Progress In Research On Nodular Scleroderma

Nodular scleroderma (NS), also known as keloid-like scleroderma (KS), is a rare subtype of scleroderma, which was first described by Addison in 1854. The etiology and pathogenesis are unclear, and the diagnosis mainly depends on clinical and histopathological examination. The clinical research progress of this disease is summarized as follows.

1. Etiology and pathogenesis

1.1 Cause

The cause of this disease is unclear. It has been reported that hepatitis C virus (HCV) infection is closely related to certain skin diseases such as pruritus, cutaneous vasculitis and lichen planus, long-term HCV infection and others. Interactions of environmental factors lead to problems with autoimmune regulation, and can also cause nodular lesions in patients with scleroderma. In addition, acid-resistant microorganisms, penicillamine, and long-term exposure to silicon may also be associated with the development of nodular scleroderma.

1.2 Pathogenesis

The pathogenesis is unknown. Some scholars believe that the appearance of keloid nodules is caused by the scar tissue of patients with scleroderma itself, but more literature reports do not support this view, because many patients do not have the history and family history of keloids. A scar-like change occurred after the diagnosis of scleroderma. The disease occurs in the chest bulge, which may be due to the skin tension in these parts, which leads to excessive proliferation of collagen fibers and scar formation. In addition, some scholars have suggested that there may be severe itching before the nodules are produced. This may be caused by the release of histamine and other chemicals from the mast cells infiltrated around the dermal blood vessels in the skin lesions. Damage to keratinocytes, fibroblasts, and endothelial cells releases some cytokines, such as beta-interleukin-1 (β-IL1) precursors. In addition, it can enhance the degranulation of mast cells, which promotes the conversion of inactive β-IL-1 precursor to active β-IL-1. The active β-IL-1 subsequently induces platelet origin as a fibrotic factor. Production of platelet-derived growth factor (PDGF). The overexpression of PDGF and transforming growth factor-β (TGF-β) is closely linked to the development of scleroderma, which may regulate the synthesis of collagen fibers through the TGF-β receptor. TGF-β is an important cytokine that regulates the synthesis of collagen fibers. It stimulates the proliferation of fibroblasts, regulates the synthesis of extracellular matrices, inhibits the activity of metalloproteinases, and increases the activity of protease inhibitors. TGF-β can also induce the expression of connective tissue growth factor (CTGF) in fibroblasts in nodular scleroderma, and its content is higher than that of general scleroderma. In addition, cartilage oligomeric matrix protein (COMP), XII collagen, and type 1 fibril protein in nodular scleroderma lesions were higher than peripheral skin lesions or normal skin, and COMP was induced by TGF-β. It is an important cytokine that stimulates fibrosis in scleroderma, and participates in the regulation of dermal collagen fiber network and maintenance of fibroblast activity. It has also been reported that the expression of COMP in keloids is increased. Mast cells themselves also produce some inflammatory cytokines and growth factors, including IL-1, IL-2, TNF-α, PDGF and TGF-β, which promote the production of extracellular mucin and cause tissue remodeling. The expression of mucin reflects the degree of fibrosis of the skin. Mucin can be produced by fibroblasts, glial cells, smooth muscle cells, and epithelial tumor cells. In patients with scleroderma, collagen fibers are densely distributed, so fibroblasts may be the main source of mucin. Normal skin mucins are often distributed in the dermal papilla, while scleroderma patients are often distributed throughout the dermis and predominantly in the dermis. Therefore, the occurrence of nodular scleroderma may be the interaction of cytokines, cellular proteins and local factors.

2. Epidemiology

In China, the incidence of scleroderma in connective tissue diseases is second only to rheumatoid arthritis and lupus erythematosus. About half of nodular scleroderma is secondary to systemic scleroderma, 1/4 is secondary to localized scleroderma, and the remaining patients are congenital scleroderma. Domestic Li Huizhu first reported in 1 case of a patient with nodular scleroderma, which initially showed facial skin tightness and hardening of the trunk and upper limb skin, followed by erythema nodules in the front chest, breast, shoulder, upper arm and other parts. To date, of the 9 cases reported in the country, 5 have nodules in the process of systemic scleroderma, 1 has localized scleroderma, and 3 have no scleroderma, but are on the surface of normal skin. There are gradually scattered or multiple scar-like nodules.

3. Clinical manifestations

The disease usually occurs in African Americans and women. The age of 3 to 70 years old can be affected. The average age is 41 years old. The skin lesions occur in the neck, upper limbs, shoulders, trunk and other parts. Or a solid, skin-like, scar-like nodule or red irregular plaque in the hardened area of ​​the skin. The diameter is about 2mm to 3cm, and it can also be expressed as an annular hardening plaque. Some skin lesions can be arranged in a line. No pain, some cases with localized itching. Nodular lesions usually occur 2 to 8 years after the onset of scleroderma. Previous reports of nodular scleroderma mainly have two manifestations: 1 Multiple nodules appear in the process of systemic scleroderma, and nodules begin in 1 to 2 years after the onset of systemic scleroderma, after which 2 months to 1 year becomes multiple; 2 does not involve systemic scleroderma, only a single or occasional multiple keloid rash or nodule in the neck, trunk, limbs, etc., is a localized scleroderma A subtype of young people, good hair. In addition, localized scleroderma can also be associated with nodular scleroderma. Immunosuppressive agents for the treatment of scleroderma do not prevent their progression to nodular scleroderma.

4. Laboratory inspection

Laboratory tests for nodular scleroderma are similar to those of localized or systemic scleroderma. Anti-Scl-70 antibodies are often positive when combined with systemic scleroderma. U3RNP can be positive when there is cardiopulmonary involvement, especially with pulmonary hypertension. Anti-centromere antibodies are often positive in localized scleroderma and CREST syndrome. In addition, anti-nuclear antibody-positive (spot-type or nucleolar type), rheumatoid factor-positive, syphilis serological false positive and other immunological examination abnormalities may also occur.

5. Histopathology

Nodular scleroderma is divided into three categories in histopathology: First, similar to typical scleroderma, thickened, crowded, homogenized collagen fibers are parallel to the epidermis and lack fibroblasts. Occasionally lymphocytes around the blood vessels, plasma cells infiltrated, and sweat gland extrusion phenomenon. The second is similar to keloid, which is characterized by thickened eosinophilic or hyalinized collagen bundles in the dermis, parallel to the epidermis or disordered in a nodular or whirlpool shape, with abundant fibroblasts and mucin deposits visible between them. The central elastic fibers of the lesions were reduced. In some cases, lymphocytes and plasma cells were infiltrated around the blood vessels, and there was a normal dermis separation between the proliferating collagen fibers and the epidermis. Third, the characteristics of both of them appear at the same time, which can be manifested by increased collagen fiber bundles and fibroblasts, and collagen fibers without obvious hyaline degeneration.

6. Diagnosis and differential diagnosis

Most scholars believe that nodular scleroderma (NS) is equivalent to keloid scleroderma (KS), and a few scholars believe that they have different morphological changes: nodular scleroderma appears in large numbers. Small, complex, isolated nodules, and keloid scleroderma appear as scattered, relatively large, brown or purple plaques with pseudopods, similar to keloids. Some scholars believe that: clinical and pathological findings similar to scleroderma should be named “nodular scleroderma”, similar to keloid should be named “kelsy scleroderma”, but there are actually many cases of clinical and pathological The characteristics are somewhere in between and are more difficult to distinguish. Nodular scleroderma needs to be differentiated from keloid and rash collagen tumors clinically and pathologically. Keloids occur in the sternal stalk area, usually with a family history or ethnic history. Microscopically, hyperplastic collagen fibers are tightly connected to the atrophic epidermis, and there is no normal dermal tissue separation between the epidermis, while nodular scleroderma is generally absent. A clear history of trauma, the proliferation of collagen fibers and the epidermis are separated by normal dermal tissue. There is no systematic change in rash collagenoma, and nodular scleroderma usually develops nodules from months to years after the onset of scleroderma. Histologically, the collagen homogenization is not obvious. In addition, similar nodules can be found clinically in skin myofibromatosis, fibromatosis, and nodular skin amyloidosis, and pathology and nodular scleroderma are relatively easy to identify.

7. Treatment and prognosis

Nodular scleroderma rarely improves on its own, there is no definitive treatment, including phototherapy (long-wave UV: UVAl, 340 ~ 400nm), in vitro photochemotherapy, oral or topical application, intradermal injection of glucocorticoids, antibiotics , methotrexate and methylprednisol impact therapy, non-steroidal anti-inflammatory drugs, blood circulation and phlegm drugs, cyclosporine, topical calcipotriol, tacrolimus or imiquimod ointment. It has been reported that in vitro photochemotherapy (UVA exposure after oral administration of 8-methoxypsoralen, 2 times/month) After treatment of 1 case of nodular scleroderma for 3 months, the patient’s hands are softer and the activity is better. The painful ulcer of the finger heals, the nodule becomes soft and gradually disappears, and after 10 months, the nodule disappears completely, and the mechanism may be inhibition of collagen fiber synthesis by TNF-α. One patient in China used glucocorticoids (methylprednisolone 40mg/d, gradually reduced to 6 months) combined with compound glycyrrhizin (20 days), non-steroidal anti-inflammatory drugs (Oxaprozin) After oral administration for 2 months), vitamin B1 and vitamin B12 were cured and stopped after one and a half years. No recurrence was followed.