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Scleroderma Treatment & Management

  • Author: Sergio A Jimenez, MD; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Oct 26, 2015
 

Approach Considerations

Current treatment of systemic sclerosis is directed toward managing complications and providing symptomatic relief. In addition, a range of disease-modifying treatments have been investigated.

Disease-modifying treatment aims at inhibiting tissue fibrosis and vascular and immune system alterations, which are the three crucial components of disease pathogenesis.[131, 132, 133, 134, 135, 136, 137] Therapies targeting cytokine signalling, including interleukin-6 (IL-6), and other immune-inflammatory therapies, have produced promising results.[138] To date, the US Food and Drug Administration (FDA) has not approved any disease-modifying therapies for systemic sclerosis. In June 2015, however, the FDA granted breakthrough therapy designation to the IL-6 receptor antagonist tocilizumab, to expedite its development as a treatment for systemic sclerosis.[139]

No placebo-controlled studies have demonstrated clear superiority for any drug except for a modest benefit from use of methotrexate.[140, 141] Numerous uncontrolled prospective and retrospective trials along with post-hoc analysis have suggested a beneficial effect from mycophenolate mofetil.[142, 143, 144] Retrospective uncontrolled studies also supported a beneficial role for D-penicillamine,[145] but a large high-dose versus low-dose controlled trial failed to demonstrate benefits of the higher dose versus the lower dose.[146]

Other agents are currently being studied for skin and lung involvement. For example, trials of rituximab have yielded promising results, with improvement of skin fibrosis and prevention of worsening lung fibrosis.[147, 148, 149, 150]

Allogeneic bone marrow transplantation has been shown to be effective in uncontrolled studies[151, 152, 153, 154, 155, 156, 157] but given its high rate of procedure related complications, results from larger prospective trials should be evaluated before further recommendations. Current studies of autologous stem cell transplantation, including a large randomized control study, the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, are ongoing.

Skin Fibrosis

Numerous experimental drugs or interventions have been investigated for treatment of skin induration and fibrosis in systemic sclerosis. Interventions that have demonstrated benefit include the following:

Interventions that have failed to demonstrate significant benefit for treatment of skin induration and fibrosis in systemic sclerosis include the following:

  • Human relaxin [159]
  • Interferon-alpha [160]
  • Anti–transforming growth factor beta antibodies [161]
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Pruritus

Treatment measures for pruritus include the following[162] :

  • Moisturizers
  • Histamine 1 (H1) and histamine 2 (H2) blockers
  • Tricyclic antidepressants
  • Trazodone
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Raynaud Phenomenon

Raynaud phenomenon can be treated with the following agents[44, 45, 163] :

  • Calcium channel blockers (increasing the dose to tolerance)
  • Prazosin
  • Prostaglandin derivatives (eg, prostaglandin E1)
  • Dipyridamole
  • Aspirin
  • Topical nitrates

Sildenafil, an inhibitor of phosphodiesterase 5 (PDE-5), has been approved for treatment of pulmonary hypertension. In addition, it has been shown to be effective and well tolerated in patients with Raynaud phenomenon.[164, 165, 166]

In the event of thrombosis and vascular flow compromise, a tissue plasminogen activator, heparin, and urokinase may be necessary.[167] In very severe cases, patients may benefit from intravenous iloprost or related prostanoids. Some patients may require pharmacologic cervical sympathectomy or surgical digital sympathectomy.[168, 169, 170]

Digital ulcers

Repeated episodes of Raynaud phenomenon in individuals with systemic sclerosis may result in digital ulcers. Bosentan, a dual endothelin receptor antagonist approved for treatment of systemic sclerosis-associated pulmonary hypertension, may curtail the formation of new digital ulcers.[171, 172, 173] Ambrisentan and other endothelin receptor antagonists have also shown beneficial effects in preliminary or open label studies.[174, 175]

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Gastrointestinal Involvement

Treatments for gastrointestinal symptoms of systemic sclerosis include the following[50, 176, 177] :

  • Antacids
  • Histamine 2 (H2) blockers
  • Reflux and aspiration precautions
  • Proton pump inhibitors
  • Prokinetic agents
  • Octreotide
  • Stool softeners
  • Laxatives
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Pulmonary Fibrosis/Alveolitis

Although there is some controversy regarding the beneficial effects of immunosuppressive therapy in idiopathic pulmonary fibrosis, numerous studies support the use of these agents in systemic sclerosis–associated interstitial lung disease.[178, 179] Pulmonary fibrosis in systemic sclerosis has been successfully treated with cyclophosphamide, either orally or in intravenous pulses.[180, 181, 182] Several nonrandomized studies have also shown benefit from mycophenolate mofetil.[142, 143, 144, 183, 184]

 

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Pulmonary Hypertension

Numerous newer agents have been approved by the FDA for the treatment of pulmonary arterial hypertension (PAH). These include the following:

  • Prostaglandin derivatives such as epoprostenol, treprostinil, beraprost, and iloprost
  • Phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil and tadalafil
  • Endothelin receptor antagonists such as bosentan, ambrisentan and macitentan

The combination of ambrisentan and tadalafil was approved by theFDA in Octobetr 2015 as up-front therapy for PAH to reduce the risk of worsening disease and improve exercise ability.[185] In a prospective multicenter open-label trial by Hassoun et al, this combination significantly improved hemodynamics, right ventricular structure and function, and functional status in treatment-naïve systemic sclerosis patients with PAH.[186]

One study reported that warfarin provided no significant benefit in either systemic sclerosis-associated or idiopathic pulmonary arterial hypertension.[187]

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Scleroderma Renal Crisis

Patients with diffuse, rapidly progressive skin involvement have the highest risk of developing scleroderma renal crisis. Renal crisis occurs in about 10% of all patients with systemic sclerosis.

Renal crisis is observed within 4 years of diagnosis in about 75% of patients but may develop as late as 20 years after diagnosis. Renal crises are slightly more common in blacks than in whites, and men have a greater risk than women. The presence of RNA polymerase III antibodies increases the risk for renal crisis.

Scleroderma renal crisis that is not treated promptly and aggressively invariably leads to renal failure requiring dialysis or renal transplantation, or even death. Consequently, it is critical to check blood pressure, monitor serum creatinine, and start angiotensin-converting enzyme (ACE) inhibitors at the earliest signs of hypertension in at-risk patients.

High doses of corticosteroids should be avoided in patients with systemic sclerosis owing to an increased risk of developing renal crisis.

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Musculoskeletal Symptoms

Carpal tunnel entrapment symptoms may require local corticosteroid injections although frequently these symptoms resolve spontaneously.

Myositis may be treated cautiously with steroids (first choice), or with methotrexate or azathioprine in corticosteroid-resistant cases or when there are contraindications to corticosteroid use. Doses of prednisone greater than 40 mg/d are associated with a higher incidence of scleroderma renal crisis.

Arthralgias can be treated with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).

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Pregnancy

Pregnancy in women with systemic sclerosis is considered a high risk because of a higher risk of pregnancy loss and higher complication rates, but a diagnosis of systemic sclerosis without pulmonary hypertension is not an absolute contraindication for pregnancy. However, there is an increased risk of maternal mortality during pregnancy in patients with pulmonary hypertension and some consider that pulmonary hypertension is a contraindication for pregnancy.[188] A study of 50 patients (67 pregnancies) showed that 18% miscarried, 26% delivered preterm, and 55% delivered at full term.

Pregnancy risk is greatest in those who have had the disease for less than 4 years and who also have diffuse cutaneous involvement.

Some systemic sclerosis symptoms may increase during pregnancy (eg, edema, arthralgias, GERD). Skin manifestations are not reported to worsen. Raynaud symptoms may improve during pregnancy, only to worsen after delivery.

Certain medications, such as d-penicillamine, mycophenolate mofetil, cytotoxic agents, and ACE inhibitors, should be discontinued prior to pregnancy

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Surgical Care

Digital sympathectomy and botulinum toxin injections may be used in patients with severe Raynaud phenomenon who have an unrelenting acute attack and who are threatened by digital loss. Many ulcers require management by a wound care specialist. Debridement or amputation may be required in severe ischemic or infected digital lesions. Digital sympathectomy may be indicated in severe cases.

Hand surgery may be performed to correct severe flexion contractures.

Removal of severely painful, draining or infected calcinotic deposits is occasionally required.

Surgical fundoplication may be required to treat severe esophageal reflux with complicating aspiration pneumonitis. Laser ablation or even gastric antrectomy may be required to control persistent bleeding caused by gastric antral vascular ectasia (GAVE).

Episodes of acute abdominal pain need to be evaluated with extreme care to avoid the misdiagnosis of an acute abdomen since occasionally patients with systemic sclerosis present with symptoms of acute abdomen that resolve with proper medical treatment and do not require surgical intervention (pseudo acute abdomen).

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Diet

There are no specific dietary recommendations in patients with systemic sclerosis. Appropriate caloric intake should be encouraged. The following points may be considered:

  • Patients with esophageal involvement should avoid hard solid foods
  • Patients with intestinal hypomotility may benefit from high-fiber diets
  • Vitamin deficiencies and malabsorption should be addressed in patients with frequent or severe bacterial overgrowth
  • Large doses of vitamin C (>1000 mg/d) should be avoided because this stimulates collagen formation and may enhance fibrotic tissue deposition
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Activity

See the list below:

  • Ensure that the patient maintains a core body temperature to try to minimize the occurrence of Raynaud phenomenon episodes.
  • Assist the patient in avoiding contamination of any skin wound caused by ischemic lesions or calcinosis.
  • Digital ulcers must be kept clean and dry.
  • Instruct the patient to perform continuous physical and occupational therapy to maintain joint range of motion and to minimize or delay joint contractures.
  • Patients with pulmonary fibrosis should be encouraged to receive pulmonary rehabilitation treatment.
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Consultations

All patients with systemic sclerosis should be treated in conjunction with an experienced rheumatologist who has a full understanding of the disease, the complications of the therapies, and the frequently serious adverse effects. Consultation with an experienced practitioner can help avoid potentially fatal pulmonary, vascular, or renal complications.

Patients with systemic sclerosis may need to be treated by other subspecialists, depending on the involvement of specific organ systems (eg, cardiologist, pulmonologist, gastroenterologist, nephrologist, endocrinologist, vascular surgeon, wound care specialist, hand surgeon).

Renal and lung transplantation are performed in specialized centers for patients with end-stage renal or lung involvement.

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Long-term Monitoring

Evaluate the patient every 3-6 months, depending on the disease activity and progression. Serial skin scoring (also known as the modified Rodnan skin score) is useful for monitoring skin changes over time. New techniques are currently being studied. For example, durometry, a technique for objectively measuring skin involvement, uses digital, hand-held, spring-loaded devices that measure hardness by applying an indentation load.[189] Follow up for other complications, as well.

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Contributor Information and Disclosures
Author

Sergio A Jimenez, MD MACR, FACP, FRCP(UK, Hon), Professor and Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases, Jefferson Medical College of Thomas Jefferson University

Sergio A Jimenez, MD is a member of the following medical societies: Royal College of Physicians, American Society for Biochemistry and Molecular Biology, American College of Physicians, American College of Rheumatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Fabian A Mendoza, MD, FACR Assistant Professor of Medicine, Division of Rheumatology, Jefferson Medical College and Jefferson Institute of Molecular Medicine; Associate Director of The Scleroderma Center, Director of Scleroderma Program, Thomas Jefferson University

Fabian A Mendoza, MD, FACR is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

John Varga, MD Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University

John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical and Translational Research, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

Patrick M Cronin, DO, FACR Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital

Patrick M Cronin, DO, FACR is a member of the following medical societies: American College of Rheumatology, American Osteopathic Association, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Andrew S Koenig, DO Consulting Staff, Division of Rheumatology, Rancoccas Hospital

Andrew S Koenig, DO is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Osteopathic Association

Disclosure: Nothing to disclose.

Marie Spevak O'Brien, DO Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group

Marie Spevak O'Brien, DO is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association, American Osteopathic Association, International Society for Clinical Densitometry, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Acknowledgments

The assistance of Kenneth Brown in the preparation of this manuscript is gratefully acknowledged.

Sergio A Jimenez, MD, was recipient of NIH/NIAMS grant #RO-1 AR19616.

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Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.
A radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral osteolysis).
Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.
Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.
Barium swallow demonstrating reflux into the distal esophagus, as well as an accordion appearance in the duodenum.
Skin biopsy showing extensive fibrosis. The biopsy has a square morphology, which reflects the rigidity of the tissue biopsy specimen due to striking pan-dermal sclerosis. In addition, the fibrosing reaction extends into the panniculus. The number of adnexal structures is reduced, another characteristic feature of scleroderma. A significant inflammatory cell infiltrate is not observed. This is in contradistinction to morphea, in which a prominent inflammatory cell infiltrate is present.
Skin biopsy showing severe fibrosis. The fibrosis reflects a widening of collagen bundles in concert with an increase in the number of collagen fibers. Note the superimposed deposition of the newly synthesized delicate collagen bundles interposed between the preexisting collagen bundles, the latter appearing wide and manifesting a hyalinized morphology.
Overall scheme illustrating a current understanding of SSc pathogenesis. Hypothetical sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in tissue fibrosis.
Table.
Table 1: ACR/EULAR Revised Systemic Sclerosis Classification Criteria
Item Sub-item(s) Score*
Skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints (presence of this criterion is sufficient criterion for SSc classification) None 9
Skin thickening of the fingers (count the higher score only) Puffy fingers 2
Sclerodactyly (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints) 4
Fingertip lesions (count the higher score only) Digital tip ulcers 2
Fingertip pitting scars 3
Telangiectasia None 2
Abnormal nailfold capillaries None 2
Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension 2
Interstitial lung disease 2
Raynaud phenomenon None 3
Systemic sclerosis–related autoantibodies (maximum score is 3) Anticentromere 3
Anti–topoisomerase I 3
Anti–RNA polymerase III 3
*The total score is determined by adding the maximum score in each category. Patients with a total score equal to or greater than 9 are classified as having definite systemic sclerosis (modified from van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. Nov 2013;65(11):2737-47.[5] )
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