Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare autoimmune disease that causes microvascular damage and excessive collagen deposition in the skin and internal organs.^1,2 The diagnosis of SSc is clinical, and early detection of the disease can help limit organ damage.¹ However, reaching a diagnosis of SSc can be challenging due to the heterogeneous clinical presentation of the disease and because up to 20% of patients with SSc present with features that overlap with other connective tissue diseases.³ 

The differential diagnosis of SS considers skin manifestations, vascular features, and complications in internal organs. The differential diagnosis of skin features accounts for diseases that cause skin or subcutaneous fibrosis, as well as infiltrative skin diseases. Peripheral vascular diseases, such as vasculitis, are considered when evaluating vascular features. In addition, the inflammatory features observed in patients with SSc are also included in the differential diagnosis of other immune-mediated rheumatic diseases, such as lupus, arthritis, and myositis.³

In addition to the previously mentioned diseases, there are other conditions that need to be considered in the differential diagnosis of SSc. These include eosinophilic fasciitis (EF), scleromyxedema, scleredema, and nephrogenic systemic fibrosis (NSF).¹

Eosinophilic Fasciitis

Eosinophilic fasciitis is a rare inflammatory connective tissue disease characterized by acute, painful erythema and swelling of the limbs.² EF shares many clinical features with SSc, such as skin thickening, joint pain, and muscle weakness.^2,4 

Eosinophilic fasciitis is distinguished from SSc by its rapid onset and its associations with eosinophilia and peripheral blood eosinophilic infiltration into the fascia. In addition, Raynaud phenomenon is uncommon in patients with EF, and EF does not present with digital ulcers or internal organ involvement, which are characteristic of SSc.^1,2,4

Read more about SSc clinical features

Scleromyxedema

Scleromyxedema is a rare primary mucinosis that is characterized by diffuse skin thickening, monoclonal gammopathy, and systemic involvement.^2,4 Scleromyxedema can resemble SSc in its clinical presentation, such as skin thickening and limited mouth opening.⁴ 

Scleromyxedema is distinguished from SSc by the absence of Raynaud phenomenon, digital ulcers, and internal organ involvement. Additionally, there is involvement of the skin on the middle of the back in scleromyxedema, which is not observed in SSc. Extracutaneous manifestations can be observed in patients with scleromyxedema at the cardiovascular, pulmonary, renal, gastrointestinal, and central nervous system levels.⁴

Skin biopsies of patients with scleromyxedema typically show dermal fibrosis, perivascular inflammation, and deposition of mucin and fibrocytes, features not typically seen in SSc.¹

Read more about SSc diagnosis

Scleredema 

Scleredema is a rare skin disorder resulting from a thickened dermis and the deposition of mucin that is often associated with a history of upper respiratory infection (typically streptococcal), diabetes mellitus, or blood dyscrasia.^2,4 It causes symmetrical, diffuse, progressive nonpitting swelling and induration of the upper part of the body.² Although the skin lesions are similar to those observed in SSc, their distribution is different.⁴ Digits are usually not affected, which also contrasts with SSc. Another feature that distinguishes scleredema from SSc is the lack of Raynaud phenomenon.¹

Testing also differentiates scleredema from SSc, as ANA and other autoantibodies are usually negative. In scleredema, nail fold capillary examination is normal, and skin biopsy often shows dermal fibrosis with mucin deposition but no perivascular inflammation.¹

Read more about SSc testing

Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis is a rare disorder that occurs in patients with severe renal insufficiency. It is characterized by skin thickening with local burning sensation and severe pruritus, severe contractions of joints, and internal organ involvement that can be fatal.^2,4 NSF is a possible adverse event following exposure to gadolinium-based contrast agents used in magnetic resonance imaging (MRI) studies in patients with renal insufficiency.^1,2

Nephrogenic systemic fibrosis can resemble SSc in its clinical presentation due to the observed skin thickening and joint contractures. However, NSF is distinguished from SSc by the absence of the Raynaud phenomenon, telangiectasia, and autoantibodies commonly observed in SSc.^1,4

Read more about SSc signs and symptoms

Other Syndromes

Eosinophilia myalgia syndrome and toxic oil syndrome represent other disorders that can result in patients experiencing symptoms similar to classic scleroderma. Eosinophilia myalgia syndrome is a rare disorder associated with the ingestion of L-tryptophan supplements that leads to severe myalgias.^1,2,4 

Toxic oil syndrome was a toxic epidemic in Spain that was linked to the consumption of aniline-denatured and refined rapeseed oil that had been illegally sold as olive oil. It is associated with livedo reticularis and pulmonary infiltrates.^1,2

Read more about SSc prognosis

Drug-Induced Pseudoscleroderma

Several drugs can induce scleroderma-like conditions. These include Blenoxane® (bleomycin), pentazocine, cocaine, D-penicillamine, vitamin K, vitamin B12, interferon-β1a, Taxol® (paclitaxel), and gemcitabine. The differential diagnosis of SSc can be guided by the absence of scleroderma-specific autoantibodies.²

References

1. Adigun R, Goyal A, Hariz A. Systemic sclerosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated May 8, 2022. Accessed April 10, 2023.

2. Ferreli C, Gasparini G, Parodi A, Cozzani E, Rongioletti F, Atzori L. Cutaneous manifestations of scleroderma and scleroderma-like disorders: a comprehensive review. Clin Rev Allergy Immunol. 2017;53(3):306-336. doi:10.1007/s12016-017-8625-4

3. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699. doi:10.1016/S0140-6736(17)30933-9

4. 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

Reviewed by Hasan Avcu, MD, on 4/19/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.