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] Therapies targeting cytokine signalling, including interleukin-6 (IL-6), and other immune-inflammatory therapies, have produced promising results. [136]
To date, the US Food and Drug Administration (FDA) has approved nintedanib and as well as tocilizumab for refractory, progressive intersitial lung disease due to systemic sclerosis.
A phase 3 trial of tocilizumab in systemic sclerosis failed to meet its primary endpoint of improvement in modified Rodnan skin score; however, tocilizumab therapy did result in preservation of lung function. After 48 weeks, decline in lung function from baseline, as defined by changes in predicted forced vital capacity (FVC), had occurred 50.5% of patients in the tocilizumab arm, versus 70.3% of those in the placebo arm (P = 0.015). In patients with systemic sclerosis–related interstitial lung disease, a clinically meaningful decline of 10% or more in lung function was seen in 24.5% of placebo recipients, compared with 8.6% of tocilizumab recipients. Supporting the FVC results, high-resolution computed tomography showed less progression of lung fibrosis with tocilizumab than with placebo. [137, 138, 139]
No placebo-controlled studies have demonstrated clear superiority for any drug except for a modest benefit from use of methotrexate [140, 141] and improvement in scleroderma-related interstitial lung disease with cyclophosphamide. [142, 143] Numerous uncontrolled prospective and retrospective trials along with post-hoc analysis have suggested a beneficial effect from mycophenolate mofetil. [144, 145, 146] Retrospective uncontrolled studies also supported a beneficial role for D-penicillamine, [147] but a large high-dose versus low-dose controlled trial failed to demonstrate benefits of the higher dose versus the lower dose. [148]
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. [149, 150, 151, 152] The tyrosine kinase inhibitor nintedanib is approved for slowing the rate of decline in pulmonary function in adults with systemic sclerosis–related interstitial lung disease.
Phototherapy using longer-wavelength ultraviolet A (UVA) light (ie, UVA1, 340-400 nm) has proved beneficial for cutaneous lesions in scleroderma. UVA1 inhibits the inflammatory process and can soften former sclerotic skin lesions. However, data on this technique remain limited, and the most effective dose has yet to be determined. [153]
No serious systemic effects of UVA1 phototherapy have been reported. Skin pigmentation or tanning, which can persist for months, is the most common acute adverse effect; uncommon acute adverse effects include reactivation of herpes simplex, cholinergic urticaria, and transient and reversible changes in the appearance of moles. The risk of long-term adverse effects, particularly skin cancer, has not been determined. [153]
Transplantation
Hematopoietic stem cell transplantation (HSCT) has been shown to be effective. However, it is associated with a high rate of procedure-related complications. [154, 155, 156, 157]
In the prospective Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3 comparison of autologous HSCT with 12 successive monthly intravenous pulses of cyclophosphamide in 156 patients with early diffuse cutaneous systemic sclerosis, HCST was associated with higher treatment-related mortality than in the first year after treatment. However, HCST conferred a significant long-term survival benefit. [158]
In ASTIS during the first year, 13 events, including 8 treatment-related deaths, occurred in the HSCT group and 8 events with no treatment-related deaths occurred in the control group (16.5% vs. 10.4%, respectively). At 4 years, however, 15 events had occurred cumulatively in the HSCT group compared with 20 events in the control group (19% vs 26%, respectively). [158]
In the Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trial, a randomized, open-label, phase 2 trial in 75 patients with severe scleroderma, autologous HSCT improved event-free and overall survival, at a cost of increased expected toxicity, compared with 12 monthly infusions of cyclophosphamide. Rates of treatment-related death and post-transplantation use of disease-modifying antirheumatic drugs (DMARDs) were lower than those in previous reports of nonmyeloablative transplantation. [159]
In SCOT participants who received a transplant or completed 9 or more doses of cyclophosphamide, event-free survival was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02) at 54 months and 74% vs 47%, respectively, at 72 months (P = 0.03), By 54 months, 9% of the participants in the transplantation group had initiated DMARDs, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months; no treatment-related deaths occurred in the cyclophosphamide group. [159]
A review by Sullivan et al of HSCT for patients with scleroderma and pulmonary involvement suggested that indications for referral for HSCT in this population may include the following [160] :
-
Diffuse cutaneous systemic sclerosis with internal organ involvement
-
Age < 65 years
-
Disease duration < 5 years
-
Modified Rodnan skin thickness score (MRSS) >15
-
Early pulmonary involvement, documented on high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs)
These authors recommended the following as PFT criteria for pulmonary involvement [160] :
-
Forced vital capacity (FVC) or hemoglobin‐adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) between 80% and 45% predicted
-
A decline in FVC of > 10% or DLCO of > 15% on serial testing
-
Failure to respond to initial therapy on serial PFT monitoring
Recommended exclusion criteria for HSCT include the following [160] :
-
FVC or hemoglobin‐adjusted DLCO of < 45% predicted
-
Pulmonary arterial hypertension
-
Cardiac insufficiency or involvement with systemic sclerosis
-
Kidney insufficiency
-
Prior cyclophosphamide treatment of > 6 months’ duration
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:
-
Bovine collagen [161] - Possible benefit in late-phase disease
Interventions that have failed to demonstrate significant benefit for treatment of skin induration and fibrosis in systemic sclerosis include the following:
Pruritus
Treatment measures for pruritus include the following [165] :
-
Moisturizers
-
Histamine 1 (H1) and histamine 2 (H2) blockers
-
Tricyclic antidepressants
-
Trazodone
Raynaud Phenomenon
Raynaud phenomenon can be treated with the following agents [50, 51, 166] :
-
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. [167, 168, 169]
In the event of thrombosis and vascular flow compromise, a tissue plasminogen activator, heparin, and urokinase may be necessary. [170] In very severe cases, patients may benefit from intravenous iloprost or related prostanoids. Some patients may require pharmacologic cervical sympathectomy or surgical digital sympathectomy. [171, 172, 173]
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. [174, 175] Combination therapy with iloprost and bosentan has also shown benefit in reducing new digital ulcers. [176] Ambrisentan and other endothelin receptor antagonists have also shown beneficial effects in preliminary or open-label studies. [177, 178]
Gastrointestinal Involvement
Treatments for gastrointestinal symptoms of systemic sclerosis are listed below. [56, 179, 180]
Gastroesophageal reflux disease:
-
Antacids
-
Histamine 2 (H2) blockers
-
Reflux and aspiration precautions
-
Proton pump inhibitors
Gastroparesis:
-
Prokinetic agents
-
Octreotide
Colonic / anorectal dysmotility:
-
Stool softeners
-
Laxatives
Some patients with scleroderma may also develop small intestinal bacterial overgrowth (SIBO). This manifestation generally improves with the addiition of rifaximin. [181]
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. [182, 183] Pulmonary fibrosis in systemic sclerosis has been successfully treated with cyclophosphamide, either orally or in intravenous pulses. [184, 142, 143] Several nonrandomized studies showed benefit from mycophenolate mofetil. [144, 145, 146, 185, 186] The Scleroderma Lung Study II (SLS-II), a double-blind, parallel group, randomized controlled trial, found that a 2-year course of mycophenolate mofetil was better tolerated and associated with less toxicity than 12 months of oral cyclophosphamide, and yielded comparable significant improvements in lung function, dyspnea, lung imaging, and skin disease. [187]
Nintedanib was approved by the FDA in 2019 to slow the rate of decline in pulmonary function in patients who have interstitial lung disease associated with scleroderma. Nintedanib is a tyrosine kinase inhibitor that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of interstitial lung diseases.
Approval of nintedanib was based on results from the phase 3 SENSCIS trial (n=576). Results showed that nintedanib slowed the loss of pulmonary function by 41 mL/year in patients with systemic sclerosis–related interstitial lung disease relative to placebo, as measured by forced vital capacity (FVC) over a 52-week period. [188]
Tocilizumab, an anti-IL-6 inhibitor has also shown promise for the treatment of interstitial lung disease due to scleroderma. In the focuSSed trial with open-label extension, the decline in FVC over 48 months was 14 mL in the tocilizumab group compared with 255 mL in the placebo group. [189]
Pulmonary Hypertension
Numerous 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 the FDA in 2015 as up-front therapy for PAH to reduce the risk of worsening disease and improve exercise ability. [190] 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. [191]
One study reported that warfarin provided no significant benefit in either systemic sclerosis–associated or idiopathic pulmonary arterial hypertension. [192]
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. [45]
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 kidney failure requiring dialysis or kidney 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. The preferred ACE inhibitor of choice is captopril, owing to its short half-life and ease to titrate quickly, which aid in managing the hypertensive urgency that is common in patients presenting with scleroderma renal crisis.
High doses of corticosteroids (> 20 mg) should be avoided in patients with systemic sclerosis owing to an increased risk of developing renal crisis.
Musculoskeletal Symptoms
Carpal tunnel entrapment symptoms may require local corticosteroid injections although frequently these symptoms resolve spontaneously.
Myositis may be treated cautiously with corticosteroids (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. Use of methotrexate should be guarded if there is severe or active baseline pulmonary interstitial disease.
Arthralgias can be treated with acetaminophen. In cases of more severe arthritis or inflammatory arthritis, low-dose prednisone (10 mg) may be considered for the short term. Hydroxychloroquine is generally the preferred first-line therapy for long-term treatment. Methotrexate, biologics (such as tocilizumab or abatacept), and Janus kinase inhibitors (such as tofacitinib) may also be considered in refractory cases.
Physical therapy has been shown to be beneficial in improving hand function in patients with scleroderma. [193, 194, 195] In a randomized controlled trial in 24 patients with systemic sclerosis, Maitland's joint mobilization and therapeutic exercises, twice weekly for 12 weeks, improved hand functionality, reduced pain in the hands and wrists, increased range of motion, and improved quality of life. [193] In another study, a 4-week complex, supervised rehabilitation protocol in 27 patients improved hand and overall function for up to 6 months, compared with a control group of 24 patients prescribed a home exercise program alone. However, the improvement was not sustained after 6 months, suggesting that the rehabilitation program should be repeated every 3-6 months. [195]
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, maternal mortality during pregnancy is increased in patients with pulmonary hypertension and some consider pulmonary hypertension to be a contraindication for pregnancy. [196] 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, gastroesophageal reflux disease [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 angiotensin-converting enzyme (ACE) inhibitors, should be discontinued prior to pregnancy
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).
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.
A study of 51 Romanian patients with systemic sclerosis found that 25hydroxy-hydroxyvitamin D serum levels were insufficient in approximately two thirds of cases, and inadequate in almost one quarter. Vitamin D levels did not correlate with extent of skin involvement, but low levels did seem to be related to more aggressive disease with multivisceral and severe organ involvement, especially pulmonary and cardiac. [197]
Activity
Recommendations regarding activity include the following:
-
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.
-
Encourage patients with pulmonary fibrosis to receive pulmonary rehabilitation treatment.
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).
Kidney and lung transplantation are performed in specialized centers for patients with end-stage kidney or lung involvement.
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. Patients with scleroderma need annual ECGs (to screen for cardiac arrhythmias) and serial pulmonary function tests (PFTs) to screen for interstitital lung disease/pulmonary hypertension. Annual transthoracic echocardiograms may also be considered for screening. Durometry, a technique for objectively measuring skin involvement, uses digital, hand-held, spring-loaded devices that measure hardness by applying an indentation load. [198]
-
Scleroderma: Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
-
Scleroderma: Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
-
Scleroderma: 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).
-
Scleroderma: 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.
-
Scleroderma: 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 proposed sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in systemic sclerosis. 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. The activated myofibroblasts produce exaggerated amounts of extracellular matrix, resulting in tissue fibrosis.
Tables
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 ≥ 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. [1] ) |
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