Description of DFUs in patients with lipodystrophy
Among 90 metreleptin naïve patients with lipodystrophy and diabetes, DFUs were observed in 9 subjects. These foot ulcers have been briefly reported recently [5]. A more detailed description of these ulcer episodes in individual patients are presented below.
Patient-1 developed a small (1 x 0.5 cm) grade 1 ulcer on the dorsum of his right foot. The patient had diabetic neuropathy but the absence of typical features of a neuropathic ulcer such as an ulcer forming on the pressure points on the limb or callus formation prompted us to search for PAD. CT angiography revealed heavy calcifications in both extremity arteries and severe stenosis in the right common iliac artery (CIA), right superficial femoral artery (SFA), and P1 segment of the right popliteal artery (PA) (Fig.1A).
Patient-2 had multiple episodes of predominantly neuropathic type ulcers. She was first presented with a 3 x 2 cm ulcer located on the right middle toe complicated with osteomyelitis and local gangrene. The vascular assessment revealed non-significant stenosis in the right CIA and bilateral chronic occlusions in the posterior tibial artery (PTA). The revascularization of the right PTA was unsuccessful due to severe calcifications. The ulcer did not heal despite off-loading and treatment with ampicillin/sulbactam (52 days) followed by piperacillin/tazobactam (9 days), tigecycline/ciprofloxacin (17 days) and moxifloxacin (14 days). This episode required a minor amputation. In the subsequent year, she developed an ulcer on the dorsum of the big toe (1 x 1 cm) complicated with cellulitis spreading to the right anterior tibia. Cellulitis healed with ampicillin/sulbactam (18 days) followed by clindamycin/ciprofloxacin (4 days), and the ulcer improved with local wound care. However, she was admitted a few months later with a purulent section coming from the ulcer and a newly developed ulcer under the little toe. Her ulcer on the right toe was bigger this time (3 x 3 cm). Osteomyelitis was detected. Culture work-up revealed multiple organisms. The ulcer healed after vacuum-assisted closure (VAC) therapy along with local debridement and prolonged antibiotic treatment with clindamycin/ciprofloxacin (85 days), followed by imipenem/linezolid (15 days) and ertapenem/daptomycin (30 days). Several months later, she presented with multiple small neuropathic ulcers (ranging from 1 to 3 cm) located under the right metatarsal head complicated with osteomyelitis. These ulcers healed after debridement and curettage of the first metatarsal bone along with antibiotics (clindamycin/ciprofloxacin for 57 days). Her fifth episode occurred on her left foot under the big toe. This neuropathic ulcer required prolonged antibiotic treatment for osteomyelitis including ampicillin/sulbactam (206 days) followed by clindamycin/ciprofloxacin 116 days). A few years later, she presented with a severe DFU in the right foot (Fig. 1B). CT angiography revealed heavy calcifications and severe stenosis in the right SFA. As predilatation with the plain old balloon angioplasty (POBA) under nominal pressure (10 atm) was insufficient, high-pressure drug-eluting balloon (DEB) angioplasty was performed under 20 atm for 3 minutes to the right SFA. After the successful vascular intervention, the patient underwent below-the-knee amputation.
Patient-3 presented with a gangrenous ulcer on her left big toe and first metatarsus, spreading to the forefoot, which was complicated with cellulitis of surrounding tissues and osteomyelitis (Fig. 1C-I). Left popliteal artery stenosis was detected and the patient underwent a below-the-knee amputation. About 2 years later, she developed a bullous lesion on the lateral malleolus of the right leg (2 x 2 cm) which was complicated with mild superficial cellulitis. Non-significant right proximal superficial artery stenosis was detected. The lesion healed with local wound care. A few months after, she presented with a grade 1 neuropathic ulcer surrounded by callous in her right big toe (Fig. 1C-II).
Patient-4 developed a 5 x 3 cm ulcer on the plantar aspect of the first right metatarsal head which was complicated with cellulitis and abscess formation. Posterior and anterior tibial artery occlusions were detected. The ulcer healed after treatment with debridement and parenteral clindamycin and ciprofloxacin for 14 days.
Patient-5 presented with a neuropathic ulcer on the plantar surface of the right big toe complicated with cellulitis, abscess formation, osteomyelitis, and local necrosis. The infection progressed despite treatment with systemic antibiotics and the episode resulted in the amputation of the right toe.
Patient-6 developed a predominantly neuropathic ulcer on the plantar aspect of the left big and fourth toes which was complicated with abscess formation, osteomyelitis, and necrosis. Wound culture showed multiple microorganisms over time. She was treated with parenteral ciprofloxacin/piperacillin/tazobactam (7 days) followed by amoxicillin/clavulanic acid and ciprofloxacin (15 days). The episode resulted in auto-amputation of the two toes but the infection did not heal. The patient was discharged with wound care but readmitted several months later with disseminated infection and died due to sepsis despite treatment with broad-spectrum antibiotics.
Patient-7 presented with a necrotic forefoot ulcer complicated with osteomyelitis (Fig. 1D-I). The patient was treated with transmetatarsal amputation first, but she developed infected tissue necrosis after her first surgery (Fig. 1D-II) and underwent below-knee amputation.
Patient-8 was admitted because of bullous lesions on the plantar surfaces of toes (Fig. 1E). She received 7 days of amoxicillin-clavulanic acid, and the lesions healed after minor debridement.
Patient-9 first presented with a large neuropathic ulcer on the dorsal aspect of the forefoot and midfoot, which was complicated with osteomyelitis (Fig. 1F-I). This patient later presented with another neuropathic ulcer and underwent a toe amputation (Fig. 1F-II).
Comparison of patients with lipodystrophy developing DFU to those without DFU
Clinical characteristics of lipodystrophy patients developing DFUs are presented in Table 1. The characteristics of patients with lipodystrophy developing DFUs were compared to lipodystrophy patients with diabetes but no DFUs (Table 2). Patients with DFUs had longer disease durations for lipodystrophy and diabetes. Their glycemic control was worse. All patients developing DFUs were on insulin, while half of lipodystrophy patients without DFUs were still being treated with oral antidiabetics, another indicator of the presence of more severe diabetes in patients developing foot ulcers. Retinopathy, neuropathy and PAD were more commonly detected among patients with lipodystrophy developing DFUs. Patients with DFUs tended to have lower leptin levels. Also, patients with DFUs were more likely to have decreased estimated glomerular filtration rate (eGFR).
The time from diagnosis of diabetes to first DFU was significantly shorter for patients with GL compared to partial lipodystrophy (Fig.2). ROC analysis revealed the time from the clinical diagnosis of lipodystrophy, duration of diabetes and HbA1c as predictors of DFUs (data controlled for age, gender, and smoking history). Although leptin level had an area under the curve (AUC) value greater than 0.7, its predictive value did not reach statistical significance (Table 3).
The multiple logistic regression model estimated significant associations between DFUs and GL (odds ratio (OR): 40.81, 95%CI: 3.31 - 503.93, p = 0.004), long-term diabetes (≥ 15 years; OR: 27.07, 95%CI: 2.97 - 246.39, p = 0.003), the amount of time since the clinical diagnosis of lipodystrophy (≥ 11 years; OR: 22.90, 95%CI: 3.67 - 143.09, p = 0.001), and decreased eGFR (OR: 13.35, 95%CI: 1.96 - 90.67, p = 0.008), when data were adjusted for age, gender, smoking (Table 4).