Diabetic foot ulcer with overlap syndrome: A case report and review of literature

Abstract

BACKGROUND

Diabetic foot ulcer (DFU) is a common and serious complication among individuals with diabetes. However, the co-occurrence of DFU with overlap syndrome, particularly involving anti-synthetase syndrome (ASS) and systemic sclerosis (SSc), is exceptionally rare.

CASE SUMMARY

We report a case of overlap syndrome (ASS and SSc) with diabetes manifesting as biped gangrene. The patient, a 60-year-old female, presented with painful ulcers on both heels that had persisted for nine months. She was diagnosed with DFU, which was likely attributable to SSc, suboptimal long-term glycemic control, and glucocorticoid therapy. Following four months of treatment, the patient demonstrated significant improvement and was subsequently discharged. At the one-year follow-up, the patient developed new cyanotic ulcers on the right 4^th and 5^th toes ten months post-discharge that resolved completely within 3 months following conservative management. The four-year follow-up revealed persistent intermittent cyanosis without ulcer recurrence, although progressive interstitial lung disease necessitated prolonged bed rest.

CONCLUSION

SSc-related foot ulcers demonstrate favorable outcomes when managed with conventional wound care combined with vasoactive agents.

Key Words: Diabetic foot ulcer; Overlap syndrome; Anti-synthetase syndrome; Systemic scleroderma; Case report

Core Tip: Diabetic foot ulcers (DFUs), although common in diabetes, rarely coexist with connective tissue diseases, particularly overlap syndromes. We describe a unique case involving DFUs with overlap syndrome [systemic sclerosis (SSc) and anti-synthetase syndrome (ASS)]. Literature analysis revealed three key patterns in SSc-related foot ulcers: Low incidence, predominant toe involvement, and rare diabetes comorbidity. No ASS-related foot ulcer cases have been reported. The prognosis of SSc-related foot ulcers is generally favorable, with standard DFU therapies (notably autologous platelet-rich gel) showing efficacy. Bosentan and calcium channel blockers may have therapeutic and preventive effects on SSc-related foot ulcers.

INTRODUCTION

Overlap syndrome refers to a clinical condition that satisfies the diagnostic criteria for at least two distinct connective tissue diseases (CTDs), such as dermatomyositis/polymyositis, systemic sclerosis (SSc), rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus[1]. Anti-synthetase syndrome (ASS), as a rare subtype of idiopathic inflammatory myopathy, is defined by the triad of interstitial lung disease (ILD), inflammatory myopathy, and the presence of anti-aminoacyl-tRNA synthetase antibodies, accompanied by systemic manifestations including fever, Raynaud’s phenomenon, mechanic’s hands, and polyarthritis[2,3]. SSc, another rare CTD, is characterized by progressive fibrosis affecting cutaneous tissues, microvasculature, and visceral organs[4]. Although previous studies have reported the coexistence of ASS and SSc[5], the synergistic complications arising from this overlap remain underexplored.

Therapeutic management of both ASS and SSc often requires long-term glucocorticoid (GC) administration, which may exacerbate pre-existing diabetes mellitus[6]. The concurrent presence of hyperglycemia and the intrinsic immunosuppressive effects of GC therapy synergistically increase susceptibility to bacterial, viral, and fungal infections[7,8]. This risk is especially pronounced in patients with foot trauma. Notably, microvascular dysfunction and dermal fibrosis induced by SSc may further worsen diabetic foot ulcers (DFUs)[9]. We present a novel clinical case featuring the rare coexistence of DFU, ASS, and SSc, complemented by a systematic literature review to advance the understanding and management of SSc-associated foot ulcers. To our knowledge, this represents the first reported case of DFU associated with ASS and SSc in the literature.

CASE PRESENTATION

Chief complaints

A 60-year-old woman presented to the endocrinology department in October 2020 due to intermittent cough, sputum production, and shortness of breath for 4 years, and bilateral foot ulcers for 9 months.

History of present illness

The patient’s medical history included ILD and diabetes, diagnosed in January 2017. During hospitalization, symptoms improved significantly with methylprednisolone, anti-infective agents, and supportive care; regular prednisone use was undertaken after discharge (Figure 1). In November 2017, she developed fingertip gangrene accompanied by Raynaud’s phenomenon. Nailfold capillaroscopy revealed marked microvascular ischemia with inflammatory alterations. Immunological testing revealed positivity for the anti-nuclear antibody, anti-scleroderma-70 antibody, anti-Sjogren’s-syndrome-related antigen A (anti-SSA) antibody, anti-SSA antibody, and anti-glycyl-tRNA synthetase (anti-EJ) antibody. Skin biopsy of the right deltoid muscle demonstrated eosinophilic changes in dermal collagen along with mild perivascular lymphocytic infiltration, while skeletal muscle biopsy revealed focal degeneration and necrotic muscle fibers. Based on these findings, she was diagnosed with ASS and SSc. Following methylprednisolone, cyclophosphamide, and supportive care, her symptoms improved significantly, and she was discharged on regular prednisone (Figure 1).

Figure 1 The timeline diagram of patient diagnosis and treatment. anti-Scl-70 antibody: Anti-scleroderma-70 antibody; anti-SSA antibody: Anti-Sjogren’s-syndrome-related antigen A antibody; anti-EJ antibody: Anti-glycyl-tRNA synthetase.

The patient, who was a non-smoker, was admitted with the following medication regimen: Isophane protamine recombinant human insulin (4 U q.d.), miglitol (50 mg t.i.d.), prednisone (10 mg b.i.d.), colchicine (0.5 mg q.d.), pirfenidone (200 mg b.i.d.), lansoprazole (30 mg q.d.), and acetylcysteine (600 mg b.i.d.).

History of past illness

The patient was diagnosed with hyperlipidemia and osteoporosis in January 2020, and received alfacalcidol (0.25 μg q.d.). She denied a history of infectious diseases (e.g., hepatitis, tuberculosis), drug allergy, surgery, or trauma.

Personal and family history

No relevant personal or family history was reported.

Physical examination

Upon admission, the patient’s vital signs were stable (temperature: 36.4 °C; blood pressure: 122/75 mmHg). Physical examination revealed evidence of malnutrition (body mass index: 17.06 kg/m²) and bilateral Velcro rales on pulmonary auscultation. The skin of the right index and middle fingers was slightly hard, and the local skin was slightly thickened. Lower extremity assessment revealed a 3.0 cm × 2.5 cm wound on the right heel and a 2.5 cm × 2.0 cm circular wound on the left heel, both demonstrating gangrenous changes with minimal yellow exudate (Figure 2). Vascular examination indicated non-palpable posterior tibial and popliteal arteries bilaterally, along with weak dorsal pedal pulsation. Neurological evaluation disclosed diminished thermoesthesia and vibratory sensation in both feet, accompanied by significant pain (visual analog scale: 8/10). The ankle-brachial index (ABI) was within normal limits (right: 1.23; left: 1.11).

Figure 2 The condition of the patient’s foot ulcers.

Laboratory examinations

Laboratory findings on admission are summarized in Table 1. A comprehensive evaluation demonstrated normal profiles for cardiac, hepatic, renal, thyroid, and coagulation functions. Further investigations, including serum protein electrophoresis, immunofixation electrophoresis, immunoglobulin light chains, blood light chain (κ and λ), and complement components (C3 and C4), yielded unremarkable results.

Table 1 The primary laboratory test findings of the patient at admission and discharge.

Item	Admission	Discharge	Reference range
Red blood cell count (1012/L)	3.69	4.49	3.8-5.1
Blood platelet count (109/L)	146	233	100-300
White blood cell count (109/L)	8.52	8.57	5.5-9.5
Percentage of neutrophils (%)	82	73.4	40-75
Parathyroid hormone (pmol/L)	10.00	NA	1.60-6.90
25-hydroxyvitamin D3 (nmol/L)	44.9	NA	47.7-144
Erythrocyte sedimentation rate (mm/h)	46.0	51.0	< 38
C-reactive protein (mg/L)	6.80	4.14	< 5
Procalcitonin (mg/mL)	< 0.02	< 0.02	< 0.046
Interleukin-6 (pg/mL)	12.70	5.56	0.00-7.00
Creatine kinase (IU/L)	34	30	20-140
Total cholesterol (mmol/L)	6.16	5.96	2.8-5.7
Triglyceride (mmol/L)	7.39	3.03	0.29-1.83
Glycosylated hemoglobin (%)	10.3	6.9	4.5-6.1
Glycated Albumin (%)	23.24	NA	9-14
Serum cortisol (8:00-10:00) (nmol/L)	15.60	NA	133.0-537.0
Corticotropin (ng/L)	< 1.00	NA	5.00-78.00
24-hour urinary free cortisol (ug/24-hour)	474.6	NA	20.3-127.6
Bone alkaline phosphatase (ug/L)	11.05	NA	11.4-24.6
β-crosslaps (ng/mL)	0.158	NA	0.556-1.008
Propeptide of type I procollagen (ng/mL)	10.80	NA	Post-menopause: 21.32-112.8
N-MID osteocalcin (ng/mL)	1.5	NA	15-46
B cell count (cell/μL)	43	NA	175-332
CD3 cell count (cell/μL)	277	NA	941-2226
CD4 cell count (cell/μL)	169	NA	471-1220
CD8 cell count (cell/μL)	101	NA	303-1003
Cryoglobulin	Negative	NA	Negative
Anti-Scl-70 antibodies	+++	NA	Negative
Anti-SSA antibody	Negative	NA	Negative
Anti-Jo-1 antibody	Negative	NA	Negative
Antineutrophil cytoplasmic antibody	Negative	NA	Negative
Anti-Pm-Scl antibody	Negative	NA	Negative
Anti-U1RNP antibody	Negative	NA	Negative

NA: Not tested at discharge; Anti-Scl-70 antibody: Anti-scleroderma-70 antibody; Anti-SSA antibody: Anti-Sjogren’s-syndrome-related antigen A antibody; Anti-Jo-1 antibody: Anti-histidyl-tRNA synthetase antibody; Anti-Pm-Scl antibody: Anti-Pm-scleroderma antibody; Anti-U1RNP antibody: Anti-U1 small nuclear ribonucleoprotein antibody; CD: Cluster of differentiation.

Imaging examinations

Radiographic examination revealed reduced bone density bilaterally in the feet. Computed tomography (CT) of the chest demonstrated bilateral pulmonary interstitial fibrosis with inflammation (Figure 3A). Magnetic resonance imaging of the lower extremities showed soft tissue swelling and heel defects, which were particularly pronounced in the right foot (Figure 3B and C). Doppler ultrasound identified atherosclerotic plaques in the bilateral lower limb arteries and bilateral common carotid arteries, while CT angiography of the thighs and calves revealed no significant abnormalities. Histopathological analysis of foot specimens demonstrated coagulative necrosis with prominent inflammatory cell infiltration.

Figure 3 Imageological examinations. A: Computed tomography of the chest; B: Magnetic resonance imaging of the right foot (T1-weighted and sagittal image); C: Magnetic resonance imaging of the left foot (T1-weighted and sagittal image).

FINAL DIAGNOSIS

Based on a comprehensive clinical evaluation and diagnostic investigations, the patient was diagnosed with DFU classified as Wagner grade 4.

TREATMENT

To mitigate the potential adverse effects of prednisone on glycemic control and wound healing while sustaining disease control in CTD, the dosing regimen was adjusted from 10 mg b.i.d. (20 mg/day) to 17.5 mg q.d. (17.5 mg/day)[10]. During hospitalization, a comprehensive treatment protocol was implemented, encompassing glycemic management (fasting blood glucose 5-8 mmol/L; postprandial blood glucose 8-12 mmol/L), circulation enhancement, neurotrophic support, antimicrobial therapy, anti-inflammatory measures, immunomodulation, gastrointestinal protection, antiplatelet therapy, lipid-lowering interventions, osteoporosis management, and pain control. The left foot ulcer healed completely within two months following four sessions of ultrasonic debridement, one cycle of negative pressure wound therapy (NPWT), two applications of autologous platelet-rich gel (APG), and four treatments with timolol (Figure 2). The wound on the right foot with a sinus tract required extended management, involving nine sessions of ultrasonic debridement, three cycles of NPWT, and six applications of APG.

OUTCOME AND FOLLOW-UP

After four months of treatment, the patient achieved complete wound closure (Figure 2), and prednisone was tapered to 15 mg/day upon discharge (February 2021). During the one-year post-discharge phone follow-up (April 2022), we learned that the patient had developed new-onset cyanotic ulcers on the right fourth and fifth toes ten months after discharge (December 2021). These ulcers resolved completely within approximately three months following home management including disinfection, dressing changes, and supportive care. Subsequent four-year follow-up (March 2025) revealed persistent intermittent toe cyanosis without ulcer recurrence, although progressive ILD had led to prolonged bed rest (Figure 1).

DISCUSSION

We conducted a systematic search of PubMed, Web of Science, and Excerpta Medica Database for studies published from database inception to March 27, 2025, that reported cases of SSc and/or ASS with foot ulcers. The search utilized the following MeSH terms: “Scleroderma, systemic”, “anti-synthetase syndrome”, “leg ulcer”, and “foot ulcer”. Studies were eligible if they reported foot ulcers in patients with SSc and/or ASS, without restriction based on publication language or date. Following preferred reporting items for systematic reviews and meta-analyses guidelines[11], two investigators independently screened titles, abstracts, and full texts in duplicate. Eligible document types included original research articles, case reports, case series, conference abstracts, and literature reviews containing explicit case descriptions. The final selection consisted of 27 eligible publications, with the screening process outlined in Figure 4.

Figure 4 The preferred reporting items for systematic reviews and meta-analyses flow diagram of literature screening.

All included cases are systematically compiled in Supplementary Table 1. The review identified 38 SSc patients with foot ulcers across 27 studies, while no published ASS cases with foot ulcers were documented. Patient ages ranged from 15 to 91 years, including two adolescents aged 15 years. Females predominated (31 vs 6 males), with one case lacking sex documentation[12]. Raynaud’s phenomenon was documented in 18 cases, with the status remaining unreported for the remaining individuals. Ulcers predominantly affected the toes. Vascular assessments revealed lower extremity arterial stenosis/occlusion in 57.7% (15/26) of evaluated patients. Key systemic regimens comprised analgesics, antibiotics, immunosuppressants, bosentan, GCs, anticoagulants, calcium channel blockers (CCBs), lipid-lowering agents, antiplatelet drugs, and vasodilators. Primary local interventions included antimicrobials, collagenase, debridement, advanced dressings, Natrox^® oxygen, hyperbaric oxygen therapy, analgesics, botulinum toxin, local anesthetics, revascularization, platelet-rich plasma/fibrin therapies, skin grafting, and amputations.

While SSc predominantly induces vascular damage resulting in finger ulcers, foot ulcers are relatively uncommon but often very painful[13]. Although foot pain and dysfunction are frequently reported in SSc patients[14], the incidence of foot ulcers varies considerably across studies, ranging from 3.2%[15], 6.9%[14], to 20%[16].

The mechanism of SSc-induced foot ulcers involves three key aspects: Large and small vessel damage; Peripheral neuropathy; Long-term GC use causing hyperglycemia and immunosuppression. Firstly, SSc induces macrovascular lesions featuring intimal hyperplasia, while fibrinoid vasculopathy primarily targets arterioles[15,17]. Bohelay et al[18] reported that lower limb ulcers in SSc patients result from venous dysfunction (49%) or ischemia (47%) associated with macro/microvascular injury. Ulcers due to micro- or macrovascular ischemia exhibit higher amputation/recurrence rates and poorer prognosis. Cassius et al[17] found that 76% of SSc patients have inadequate perfusion in the lower limbs, and 28% have elevated ABI, indicating arterial stiffness. Small vessel lesions in skin biopsies around foot ulcers serve as key indicators for establishing SSc as the underlying cause. Secondly, bedside sensory testing reveals significantly higher rates of abnormal foot vibratory sensation in SSc patients compared to healthy controls, and the duration of Raynaud’s phenomenon correlates positively with the presence of peripheral neuropathy[19]. Peripheral sensory neuropathy of the feet, affecting both large and small nerve fibers, is a common manifestation in SSc patients[20]. Moreover, large fiber peripheral neuropathy is common in SSc, contributing to sensory loss and muscle weakness, thereby elevating the risk of foot ulcers and falls[21]. Finally, beyond the influence of SSc itself, GC therapy further elevates the risk of foot ulcers. This occurs through two mechanisms: (1) GCs can induce hyperglycemia and steroid diabetes[6]; and (2) Their inherent immunosuppressive effects increase susceptibility to foot infections[8].

The hallmark cutaneous manifestation of ASS, mechanic’s hands, presents as hyperkeratotic fissures along the radial fingers, palms, and thumb ulnar aspect, frequently associated with anti-histidyl-tRNA synthetase antibodies[22]. Notably, anti-EJ-positive cases may manifest fingertip eczema[23], whereas anti-alanyl-tRNA synthetase-positive ASS can induce digital ulcers in the absence of sclerodactyly[24]. To date, no documented cases have established a direct link between ASS and foot ulcer development.

Our literature review identified two diabetic cases with arterial stenosis/occlusion presenting exclusively with toe ulcers. One patient succumbed to sepsis following a below-knee amputation, whereas the other achieved complete ulcer resolution without surgical intervention within 3 months[25]. Overlap syndrome involving SSc and systemic lupus erythematosus was diagnosed in four patients[26,27]. Thirteen patients presented with pre-existing digital or lower extremity ulcerations before hospital admission. One case demonstrated recurrence two weeks post-healing due to significant hemorrhage at the medial ankle anastomosis site[28], and another developed a de novo right gastrocnemius ulcer concurrent with persistent left medial malleolus lesions. Post-remission follow-up data were available for four patients[28-30], indicating sustained ulcer-free periods of 12 months (three cases) and 18 months (one case), respectively. Long-term monitoring data were unavailable for the remaining cases.

Foot ulcers in SSc patients generally exhibit favorable prognoses when managed according to conventional DFU protocols, supplemented by bosentan and CCBs in specific cases. Notably, our clinical experience suggests APG may offer therapeutic potential for managing SSc-associated foot ulcers. Condorelli et al[31] demonstrated the therapeutic efficacy of platelet-rich plasma (main components of APG) in accelerating the healing of ulcers associated with SSc, while concurrently alleviating pain symptoms. The oral dual endothelin receptor antagonist bosentan, an established therapy for SSc-associated pulmonary arterial hypertension, has exhibited both prophylactic and therapeutic benefits in the management of digital ulcers[32]. Emerging evidence further suggests its potential efficacy in treating lower extremity ulcers, particularly in cases characterized by compromised peripheral microcirculation[13,27,33]. Pathophysiological investigations revealed elevated serum levels of endothelin-1 (ET-1) in patients with SSc, where this potent mediator exerts profibrotic, proliferative, and proinflammatory effects through interactions with vascular smooth muscle cells, fibroblasts, macrophages, and endothelial cells[27,34]. This molecular mechanism highlights the critical role ET-1 in mediating the vascular structural abnormalities that are characteristic of SSc. Pharmacologically, bosentan may facilitate vascular remodeling and ulcer resolution by inhibiting the ET-1 pathway. CCBs remain important agents for managing digital ischemia and preventing ulceration, leveraging their triple therapeutic action: Vasodilation, platelet inhibition, and antithrombotic properties[35,36]. Although revascularization procedures are occasionally employed for SSc-associated foot ulcers, their limited effectiveness is likely attributable to the disease’s distinctive involvement of arteriolar occlusion. This pathophysiological complexity underscores the essential role of systemic pharmacotherapy within comprehensive management strategies.

Our study has several limitations. Firstly, although ASS is associated with an elevated risk of malignancies[37], and standard clinical protocols for such patients mandate tumor screening (e.g., CT scans, mammography, colonoscopy), these procedures were not systematically performed in our patient. Secondly, while SSc predominantly affects small vessels, the absence of vascular biopsies from ulcer-adjacent tissues precludes definitive confirmation of SSc-related microangiopathy as a direct contributor to foot ulcer pathogenesis. Finally, our literature review was limited to case reports, excluding cross-sectional studies that have reported SSc-associated foot ulcer incidence rates; this omission stems from insufficient granular patient-level data in available publications.

Collectively, we propose that SSc contributed to the pathogenesis of DFU in our case, despite the absence of vascular biopsy confirmation from peri-wound tissues[15]. Key evidence includes: (1) Gangrene in the absence of macrovascular disease, which may indicate SSc-related microangiopathy; (2) Recurrent cyanotic ulcers despite adequate glycemic control; and (3) A history of Raynaud’s phenomenon and digital gangrene. Strategies for preventing recurrence should prioritize therapies such as bosentan and CCBs, which target microvascular dysfunction.

CONCLUSION

This is the first reported case in the literature of a DFU associated with ASS and SSc. Despite successful healing following systemic and localized treatment, the ulcer recurred 10 months later. Consequently, in managing such patients, it is essential to judiciously administer GCs and immunosuppressants to maintain optimal control of the CTD while minimizing drug-related impacts on ulcer healing. Additionally, emphasis should be placed on strategies to prevent ulcer recurrence.