Scleroderma: Nomenclature, etiology, pathogenesis, prognosis, and treatments: Facts and controversies - PDF Document

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  1. Clinics in Dermatology (2013) 31, 432–437 Scleroderma: Nomenclature, etiology, pathogenesis, prognosis, and treatments: Facts and controversies Nicole Fett, MD⁎ Departments of Dermatology, Philadelphia VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Abstract Scleroderma refers to a heterogeneous group of autoimmune fibrosing disorders. The nomenclature of scleroderma has changed dramatically in recent years, with morphea (localized scleroderma), limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma encompassing the currently accepted disease subtypes. Major advances have been made in the molecular studies of morphea and systemic sclerosis; however, their etiologies and pathogenesis remain incompletely understood. Although morphea and systemic sclerosis demonstrate activationofsimilar inflammatory and fibrotic pathways, important differences insignalingpathwaysand gene signatures indicate they are likely biologically distinct processes. Morphea can cause significant morbidity but does not affect mortality, whereas systemic sclerosis has the highest disease-specific mortality of all autoimmune connective tissue diseases. Treatment recommendations for morphea and systemic sclerosis are based on limited data and largely expert opinions. Current collaborative efforts in morphea and systemic sclerosis research will hopefully lead to better understanding of the etiology and pathogenesis of these rare and varied diseases and improved treatment options. Published by Elsevier Inc. What is in a name? physicians (patients and doctors alike hear scleroderma and assume the diagnosis is systemic sclerosis, which leads to unnecessary stress). In general, experts in the field of pediatric localized scleroderma prefer to keep the scleroder- ma moniker to stress the morbidity associated with the linear variants of this disease in their patient population. Patients with LcSSc and DcSSc almost universally will have positive antinuclear antibodies (ANA), Raynaud’s phenomenon, and nailfold capillary changes.1,2Patients with LcSSc develop sclerosis of the skin distal to their elbows and knees and have facial involvement. Patients with DcSSc develop proximal, in addition to distal, sclerosis. Patients with LcSSc are more likely to have anti-centromere antibodies, whereas patients with DcSSc are more likely to have anti-topoisomerase I (anti-Scl70) or anti-RNA poly- merase III antibodies.1,2Patients with LcSSc and DcSSc are Scleroderma is a disease label fraught with misunder- standings. In recent years, the nomenclature of scleroderma has been replaced by more precise terminology, character- izing disease subsets defined by clinical findings, serologic data, and prognosis. The subsets include localized sclero- derma (ie, morphea), limited cutaneous systemic sclerosis (LcSSc; previously referred to as CREST syndrome), diffuse cutaneous systemic sclerosis (DcSSc), and systemic sclerosis sine scleroderma. Experts in the field of adult localized scleroderma prefer to refer to this clinical entity as morphea, to decrease miscommunication with patients and referring ⁎Corresponding author. Tel.: +1 608 345 1238; fax: +1 866 755 0625. E-mail address: 0738-081X/$ – see front matter. Published by Elsevier Inc.

  2. Morphea and systemic sclerosis 433 approximately equally likely to develop interstitial lung disease (ILD), but patients with LcSSc are at higher risk for fibrosis of their pulmonary artery leading to pulmonary artery hypertension (PAH).1,2Patients with DcSSc are at higher risk for renal crisis than their LcSSc counterparts.1,2 Morphea is a diverse disease as well, with distinct clinical presentations: circumscribed morphea (with superficial and deep variants), linear morphea (with trunk/limb variant and head variant), generalized morphea, pansclerotic morphea, and mixed morphea.3Linear morphea is more likely to affect children and involve underlying structures including soft tissue, bone, and when on the head and neck, the central nervous system.3Patients with generalized morphea are more likely to have positive autoantibodies and systemic symptoms including myalgia, arthralgia, and fatigue.3–6To date, no studies have assessed the differences in the pathophysiology of morphea subtypes. The combination of genetics and a second environmental “hit” is thought to cause endothelial cell injury, resulting in up-regulation of cellular adhesion molecules (VCAM, ICAM, E-selectin) and chemokines (CCL2,5,7,17,22,27, CXCL8).12,13The cellular adhesion molecules and chemo- kines recruit inflammatory mononuclear cells, of which most are T-helper (Th) cells. The Th cells (Th1, Th2, and Th17) produce interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-12, IL- 13, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-α and IFn-γ.2,14,15Production of these cytokines results in inflammation, and recruitment and activation of fibroblasts and myofibroblasts, resulting in fibrosis.12,16,17Kurzinski et al. postulate that the initial inflammatory phase is mediated by Th1 and Th17 cells and their associated cytokine profiles, with a shift in predominant cell phenotype to Th2 cells later in disease course, which results in sclerosis.14 Despite several shared pathogenic features, clinically morphea and systemic sclerosis are radically different diseases. The explanation for this distinct clinical disparity despite similar molecular pathogenic pathways remains unsolved. The following are pathogenic disparities between morphea and systemic sclerosis. In a single study comparing subjects with morphea and systemic sclerosis, subjects with morphea were found to have higher levels of IL-2 and IL-6.18In an additional study comparing the effect of peripheral blood mononuclear cells (PBMC) from subjects with morphea and systemic sclerosis on cultured fibroblasts, the PBMCs from subjects with systemic sclerosis caused a decrease in matrix metallopro- teinase-1 (a collagenase) and an increase in platelet-derived growth factor AA and BB, TNF-α, IL-13, and epidermal growth factor compared with those subjects with morphea.19 Autoantibody production is also disparate in morphea and systemic sclerosis. Greater than 95% of patients with systemic sclerosis will have a positive ANA,2,20–22whereas prevalences of ANA positivity in patients with morphea range from 20% to 80.3–5,23–25Anti-centromere antibodies, anti-topoisomerase I antibodies, and anti-RNA polymerase III antibodies are found almost exclusively in patients with systemic sclerosis.2,224In contrast, patients with morphea are more likely to have anti-single–stranded antibodies, anti- histone antibodies, and anti-topoisomerase II-α antibodies than patients with systemic sclerosis.24 Further data supporting the distinction between morphea and systemic sclerosis can be found in gene array studies. Recent data have revealed differences in gene signatures between patients with morphea, LcSSc, DcSSc, and healthy controls.26Gene array analysis revealed evidence for four separate gene signatures, subcategorized as inflammatory, proliferative/diffuse, limited, and normal-like.26These distinct gene signatures reveal that although all patients with morphea and systemic sclerosis present with increased collagen deposition, they are distinct diseases. Finally, only nine patients who presented with morphea and later developed systemic sclerosis have been reported in the literature.27–29Examination for sclerodactyly, Raynaud’s Etiology and pathogenesis: Are morphea and systemic sclerosis the same disease on one continuous spectrum, or separate diseases? The etiologies and pathogenesis of morphea and systemic sclerosis are incompletely understood at this time. A combination of factors is postulated to be involved. It is currently thought that patients who develop morphea or systemic sclerosis have an underlying genetic predisposition to these conditions, and then are exposed to an environmen- tal factor that initiates the inflammatory and fibrotic cascades. To date, no studies on specific genetic alterations have been performed in morphea; however, patients with morphea have higher rates of autoimmune diseases in their families than expected in the general population.3,5,7Several large genome-wide association studies have been performed in patients with systemic sclerosis revealing association of systemic sclerosis with multiple genetic loci including HLA class II gene region, IRF5, CD247, BANK1, STAT4, TNFSF4, and BLK genes.8For a comprehensive review of these studies, please see Romano et al.8 In morphea, several environmental factors have been postulated to be part of the etiology, including Lyme disease, trauma, radiation, medications, and viral infections.9Of these, radiation-induced morphea is most frequently de- scribed. Morphea occurs commonly on the chest wall after radiation treatment for breast cancer, with an estimated incidence of 1 in 500 patients.9–11The role of radiation in the induction of morphea is not completely understood. It has been postulated that radiation selects for activated fibro- blasts, or induces an isomorphic response due to tissue trauma, or may increase the risk for presentation of self- antigens. In systemic sclerosis, postulated environmental factors include exposure to vinyl chloride, silica dust and organic solvents, medications (bleomycin, pentazocine, cocaine), and viruses (cytomegalovirus, parvovirus B19).2,9

  3. 434 N. Fett advent of angiotensin-converting enzyme inhibitors.40 Early intervention in ILD and PAH is thought to improve patient outcomes, and therefore patients with systemic sclerosis should have annual screening for these complica- tions.41–43 phenomenon, and nailfold capillary changes at presentation is not thoroughly documented in all nine cases, raising the possibility that at least some of these cases were incorrectly diagnosed with morphea at presentation. Large cohorts of patients with morphea have reported no transitions to systemic sclerosis,3,30further supporting that morphea and systemic sclerosis are distinct diseases. Treatment Prognosis Treatment algorithms for systemic sclerosis and morphea are limited by the rarity of the diseases (which makes conducting trials with enough power to detect differences difficult), the difficulty in assessing disease improvement (validated outcome measures are lacking, which makes conducting therapeutic trials difficult) and the lack of universally used outcome measures (which makes conduct- ing meta-analysis of trials impossible). In systemic sclerosis, treatment is based on disease comorbidities. It is the responsibility of physicians caring for patients with systemic sclerosis to ensure they are being screened for ILD and PAH annually. Early detection and early treatment of these comorbidities decreases mortality42 and patients with systemic sclerosis are not always routinely screened for these complications by other physicians caring for them.44Although treatment of ILD and PAH should happen under the care of a pulmonologist, as an integral member of their health care team, dermatologists should be involved in the screening for these comorbidities. Treatment of ILD and PAH is beyond the scope of this contribution; however, several reviews of treatment options have been recently published.45–48 Patients with LcSSc and DcSSc suffer from Raynaud’s phenomonen with high frequencies. First-line therapy for Raynaud’s phenomenon is dihydropyridine-type calcium channel blockers, usually nifedipine at doses of up to 20 mg four times daily.45–48For patients who develop digital ulcerations in the setting of Raynaud’s phenomenon, the addition of bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily), or sildenafil (25 mg up to three times daily), or intravenous iloprost is recommended.45–48 Management of progressive skin involvement is depen- dent on additional comorbidities. In patients with concom- itant myositis, arthritis, or overlap syndromes, methotrexate or azathioprine are recommended.46–48Patients with con- comitant ILD should receive ILD-focused therapy, which is generally cyclophosphamide.46–48In patients with skin involvement only, mycophenolate mofetil or methotrexate are recommended.45–48 To date, there are no studies comparing subtypes of morphea and their response to treatments. Based on expert opinion, treatment of morphea should be based on disease subtype, area of involvement, activity of disease, and patient symptoms.49–51It is important to differentiate active morphea from burnt-out morphea. Active morphea (lesions with erythema, new lesions, expanding lesions) can be treated with topical or systemic immunosuppressives. Burnt- Morphea does not increase mortality; however, it is associated with significant morbidity. Linear morphea, which is most common in children, can cause significant disfigurement. Linear morphea can also involve the underlying bone and growth plates, resulting in permanent limb-length discrepancy. Children who present with morphea on the head and neck are at increased risk for neurologic and ocular involvement.31,32In a large multi- center cross-sectional evaluation of 750 children with morphea, approximately 4% had neurologic disease manifestations (defined as seizures, headaches, peripheral neuropathy, vascular malformations, behavioral changes, neuroimaging abnormalities, electroencephalogram alter- ations, and central nervous system vasculitis).31Of the children labeled as having neurologic involvement, 88% had linear morphea and involvement was almost exclu- sively on the head and neck.31Of the 750 children, 3.2% developed significant ocular involvement (defined as sclerosis of adnexal structures, anterior segment inflamma- tion, and anterior uveitis).33When only children with head and neck morphea were evaluated, approximately 14.2% had significant ocular involvement.33Anterior segment inflammation and anterior uveitis may be asymptomatic, and if left untreated, can result in irreversible vision loss. Therefore, it is recommended that children with morphea on the head and neck see an ophthalmologist every 3 to 4 months for 3 years after development of morphea.33Rarely (b1%) children developed pulmonary, cardiac, or renal involvement.31Data on adult morphea patient comorbid- ities is sparse. Adults with morphea have been reported to have an increased risk for concomitant autoimmune disorders. Both children and adults with morphea have higher levels of depression and anxiety than healthy, age- matched controls.34,35 Systemic sclerosis has the highest disease-related mortality of all autoimmune connective tissue diseases with a standard mortality ratio of 3.5, a median survival time after diagnosis of 11 years, and an absolute survival at 5 years of 77.9%.36,37Cardiopulmonary involvement (ie, ILD and PAH) accounts for the majority of the increased mortality in systemic sclerosis.36,37The median survival after diagnosis of PAH in the setting of systemic sclerosis is 2 years.38,39The median survival after diagnosis of ILD in the setting of systemic sclerosis is less than 5 years.38 Mortality associated with renal crisis has decreased with the

  4. Morphea and systemic sclerosis 435 studies,84–90and open-label trials have revealed statistically significant improvement in skin scores in subjects with diffuse systemic sclerosis and improvement in retroperito- neal fibrosis.87,90Mycophenolate mofetil also has been agreed on as a second-line agent to methotrexate by the Childhood Arthritis and Rheumatology Research Alliance Localized Scleroderma Workgroup.51 out morphea, or morphea in the damage stage, is not treatable with immunosuppression. Limited superficial plaque morphea is best treated with topical therapy or local phototherapy.49,50Treatment with twice-daily topical tacrolimus is supported by a randomized placebo-controlled trial.52Additional topical therapies that have shown benefit in prospective studies include topical imiquimod applied three to five times per week,53,54 combination calcipotriol and betamethasone dipropionate applied once to twice daily,55and calcipotriene applied and occluded twice daily.56Topical steroids, anecdotally the most commonly used therapy for plaque morphea, may be effective, but to date there are no data supporting their efficacy as a solitary agent. Phototherapy studies report improvement with narrow- band ultraviolet B (nb-uvb), UVA, low- and medium-dose UVA1, and PUVA.57–70 Deep plaque morphea may require local phototherapy (nb-uvb, UVA, low- and medium-dose UVA1, or psoralen plus UVA [PUVA]) or systemic immunosuppression.50If systemic immunosuppression is required, treatment with methotrexate in combination with a prednisone taper is supported by the strongest data.71–74In adults with morphea there is data showing improvement with methotrexate alone.75 Linear morphea of the extremities, as well as the head and neck, should be treated aggressively, particularly in children given the significant morbidity associated with untreated disease. Based on data from a randomized placebo- controlled trial, prospective case series, and expert opinion, linear morphea should be treated with methotrexate and a taper of systemic corticosteroids.49–51,71–74In some in- stances, linear morphea is a superficial process that does not involve the underlying tissues. In these cases, topical therapies noted above or phototherapy are appropriate treatment options. Generalized morphea, due to the large surface area involved, is not usually amenable to topical therapy. Generalized morphea may present as superficial or deep subtypes. Patients with generalized morphea who are not at risk for joint contractures, can initially be treated with phototherapy (nb-uvb, UVA, low-and medium-dose UVA1, or PUVA). In patients who fail 2 to 3 months of phototherapy, or in patients who cannot attend phototherapy, methotrexate with or without a systemic corticosteroid taper is recommended.49,50 Patients with morphea who fail methotrexate or have contraindications to methotrexate may undergo a trial of mycophenolate mofetil.49,51Although the evidence for using mycophenolate mofetil in the treatment of morphea is weak,76it has a more favorable side-effect profile than other systemic immunosuppressives supported by similarly weak data (cyclosporine, imitinib, D-penacilliamine, cyclo- sphosphamide, TNF-α inhibitors, or extracorporal photo- pheresis).77–83Mycophenolate mofetil has been shown to have antifibrotic properties in both in vitro and in vivo Conclusions The term scleroderma has been replaced with morphea (which is further subdivided into circumscribed, linear, generalized, pansclerotic, and mixed subtypes), LcSSc, DcSSc, and systemic sclerosis sine scleroderma. Although all four conditions demonstrate activation of similar inflammatory and fibrotic pathways in their etiopathogen- esis, important differences in signaling pathways and gene signatures indicate they are likely biologically distinct processes. Linear and generalized morphea can cause significant morbidity, but do not affect mortality. Systemic sclerosis has the highest disease-specific mor- tality of all autoimmune connective tissue diseases, the majority of which is due to cardiopulmonary involvement. Additional studies are required to determine the best treatments for systemic sclerosis and the different variants of morphea. References 1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009;360:1989-2003. 2. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol 2011;6:509-37. 3. Zulian F, Athreya BH, Laxer R, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. 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