sclerosis. Rheumatology international. Aug 2011;31(8):1051-1054.

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: Nature's most versatile biological signal? The FEBS journal. Jul 2006;273(13):2813-2838.

Panichi V, Migliori M, Taccola D, Consani C, Giovannini L. Effects of calcitriol on the immune system: new possibilities in the treatment of glomerulonephritis. Clinical and experimental pharmacology & physiology. Nov 2003;30(11):807-811.

Paocharoen V. The efficacy and side effects of oral Centella asiatica extract for wound healing promotion in diabetic wound patients. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. Dec 2010;93 Suppl 7:S166-170.

Park G, Yoon BS, Moon JH, Kim B, Jun EK, Oh S, . . . You S. Green tea polyphenol epigallocatechin-3-gallate suppresses collagen production and proliferation in keloid fibroblasts via inhibition of the STAT3-signaling pathway. The Journal of investigative dermatology. Oct 2008;128(10):2429-2441.

Patel JC. Functions of endothelium. Indian Journal of Medical Sciences. 2001;55(3):165-166.

Peterson LS, Nelson AM, Su WP, Mason T, O'Fallon WM, Gabriel SE. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960-1993. The Journal of rheumatology. Jan 1997;24(1):73-80.

Pinto AL, Oliveira NC, Gualano B, Christmann RB, Painelli VS, Artioli GG, . . . Lima FR. Efficacy and safety of concurrent training in systemic sclerosis. Journal of strength and conditioning research / National Strength & Conditioning Association. May 2011;25(5):1423-1428.

Prey S, Ezzedine K, Doussau A, Grandoulier AS, Barcat D, Chatelus E, . . . Taieb A. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. The British journal of dermatology. Nov 2012;167(5):1138-1144.

Priestley GC, Brown JC. Effects of potassium para-aminobenzoate on growth and macromolecule synthesis in fibroblasts cultured from normal and sclerodermatous human skin, and rheumatoid synovial cells. The Journal of investigative dermatology. Apr 1979;72(4):161-164.

Punithavathi D, Venkatesan N, Babu M. Protective effects of curcumin against amiodarone-induced pulmonary fibrosis in rats. British journal of pharmacology. Aug 2003;139(7):1342-1350.

Rodella LF, Favero G, Foglio E, Rossini C, Castrezzati S, Lonati C, Rezzani R. Vascular endothelial cells and dysfunctions: role of melatonin. Front Biosci (Elite Ed). 2013;5:119-129.

Rosato E, Borghese F, Pisarri S, Salsano F. The treatment with N-acetylcysteine of Raynaud's phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. Clinical rheumatology. Dec 2009c;28(12):1379-1384.

Rosato E, Cianci R, Barbano B, Menghi G, Gigante A, Rossi C, . . . Salsano F. N-acetylcysteine infusion reduces the resistance index of renal artery in the early stage of systemic sclerosis. Acta pharmacologica Sinica. Sep 2009b;30(9):1283-1288.

Rosato E, Zardi EM, Barbano B, Menghi G, Cianci R, Amoroso A, . . . Salsano F. N-acetylcysteine infusion improves hepatic perfusion in the early stages of systemic sclerosis. International journal of immunopathology and pharmacology. Jul-Sep 2009a;22(3):763-772.

Salsano F, Letizia C, Proietti M, Rossi C, Proietti AR, Rosato E, Pisarri S. Significant changes of peripheral perfusion and plasma adrenomedullin levels in N-acetylcysteine long term treatment of patients with sclerodermic Raynauds phenomenon. International journal of immunopathology and pharmacology. Oct-Dec 2005;18(4):761-770.

Sambo P, Amico D, Giacomelli R, Matucci-Cerinic M, Salsano F, Valentini G, Gabrielli A. Intravenous N-acetylcysteine for treatment of Raynaud's phenomenon secondary to systemic sclerosis: a pilot study. The Journal of rheumatology. Oct 2001;28(10):2257-2262.

Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. Feb 2004;43(2):192-197.

Semenova NI. [The role of therapeutic exercise in the overall therapy of scleroderma and psoriatic arthritis]. Vestnik dermatologii i venerologii. Apr 1973;47(4):60-64.

Sfrent-Cornateanu R, Mihai C, Stoian I, Lixandru D, Bara C, Moldoveanu E. Antioxidant defense capacity in scleroderma patients. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2008;46(6):836-841.

Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer. Sep 2005;41(13):1955-1968.

Shenouda SM, Vita JA. Effects of flavonoid-containing beverages and EGCG on endothelial function. Journal of the American College of Nutrition. Aug 2007;26(4):366S-372S.

Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology. Nov 30 2000;155(1-3):1-15.

Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, . . . Postlethwaite AE. 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. The Journal of clinical endocrinology and metabolism. Feb 2013;98(2):E298-303.

Smith MR, Gangireddy SR, Narala VR, Hogaboam CM, Standiford TJ, Christensen PJ, . . . Reddy RC. Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury. American journal of physiology. Lung cellular and molecular physiology. May 2010;298(5):L616-625.

Song K, Peng S, Sun Z, Li H, Yang R. Curcumin suppresses TGF-beta signaling by inhibition of TGIF degradation in scleroderma fibroblasts. Biochemical and biophysical research communications. Aug 12 2011;411(4):821-825.

Strong AM, Campbell A, Thomson J. The effect of oral linoleic acid and gamma-linolenic acid (Efamol [G]). The British journal of clinical practice. Nov-Dec 1985;39(11-12):444-445.

Takehara K and Sato S. Localized scleroderma is an autoimmune disorder. Rheumatology. 2005;44:274-279.

Theodore AC, Tseng CH, Li N, Elashoff RM, Tashkin DP. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study. Chest. Sep 2012;142(3):614-621.

Tinken TM, Thijssen DH, Black MA, Cable NT, Green DJ. Time course of change in vasodilator function and capacity in response to exercise training in humans. The Journal of physiology. Oct 15 2008;586(Pt 20):5003-5012.

Tjonna AE, Rognmo O, Bye A, Stolen TO, Wisloff U. Time course of endothelial adaptation after acute and chronic exercise in patients with metabolic syndrome. Journal of strength and conditioning research / National Strength & Conditioning Association. Sep 2011;25(9):2552-2558.

Todisco M. Effectiveness of a treatment based on melatonin in five patients with systemic sclerosis. American journal of therapeutics. Jan-Feb 2006;13(1):84-87.

Tourkina E, Gooz P, Oates JC, Ludwicka-Bradley A, Silver RM, Hoffman S. Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase cepsilon. American journal of respiratory cell and molecular biology. Jul 2004;31(1):28-35.

Tsai CF, Hsu YW, Ting HC, Huang CF, Yen CC. The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae). Food chemistry. Feb 15 2013;136(3-4):1337-1344.

Vacca A, Cormier C, Mathieu A, Kahan A, Allanore Y. Vitamin D levels and potential impact in systemic sclerosis. Clinical and experimental rheumatology. Nov-Dec 2011;29(6):1024-1031.

Varga J. Systemic sclerosis: an update. Bulletin of the NYU hospital for joint diseases. 2008;66(3):198-202.

Widgerow AD, Chait LA, Stals R, Stals PJ. New innovations in scar management. Aesthetic plastic surgery. May-Jun 2000;24(3):227-234.

Widlansky ME, Hamburg NM, Anter E, Holbrook M, Kahn DF, Elliott JG, . . . Vita JA. Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease. Journal of the American College of Nutrition. Apr 2007;26(2):95-102.

Wu D, Wang J. The ability of green tea to alleviate autoimmune diseases: fact or fiction? Expert review of clinical immunology. Nov 2011;7(6):711-713.

Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TY, . . . Tipoe GL. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr. Mar 21 2013.

Zarafonetis CJ, Dabich L, Devol EB, Skovronski JJ, Negri D, Yuan WY. Retrospective studies in scleroderma: pulmonary findings and effect of potassium p-aminobenzoate on vital capacity. Respiration; international review of thoracic diseases. 1989;56(1-2):22-33.

Zarafonetis CJ, Dabich L, Negri D, Skovronski JJ, DeVol EB, Wolfe R. Retrospective studies in scleroderma: effect of potassium para-aminobenzoate on survival. Journal of clinical epidemiology. 1988a;41(2):193-205.

Zarafonetis CJ, Dabich L, Skovronski JJ, DeVol EB, Negri D, Yuan W, Wolfe R. Retrospective studies in scleroderma: skin response to potassium para-aminobenzoate therapy. Clinical and experimental rheumatology. Jul-Sep 1988b;6(3):261-268.

Zarafonetis CJ. Para-aminobenzoic acid therapy in scleroderma and lymphoblastoma cutis. The Journal of laboratory and clinical medicine. Nov 1948;33(11):1462.

Zhou H, Beevers CS, Huang S. The targets of curcumin. Current drug targets. Mar 1 2011;12(3):332-347.