The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.1,2
Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.3
The subtypes of EDS were reclassified in 1998 by Beighton et al,4 and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.5 The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.8
We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.
Case Report
A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.
Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.