|Ahead of print publication
Nondigital skin ulcers in systemic sclerosis: A neglected entity
Benzeeta Pinto, Ramya Janardana, Sowmya Kaimal, B Sheba Charles, KN Sangeeta, Jasmine Mathew, Kodishala Chanakya, John Michael Raj, Vineeta Shobha
Department of Clinical Immunology and Rheumatology, Dermatology and Biostatistics, St John's Medical College, Bengaluru, Karnataka, India
|Date of Submission||08-Sep-2020|
|Date of Acceptance||25-Nov-2020|
Department of Clinical Immunology and Rheumatology, St John's Medical College, Sarjapur Road, Bengaluru - 560 034, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Skin ulcers (SUs) are a common and difficult to manage problem in systemic sclerosis (SSc) and can be broadly classified into two types: digital ulcers (DUs) and non-DUs.
Objective: The objective of this study was to analyze prevalence, associated factors, and response to therapy for non-DU.
Patients and Methods: All patients with SSc who fulfilled the 2013 ACR/EULAR criteria were included in the study. SUs were divided into DU and various types of non-DU (SU on bony prominences, SU on calcinosis, SU on lower limbs, and SU with gangrene).
Results: We included 146 patients with SSc (83.6' females) with a median follow-up of 20.5 months (interquartile range: 52). Eighty-four patients (57.5') had at least one episode of DU. Recurrent DUs despite vasodilators were seen in 36 (24.7') patients. Thirty-four patients (23.3') had non-DU. The most common type of non-DU was SU of lower limbs (23), followed by SU on bony prominences (19). The most common ulcer site was on the malleoli in the lower limbs and elbow in the upper limbs. Most of the ulcers healed in 3–6 months. Three patients developed osteomyelitis. The presence of non-DU was associated with longer duration of disease (P = 0.0009), occurrence of DU (P = 0.011), presence of gangrene (P < 0.001), or calcinosis (P < 0.001), and higher modified Rodnan skin score (P = 0.0013).
Conclusion: Non-DUs were found in a quarter of patients with SSc. They are associated with advanced disease and vasculopathy. There is an unmet need to incorporate non-DU in clinical trial outcomes and address them in patient management guidelines.
Keywords: Leg ulcers, nondigital ulcers, systemic sclerosis
|How to cite this URL:|
Pinto B, Janardana R, Kaimal S, Charles B S, Sangeeta K N, Mathew J, Chanakya K, Raj JM, Shobha V. Nondigital skin ulcers in systemic sclerosis: A neglected entity. Indian J Rheumatol [Epub ahead of print] [cited 2021 Apr 15]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=310838
| Introduction|| |
Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy, inflammation, and fibrosis of the skin and internal organs. Digital ulcers (DUs) are a common painful and disabling complication of SSc and occur in more than half the patients of SSc. They have a significant deleterious impact on the quality of life and hand function. In severe cases, DU may lead to gangrene and require amputation. The etiology of DUs is directly related to the microvascular involvement and ischemia which are central to the pathogenesis of SSc. Skin ulcers (SUs) in SSc can be broadly classified into two types: DUs and non-DUs. While DUs in scleroderma are well studied, there are little data on non-DUs in SSc. Nondigital SUs are a unique problem in SSc and, like DU, are associated with delayed healing. They may occur on bony prominences, on calcinosis, and on lower limbs. The etiology is multifactorial and both vasculopathy and nonvasculopathic mechanisms contribute. Further insight into the pathogenesis of SSc has revealed dysregulated repair that involves all components of connective tissue, involving many cell types and processes. Some studies on mesenchymal stem cells in SSc have revealed reduced proliferative potential compared to healthy controls. Circulating endothelial progenitor cells are defective in SSc and may contribute to ineffective vasculogenesis. Both of these pathologies may lead to impaired wound healing and predisposition to chronic SUs in SSc. Giuggioli et al. recently proposed a classification of SUs in SSc based on etiopathogenesis, including both digital and non-DUs. SUs were classified as (1) DUs of hands and feet, (2) SU on bony prominences, (3) SU on calcinosis, (4) SU on lower limbs, and (5) SU or DU presenting with gangrene. Although the management of DU is clearly suggested, the guidelines are silent on the management of non-DU., We conducted this study to estimate the prevalence of non-DU in our patients with SSc and analyze the clinical features and outcomes.
| Patients and Methods|| |
This was a retrospective study conducted at a tertiary care referral center. All patients with a diagnosis of SSc seen at our center and fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in the study. Data were extracted from outpatient records, inpatient records, and structured pro forma that are maintained for all patients. All patients were screened for visceral organ involvement at baseline and thereafter as indicated. The modified Rodnan skin score (MRSS) was included for analysis only if it was available at the time of diagnosis. The clinical features of ulcers were documented from outpatient and inpatient records as appropriate. All patients were screened for interstitial lung disease (ILD) with chest X-ray and pulmonary function tests. The diagnosis of ILD was confirmed with high-resolution computed tomogram (CT) of the lungs. All patients were screened for pulmonary arterial hypertension at baseline with a two-dimensional echocardiogram (ECHO). The assessment of pulmonary hypertension was based on ECHO findings of pulmonary artery systolic pressure >40 mmHg. Right heart catheterization is not routinely performed at our center.
Definition and classification of skin ulcers
SUs were classified based on the suggestions by Giuggioli et al. SU was defined as “loss of substance involving epidermis, basement membrane, and dermis.” Only ulcers that were chronic (>6 weeks duration) were included in the study. SUs were classified as described above. Other ulcer-like lesions such as digital pitting scars, fissures, and abrasions were excluded from the study.
Antinuclear antibody was tested using indirect immunofluorescence. Immunoblot was done whenever feasible using Euroimmun assay®. Arterial Doppler or CT angiogram for macrovascular disease was done as clinically indicated in the presence of absent or weak pulses, limb claudication, presence of multiple cardiovascular risk factors, or other features of arterial insufficiency. Venous Doppler was done in patients with lower-limb ulcers who had concomitant signs of venous disease, such as the presence of frank varicose veins, stasis dermatitis, or lipodermatosclerosis. Antiphospholipid (APL) antibodies – lupus anticoagulant (LA) and anticardiolipin antibody (ACLA) testing – were as per the discretion of treating physician. Statistical tests were performed using the STATA 14.2 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp L). Quantitative variables were described as mean ± standard deviation or median (interquartile range [IQR]) as appropriate. Categorical variables were described as frequencies. The independent t-test or Mann–Whitney U-test was used to compare the means or medians between two groups as appropriate. Categorical variables were analyzed using Chi-square test or Fisher's exact test. A value of P < 0.05 was considered statistically significant.
Ethical clearance was obtained from the Institutional Ethics Committee (IEC). Bioethics guidelines set by the Indian Council of Medical Research 2017 and the Helsinki Declaration 2013 were adhered to. This was a retrospective study, and a waiver of consent was obtained from IEC, St. John's Medical College Hospital, Bangalore.
| Results|| |
Clinical and demographic profile
One hundred and forty-six patients (122 females) were included in this study. The median follow-up duration of the cohort was 20.5 months (IQR: 52). The clinical features are summarized in [Table 1]. Most of the patients had a limited pattern of skin involvement (58.2').
Prevalence of skin ulcers
Eighty-four patients (57.5') had at least one episode of DU anytime during their illness. Recurrent DU despite vasodilator therapy was seen in 36 patients (24.7'). DU was associated with gangrene in 19 patients (13'). Forty-nine episodes of nondigital SUs were seen in 34 patients (23.3') during the follow-up duration.
Anti-topoisomerase (SCL70) was the most common autoantibody on our cohort detected in 73 (54.9'). Anti-centromere antibodies (ACAs) were positive in only 13 (9.8') patients. Thirty-three patients (24.8') were positive for RNP/Sm, and this constituted the second most common antibody in our series. APL antibodies (LA and ACLA) were tested in 23 patients in the entire cohort and ACLA was positive only in 1 patient.
Classification and clinical features of nondigital ulcers
Forty-nine episodes of non-DU were noted in 34 patients during the follow-up duration. The most common type of non-DU was SU of lower limbs [Table 2]. Ten patients had more than one type of non-DU. Twelve patients had more than one episode of non-DUs. Nine ulcers occurred in the first 2 years of the disease after diagnosis, 19 ulcers between 2–5 years, and 21 ulcers more than 5 years after disease onset. Twenty-four episodes of SU upper limbs were noted in 19 patients and 26 episodes of SU lower limbs in 23 patients [Figure 1]. The most common sites of ulcers on the upper limbs were elbows (15/49) followed by metacarpophalangeal joints (11/49) [Figure 1]. The other sites for ulcers on the upper limb were proximal interphalangeal joints and wrist. The most common sites of lower-limb ulcers were the malleoli (20/49), followed by the plantar aspect of the foot (6/49) [Figure 2]. In 28 episodes, ulcers occurred simultaneously on more than one site. Ulcers due to calcinosis were seen only in 7 patients. One patient with myositis overlap had ulcers due to panniculitis. One patient had a venous ulcer associated with varicose veins. Only one patient with lower-limb ulcers had loss of peripheral pulses and ischemic lower-limb pain. Arterial Doppler was done in 8 patients with lower-limb ulcers. Six of these patients with lower-limb ulcers had concomitant macrovascular arterial disease as diagnosed by Doppler. However, the changes were nonocclusive in five patients. One patient had occlusive disease with critical limb ischemia and gangrene. This patient was positive for ACLA. Most ulcers were <5 cm in diameter except for two patients who had large lower-limb ulcers. Biopsy of the ulcer was available in two patients, and both showed nonspecific inflammation.
|Figure 1: Skin ulcer on upper limbs: Left panel: ulcers on metacarpophalangeal joints; right panel: ulcer on elbow|
Click here to view
One hundred and thirty-five patients were on vasodilatory treatment. Ninety-five patients were on phosphodiesterase-5 inhibitors (PDE5is, tadalafil/sildenafil) in combination with calcium channel blockers (CCBs), 30 patients on CCB alone, 10 patients were on PDE5i alone, and 11 patients on endothelin receptor antagonists (ERA, ambrisentan/bosentan) along with CCB and PDE5i. Twenty-three patients had recurrent DU on CCBs, 10 patients had recurrent DU on tadalafil and CCB combination treatment, and 3 patients had a recurrence of DU after the addition of ERA.
Twenty-five episodes of non-DU were treated with a low-to-moderate dose of steroids. Of these, 19 episodes healed within 6 months. Twelve patients were treated with colchicine for lower-limb ulcers. Complications in the form of local infection proven by culture were documented in 19 ulcer episodes. Seventeen of these occurred in lower-limb ulcers [Figure 3]. The most common organism isolated in cultures was beta-hemolytic streptococci (5), Gram-negative enteric organisms (5), Pseudomonas (4), methicillin-sensitive Staphylococcus aureus (3), and methicillin-resistant S. aureus (3). Three patients had osteomyelitis.
Most of the ulcers healed in 3–6-month duration. In eight episodes, the ulcer took more than 6 months to heal. All these were lower-limb ulcers. Three patients underwent surgical debridement. One patient required a below-knee amputation in view of gangrene and associated arterial insufficiency.
The presence of DU was associated with male sex, longer duration of disease and Raynaud phenomenon, higher MRSS, gastrointestinal manifestations, ILD, and anti-topoisomerase antibody. The presence of non-DU was associated with longer duration of disease, occurrence of DU, DU with gangrene, calcinosis, and higher MRSS score for skin thickening [Table 1]. SU upper limbs were associated with younger age at diagnosis (P = 0.017), higher MRSS score at first visit (P = 0.0006), diffuse disease (P = 0.003), calcinosis (p=<0.001), DU with gangrene (P = 0.010), ILD (P = 0.019), SU on lower limbs (P = 0.001), and SU calcinosis (P = 0.000). Ulcers on lower limb were associated with longer disease duration (P = 0.0018), longer duration of Raynaud's phenomenon (P = 0.0194), MRSS (P = 0.0289) calcinosis (P = 0.011), SU calcinosis (P < 0.001), DU anytime (P = 0.008), and DU gangrene (P = 0.001).
| Discussion|| |
We found a higher prevalence of non-DU in our study than previously reported. The etiology of non-DU was multifactorial, however, vasculopathy and skin thickening are important in ulcers at all sites. SU on lower limbs were the most common non-DU in our series. Lower-limb ulcers occur with increased frequency in patients with connective tissue diseases as compared with general population. In a series of chronic nonhealing leg ulcers, 23' were found to be associated with immune disease. In a study by Shanmugam et al., the prevalence of lower-limb ulcers in SSc was found to be 4'. We found a higher prevalence of lower-limb ulcers in our series. Shanmugam et al. found an association of lower-limb ulcers with APL antibody positivity and genetic prothrombotic states. We had not specifically screened for APL antibodies in all patients in our series. However, only one patient of the eight with SU on lower limbs who were tested for APL antibodies was positive. Arterial insufficiency and macrovascular disease may contribute to ischemic ulcers in patients with SSc. In a series of 45 cases on lower-limb ulcers in scleroderma, 21 cases were reported as ischemic; 7 of these were macrovascular and 14 microvascular. Twenty-two ulcers in this series were reported as venous ulcers. We did not routinely do arterial or venous Doppler in our patients unless there were other features to suggest arterial or venous ulcers. The mean age of patients in our series was lower than in the above series. In addition, the prevalence of smoking and other cardiovascular risk factors was also low in our patients. Only one patient had critical limb ischemia in our series. Lower-limb ulcers in our series were most likely due to vasculopathy since they were associated with DU, indicating that microvascular ischemia may be the most important etiological factor for lower-limb ulcers. The most common site of ulcers on the lower limbs was the malleoli, which was similar to previously reported series.,
Ulcers on bony prominences of the upper limbs were the other common type of ulcer in our patients. In a study of SUs in 130 patients with SSc, only 11 patients were reported to have ulcers on bony prominences. Ulcers on bony prominences were associated with diffuse disease, skin thickening (MRSS), and vasculopathy (DU, gangrene) in our study. Two previous series also reported an association of diffuse disease and anti-topoisomerase positivity with SU of upper limbs an inverse correlation with ACAs., SUs of upper limbs were not associated with any particular antibody profile in our series. However, a higher proportion of our patients were positive for ATA as compared to Western series. Very few patients in our series had ACA positivity. Another series from South India showed that only 4' of patients had ACA positivity. This was similar to other series reported from Southeast Asia and Africa., These differences may account for the higher prevalence of ulcers in our series. All the upper-limb ulcers in our series healed in 3–6-month duration. Complications in the form of infections were only seen in 2 patients with upper-limb ulcers. The pathogenesis of SU of upper limbs is likely related to the abnormal skin, contractures, and associated microtrauma. The presence of vasculopathy may impair healing contributing to the ulcers. Very few patients in our series had calcinosis and associated ulcers. This was similar to that reported by Giuggioli et al. Calcinosis was associated with non-DU as well as ulcers on bony prominences and lower limbs.
Previous studies have shown an association of DUs with lung involvement, and pulmonary arterial hypertension. DUs in our series were associated with GI manifestations and ILD. The presence of non DUs was not associated with internal organ involvement in our series. This was similar to the observations made by Giuggioli et al. The presence of both DU and non-DU was associated with longer duration of disease. We noted that most of the non-DUs in our series occurred after 5 years of disease onset.
There are no guidelines for treatment of nondigital SUs in SSc. The role of steroids and immunomodulatory drugs is not known. Most of our patients were managed conservatively with daily dressings. Steroids and colchicine were used in a few patients in our series with good response. In the absence of controlled studies, the role of immunosuppression is not clear. Nondigital SUs in our series were associated with vasculopathy, and hence, vasodilators may aid healing. Ferreira and Scheinberg reported a case of pretibial ulcer that did not respond to conservative measures and was successfully treated with bosentan. In a series of five patients with nonhealing lower-limb ulcers, bosentan was found useful in three patients. These three patients had ulcers surrounded by severe cyanosis, indicating that bosentan may be useful in ulcers due to ischemic etiology. Very few patients in our series were on ERA, primarily due to financial constraints. The role of vasodilators in non-DUs requires further study. Various other modalities have been described for nonhealing ulcers. Few series have shown the efficacy of growth factors such as granulocyte-colony-stimulating factor and recombinant erythropoietin in SUs in SSc., Both these treatments are known to promote endothelial cell proliferation and vasculogenesis. Mesenchymal stem cells are known to have antifibrotic and angiogenic properties and may have a role in SSc ulcers. Stem cell transplantation and adipose tissue grafting have also been tried with success in ischemic ulcers in scleroderma., Hyperbaric oxygen (HBOT) has been used in chronic wounds of many etiologies. It was found to be of benefit in a small series of both digital and lower-limb ulcers in SSc. Three patients in this series had nonhealing lower-limb ulcers and were treated with HBOT. In two patients, the ulcer healed completely, and the third had a significant reduction in ulcer size. Only one patient in our series underwent split skin grafting (SSG). SSG has been used successfully in leg ulcers in rheumatoid arthritis as well as SSc. We found few complications in our series as compared to reported literature. Culture-proven infections were less common than previously reported. Osteomyelitis occurred only in three of our patients.
Our study had several limitations. The study was retrospective in nature, and hence, the exact healing time of ulcer was not available. The usual follow-up interval is 3 months, and hence, ulcers of lesser severity may have been missed. We did not screen for APL antibodies in all patients with lower-limb ulcers. Due to financial constraints, Doppler was not done for all patients with lower-limb ulcers. MRSS was not available at the time of initial diagnosis in all patients and was assessed by multiple observers. The effect of different treatment modalities was not clear due to the retrospective design.
| Conclusion|| |
Non-DUs are a common problem in SSc and are associated with vasculopathy and skin thickening. There are very few studies on etiopathogenesis and outcomes. The efficacy of various treatment modalities needs to be further explored in prospective studies. Since vasculopathy was prominent in our series, improving tissue microcirculation may be the key in both DU and non-DU. The management of this entity constitutes an unmet need that needs to be further addressed in clinical trials and guidelines on SSc.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Denton CP, Khanna D. Systemic sclerosis. Lancet 2017;390:1685-99.
Matucci-Cerinic M, Krieg T, Guillevin L, Schwierin B, Rosenberg D, Cornelisse P, et al
. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis. 2016;75:1770-6.
Guillevin L, Hunsche E, Denton CP, Krieg T, Schwierin B, Rosenberg D, et al
. Functional impairment of systemic scleroderma patients with digital ulcerations: Results from the DUO Registry. Clin Exp Rheumatol 2013;31:71-80.
Steen V, Denton CP, Pope JE, Matucci-Cerinic M. Digital ulcers: Overt vascular disease in systemic sclerosis. Rheumatology (Oxford) 2009;48 Suppl 3:iii19-24.
Rozier P, Maria A, Goulabchand R, Jorgensen C, Guilpain P, Noël D. Mesenchymal stem cells in systemic sclerosis: Allogenic or autologous approaches for therapeutic use? Front Immunol 2018;9:2938.
Del Papa N, Quirici N, Soligo D, Scavullo C, Cortiana M, Borsotti C, et al
. Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 2006;54:2605-15.
Giuggioli D, Manfredi A, Lumetti F, Colaci M, Ferri C. Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature. Autoimmun Rev 2018;17:155-64.
Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al
. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017;76:1327-39.
Knobler R, Moinzadeh P, Hunzelmann N, Kreuter A, Cozzio A, Mouthon L et al
. European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes. J Eur Acad Dermatol Venereol. 2017;31:1401-24.
Khanna D, Furst DE, Clements PJ, Allanore Y, Baron M, Czirjak L, et al
. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord 2017;2:11-8.
Nagel C, Henn P, Ehlken N, D'Andrea A, Blank N, Bossone E, et al
. Stress Doppler echocardiography for early detection of systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Res Ther 2015;17:165.
Spentzouris G, Labropoulos N. The evaluation of lower-extremity ulcers. Semin Intervent Radiol 2009;26:286-95.
Shanmugam VK, Schilling A, Germinario A, Mete M, Kim P, Steinberg J et al
. Prevalence of immune disease in patients with wounds presenting to a tertiary wound healing centre. Int Wound J 2012;9:403-11.
Shanmugam VK, Price P, Attinger CE, Steen VD. Lower extremity ulcers in systemic sclerosis: features and response to therapy. Int J Rheumatol 2010;2010:747946.
Bohelay G, Blaise S, Levy P, Claeys A, Baudot N, Cuny JF, et al
. Lower-limb ulcers in systemic sclerosis: A multicentre retrospective case-control study. Acta Derm Venereol 2018;98:677-82.
Alivernini S, De Santis M, Tolusso B, Mannocci A, Bosello SL, Peluso G, et al
. Skin ulcers in systemic sclerosis: Determinants of presence and predictive factors of healing. J Am Acad Dermatol 2009;60:426-35.
Meier FM, Frommer KW, Dinser R, Walker UA, Czirjak L, Denton CP, et al
. Update on the profile of the EUSTAR cohort: An analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 2012;71:1355-60.
Janardana R, Nair AM, Surin AK, Prakash JAJ, Gowri M, Danda D. Unique clinical and autoantibody profile of a large Asian Indian cohort of scleroderma-do South Asians have a more aggressive disease? Clin Rheumatol. 2019;38(:3179-87.
Wang J, Assassi S, Guo G, Tu W, Wu W, Yang L, et al
. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 2013;32:617-21.
Tager RE, Tikly M. Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in Black South Africans. Rheumatology (Oxford) 1999;38:397-400.
Khimdas S, Harding S, Bonner A, Zummer B, Baron M, Pope J; Canadian Scleroderma Research Group. Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry. Arthritis Care Res (Hoboken) 2011;63:142-9.
Tiev KP, Diot E, Clerson P, Dupuis-Siméon F, Hachulla E, Hatron PY, et al
. Clinical features of scleroderma patients with or without prior or current ischemic digital ulcers: post-hoc analysis of a nationwide multicenter cohort (ItinérAIR-Sclérodermie). J Rheumatol 2009;36:1470-6.
Sunderkötter C, Herrgott I, Brückner C, Moinzadeh P, Pfeiffer C, Gerss J, et al.
Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors. Br J Dermatol. 2009;160:835-43.
Ferreira ME, Scheinberg MA. Successful treatment with bosentan of non-digital skin ulcers in severe scleroderma. Ann Rheum Dis 2008;67:1784-5.
Taniguchi T, Asano Y, Hatano M, Tamaki Z, Tomita M, Kawashima T, et al.
Effects of bosentan on nondigital ulcers in patients with systemic sclerosis. Br J Dermatol 2012;166:417-21.
Giuggioli D, Magistro R, Colaci M, Franciosi U, Caruso A, Ferri C. The treatment of skin ulcers in systemic sclerosis: Use of granulocyte-colony stimulating factor (G-CSF) in 26 patients. Reumatismo 2006;58:26-30.
Ferri C, Giuggioli D, Sebastiani M, Colaci M. Treatment of severe scleroderma skin ulcers with recombinant human erythropoietin. Clin Exp Dermatol 2007;32:287-90.
Nevskaya T, Ananieva L, Bykovskaia S, Eremin I, Karandashov E, Khrennikov J, et al
. Autologous progenitor cell implantation as a novel therapeutic intervention for ischaemic digits in systemic sclerosis. Rheumatology (Oxford) 2009;48:61-4.
Del Papa N, Di Luca G, Andracco R, Zaccara E, Maglione W, Pignataro F, et al
. Regional grafting of autologous adipose tissue is effective in inducing prompt healing of indolent digital ulcers in patients with systemic sclerosis: Results of a monocentric randomized controlled study. Arthritis Res Ther 2019;21:7.
Mirasoglu B, Bagli BS, Aktas S. Hyperbaric oxygen therapy for chronic ulcers in systemic sclerosis Case series. Int J Dermatol 2017;56:636-40.
Hafner J, Schneider E, Burg G, Cassina PC. Management of leg ulcers in patients with rheumatoid arthritis or systemic sclerosis: The importance of concomitant arterial and venous disease. J Vasc Surg 2000;32:322-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]