Skin Thickening Around Fingers

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune connective tissue disease affecting multiple organ systems.1,2 Systemic sclerosis was first recognized as a clinical entity in the mid-19th century. The first description of the pathologic features of scleroderma occurred...

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Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune connective tissue disease affecting multiple organ systems.^1,2 Systemic sclerosis was first recognized as a clinical entity in the mid-19th century. The first description of the pathologic features of scleroderma occurred in 1861 when skin from an autopsy was noted to be “markedly thickened by proliferation of connective tissue.”² In 1894, Paul Gerson Unna, a German dermatopathologist, described the condition as “mainly hypertrophy of preexisting collagen bundles which affects all parts of the dermis.”²

Patients with SSc with skin involvement can be grouped into 2 subtypes: limited cutaneous SSc and diffuse cutaneous SSc. The primary targets of autoantibodies for limited cutaneous SSc are centromere proteins, and the autoantibodies associated with diffuse cutaneous SSc target topoisomerase I and RNA polymerase III.³

Limited cutaneous SSc manifests clinically with distal skin fibrosis (limited to the distal extremities and face), sclerodactyly (skin fibrosis of the fingers), telangiectasia, and calcinosis cutis. Compared with diffuse cutaneous SSc, the disease course of limited cutaneous SSc is characterized by a slower progression of skin fibrosis and later development of internal organ involvement, which includes pulmonary arterial hypertension and severe gut disease. Patients may have a long history of Raynaud phenomenon (reversible vasospasm of digital arteries) prior to development of SSc.^3,4

Diffuse cutaneous SSc clinically manifests as proximal skin fibrosis up to the elbows and knees, including the trunk. These patients are more likely to experience tendon friction rubs. Compared with limited cutaneous SSc, diffuse cutaneous SSc is characterized by rapidly progressive skin fibrosis and early occurrence of internal organ complications. Interstitial lung disease and scleroderma renal crisis are more common in patients with diffuse disease than in patients with limited disease.³

Systemic sclerosis is estimated to affect 17.6 in 100,000 people globally.⁵ Although the frequency varies depending on case definition, the prevalence of SSc is consistently higher in the US and Australia compared with Japan and Europe.⁵ Systemic sclerosis is much more common in women suggesting that hormonal or pregnancy-related factors are involved in the pathogenesis of SSc.^1,3-5 Ethnicity may play a role in SSc, with Black patients presenting at a younger mean age than White patients and more likely to have antibodies against topoisomerase I and less likely to have antibodies that are centromere-specific.⁶ Familial clustering is also significant with a 13- to 14-fold increase in the relative risk for a first-degree relative as well as various HLA class II alleles influencing disease susceptibility.^1,3-6 In addition, environmental exposures associated with an increased risk for SSc include silica dust, silicone breast implants, certain chemotherapy drugs, solvents, chemicals, and infectious agents.⁶

The pathogenesis of SSc is described as an interaction between an environmental event and genetically susceptible individuals that triggers vascular alterations, autoinflammation, and fibrosis. Activated endothelial cells from the microvascular injury upregulate expression of adhesion molecules, inflammatory mediators, and chemokines leading to recruitment of inflammatory cells. Type 2 T-helper cells secrete transforming growth factor beta β (TGF-β), interleukin (IL)-13, and IL-4. Recruited B cells then lead to overproduction of a variety of autoantibodies including anti-topoisomerase I, anti-RNA polymerase III (anti-RNAP III), anti-U3 RNP, anti-centromere, anti-Th/To, and anti-U1 RNP antibodies. Macrophages further increase the amount of TGF-β leading to a profibrotic state.^3,7,8

The diagnosis of SSc is made via history, physical examination, and fulfillment of the 2013 American College of Rheumatology and European Alliance of Associations for Rheumatology (formerly European League Against Rheumatism) criteria for the classification of SSc (Table).^3,4,9

Localized skin-thickening diseases that can appear similar to SSc include morphea and stiff-skin syndrome. Diseases that cause diffuse skin thickening include eosinophilic fasciitis, graft-vs-host disease, deposition diseases (scleredema, scleromyxedema, amyloidosis, nephrogenic systemic fibrosis), and metabolic syndromes (eg, hypothyroidism). These diseases can be differentiated from SSc via clinical history, distribution of skin involvement, autoantibody testing, and findings on skin biopsy.¹⁰ Differential diagnosis of vascular findings include other causes of peripheral vascular disorders, especially vasculitis, as well as other causes of Raynaud phenomenon including isolated Raynaud phenomenon.⁴ Also on the list of diseases to eliminate are other immune-mediated connective tissue diseases including lupus, arthritis, and myositis.⁴

Histologically, SSc has increased epidermis to subcutis thickness, thickened and sclerotic dermal collagen bundles, loss of periadnexal fat and hair follicles, compression of pilosebaceous units, and little infiltration of plasma cells and lymphocytes. Scleromyxedema, which mimics SSc, presents with histologic patterns of mucin deposition, fibroblast proliferation, and increased collagen density. Furthermore, scleredema is differentiated histologically from SSc by swelling of collagen fibers, thickening of reticular dermis, and mucin deposition without fibroblast proliferation.^4,11

Because of the diverse systemic complications of SSc, treatment of the disease is multidisciplinary and focuses on reducing morbidity and mortality. In the case patient, management will focus on treatment of skin-associated complications, which consist of several immune-modulating treatments. Methotrexate and mycophenolate mofetil have shown clinical benefit in several clinical trials, while cyclophosphamide is used for more severe skin involvement.⁴ Injection of botulism toxin has been found effective to avert Raynaud phenomenon.⁷ Lung function and skin thickening complications have been successfully addressed through B-cell depletion with rituximab. Fresolimumab, a neutralizing antibody that targets TGF-β dermal myofibroblasts, reduces skin fibrosis and dermal myofibroblasts.^4,7 The anti-IL6 receptor antibody tocilizumab has also been shown to reduce skin thickening, though not significantly when compared with placebo.⁴ Pigment alterations in skin including increased skin tone and postinflammatory hyperpigmentation may cause cosmetic concerns for the patient but, unfortunately, few treatments are available for these concerns.⁴

For the patient in this case, punch biopsy of the arm was consistent with scleroderma and, given the clinical findings, the patient was diagnosed with diffuse SSc. The patient was seen in conjunction with rheumatology and has been put on a trial of methotrexate, then mycophenolate mofetil, and more recently she was started on tocilizumab.

Sarah Friske, BBA, is a medical student at Baylor College of Medicine; Tara L. Braun, MD, is a dermatologist at Elite Dermatology in Houston, Texas.

References

1. Asano Y. Systemic sclerosis. J Dermatol. 2018;45(2):128-138. doi:10.1111/1346-8138.14153
2. Medsger TA, Benedek TG. History of skin thickness assessment and the Rodnan skin thickness scoring method in systemic sclerosis. J Scleroderma Relat Disord. 2019;4(2):83-88. doi:10.1177/2397198318823122
3. Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002. doi:10.1038/nrdp.2015.2
4. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699. doi:10.1016/S0140-6736(17)30933-9
5. Nikpour M, Stevens WM, Herrick AL, Proudman SM. Epidemiology of systemic sclerosis. Best Pract Res Clin Rheumatol. 2010;24(6):857-869. doi:10.1016/j.berh.2010.10.007
6. Furue M, Mitoma C, Mitom H, et al. Pathogenesis of systemic sclerosis—current concept and emerging treatments. Immunol Res. 2017;65(4):790-797. doi:10.1007/s12026-017-8926-y
7. Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev. 2003;2(4):181-91. doi:10.1016/s1568-9972(03)00005-3
8. 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. 2013;65(11):2737-47. doi:10.1002/art.38098
9. Tyndall A, Fistarol S. The differential diagnosis of systemic sclerosis. Curr Opin Rheumatol. 2013;25(6):692-699. doi:10.1097/01.bor.0000434599.51526.47
10. Showalter K, Gordon JK. Skin histology in systemic sclerosis: a relevant clinical biomarker. Curr Rheumatol Rep. 2020;23(1):3. doi:10.1007/s11926-020-00970-z