Credit: Adobe Stock | Trsakaoe
BALTIMORE—For most patients, the onset of systemic sclerosis (SSc) is heralded by new or worsening Raynaud’s phenomenon. However, the complications of the disease thereafter can be varied and severe.
At the 20th Annual Advances in the Diagnosis and Treatment of the Rheumatic Diseases Symposium at Johns Hopkins School of Medicine, Baltimore, Laura Hummers, MD, ScM, associate professor of medicine, co-director of the Scleroderma Center and clinical director for the Division of Rheumatology, Johns Hopkins School of Medicine, treated the audience to important clinical pearls in her presentation, Update on Scleroderma.
Evolution of SSc
At the start of the lecture, Dr. Hummers explained that our understanding of SSc has evolved in recent decades, and even the nomenclature used for the condition reflects this more nuanced view of the disease.
Example: Clinicians used to label some patients as having CREST, an acronym that stands for calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia. Dr. Hummers advises that rheumatologists avoid this terminology because it implies these features are only seen in limited cutaneous disease when, in fact, they may appear in patients with diffuse cutaneous disease as well.
In 2013, the ACR and EULAR published classification criteria for SSc in which a score of 9 or more would indicate definite SSc. The criteria include puffy hands, sclerodactyly, digital pits or ulcers, telangiectasias, abnormal nailfold capillaries, pulmonary arterial hypertension and/or interstitial lung disease (ILD), Raynaud’s phenomenon and SSc-specific autoantibodies (i.e., anticentromere, anti-topoisomerase and anti-RNA polymerase III). Dr. Hummers pointed out that skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints would be sufficient for classification as definite SSc.1
Pulmonary Hypertension
Regarding pulmonary hypertension, Dr. Hummers explained that this manifestation of disease can be insidious and develop over the course of many years. Pulmonary arterial hypertension (PAH) is the most common form of pulmonary hypertension in patients with SSc, but it can also be due to ILD, pulmonary veno-occlusive disease, or left ventricular systolic or diastolic dysfunction with increased left atrial pressure. All patients with scleroderma should be screened at least annually with transthoracic echocardiogram and pulmonary function testing. Risk factors/predictors of PAH in SSc include anticentromere antibodies, an age of onset above 60 years, severe Raynaud’s phenomenon, low diffusing capacity—especially relative to forced vital capacity—and elevated or rising right ventricular systolic pressure (RVSP) on echocardiogram.
One study from Dr. Hummers and colleagues demonstrated that, among patients with SSc, an increased number of telangiectasias was strongly associated with the presence of pulmonary vascular disease.2
A diagnosis of pulmonary hypertension ultimately relies on measurements from a right heart catheterization. In 2022, new guidelines from the European Society of Cardiology and European Respiratory Society modified the definition of pre-capillary pulmonary hypertension such that the threshold is now a mean pulmonary arterial pressure (mPAP) of >20 mmHg rather than >25 mmHg.3 Several clinical algorithms, including DETECT, have been developed to assist physicians in selecting which patients should be referred for right heart catheterization.
Dr. Hummers implores clinicians to be attuned to pulmonary hypertension screening because the goal is to catch the condition before it becomes symptomatic. Screening is particularly important in seeking to reduce mortality through early treatment. Currently, fifteen treatments are approved for patients with PAH by the U.S. Food & Drug Administration (FDA).
Raynaud’s Phenomenon
Dr. Hummers discussed her stepwise approach for managing Raynaud’s phenomenon as a symptom of SSc. Her approach includes non-pharmacologic interventions, as well as some of the same medications employed for the treatment of PAH.
Non-pharmacologic interventions that can be used for Raynaud’s with patients, said Dr. Hummers, include avoiding the cold, reducing stress/anxiety, preventing repetitive trauma to the hands, quitting or abstaining from smoking, and eschewing aggravating medications, such as beta blockers and serotonin agonists, as well as caffeine.
In patients with mild to moderate symptoms, Dr. Hummers will initiate a sustained release dihydropyridine calcium channel blocker (i.e., amlodipine, nifedipine or felodipine). If symptoms persist or if these medications are not tolerated, other options include PDE-5 inhibitors, such as sildenafil; topical nitroglycerin ointment; angiotensin receptor blockers; d and selective serotonin reuptake inhibitors.
ILD & Its Treatments
Next, Dr. Hummers discussed ILD in SSc, a topic of importance given the high morbidity and mortality associated with this manifestation of disease.
Dr. Hummers noted that about 25–90% of patients with SSc have lung involvement, and the most common pattern is nonspecific interstitial pneumonia (NSIP). She routinely screens patients for ILD with computed tomography imaging of the chest at time of initial evaluation. She is cognizant of the fact that only about 15% of patients lung disease progression over time.
Regarding evidence for treatment of ILD, the Scleroderma Lung Study I (SLS I) demonstrated that patients with symptomatic SSc-related ILD who were treated for one year with oral cyclophosphamide had improved on lung function testing that was maintained for 24 months.4 In the Scleroderma Lung Study II (SLS II), two years of treatment of SSc-related ILD with mycophenolate mofetil resulted in significant improvements in lung function with better tolerance and less toxicity than treatment with cyclophosphamide.5
Among the newer treatments for ILD in SSc are nintedanib, an antifibrotic agent, and tocilizumab, an inhibitor of interleukin (IL) 6. In the SENSCIS study, 576 patients with SSc-related ILD were randomly assigned to receive 150 mg of nintedanib by mouth twice daily or placebo. The primary end point was annual rate of decline in forced vital capacity (FVC) assessed over 52 weeks. Although patients in both arms of the study saw decline in the FVC, this decrease was less in the nintedanib group compared with the placebo group.6
In the focuSSced trial, more than 200 patients with diffuse cutaneous SSc were randomly assigned to receive 162 mg of subcutaneous tocilizumab or placebo weekly for 48 weeks. In this study, the primary skin fibrosis end point was not met, but findings for the secondary end point of FVC% predicted indicated that tocilizumab may preserve lung function in people with early SSc-ILD who also have elevated acute-phase reactants.
Based on these results, the FDA approved tocilizumab for the treatment of SSc-ILD, and this medication is now part of the pantheon of treatments for patients.
In Sum
Although no panacea for treatment of the condition exists, more can be done for patients than in years past.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- 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. Ann Rheum Dis. 2013 Nov;72(11):1747–1765.
- Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: A potential clinical marker of pulmonary arterial hypertension. J Rheumatol. 2010 Jan;37(1):98–104.
- Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618–3731.
- Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655–2666.
- Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708–719.
- Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019 Jun 27;380(26):2518–2528.
