Abstract
Digital ulcers in patients with systemic sclerosis (SSc) can be complicated by SSc-related osteomyelitis (SRO). The microbiological data and optimal management of SRO remain unclear. This single-center retrospective study involved patients with SSc aged 18 or older from April 2005 to March 2022. Diagnosis of SRO was based on clinical presentation and MRI findings. The accuracy of the superficial swab culture results was estimated using the bone culture as a reference. Temporal changes in local signs for up to a year were collected, and their association with (1) duration of antimicrobial therapy (> 6 weeks) or (2) surgical interventions was assessed using univariable analyses. Among the 2,126 patients, 46 (2.2%) were diagnosed with SRO. In seven patients whose swab and bone cultures were both available, two (28.6%) had swab cultures identifying all the organisms detected in bone cultures. Resolution of local inflammatory signs consistently preceded wound closure. Three months after therapy initiation, prolonged antimicrobial therapy was not significantly associated with the resolution of local inflammatory signs (16/19 [84.2%] vs. 12/14 [85.7%]; P = 1.00), and surgical intervention was not significantly associated with wound dehiscence (6/9 [66.7%] vs. 20/24 [83.3%]; P = 0.36). Superficial swab cultures may not reliably reflect the true causative organism of SRO. Prolonging antimicrobial therapy beyond six weeks may be of little benefit for patients with SRO when local inflammatory signs improve. Surgical intervention may be a safe and effective option for selected patients with SRO.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00296-025-05815-5.
Keywords: Systemic sclerosis, Osteomyelitis
Introduction
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular, inflammatory, and fibrotic dysfunction that affects multiple organ systems [1]. Digital ulcers are common clinical manifestations of SSc, and their prevalence among patients with SSc is 15–20% [2, 3]. The pathogenesis of SSc-related digital ulcers is multifactorial and includes vascular compromise, contracture of fingers, and calcinosis [4]. Digital ulcers are a hallmark of SSc; they are refractory to local therapy, resulting in chronic pain and functional impairment, and negatively affect the quality of life of patients [4]. Osteomyelitis is a serious complication of digital ulcers [2, 5, 6].
SSc-related osteomyelitis (SRO) shares partial characteristics with diabetic foot osteomyelitis (DFO), which also complicates ulcers in the extremities and is often treated with prolonged antimicrobial therapy with or without surgical interventions [2, 7]. However, there are some unresolved issues regarding SRO management. First, and most importantly, similar to DFO [8], treatment success in guiding antimicrobial therapy is ill-defined. These infections are locally formed, and local signs, such as preexisting ulcers, may persist regardless of the resolution of inflammation [8]. This is in contrast to vertebral osteomyelitis, in which the resolution of both systemic and local inflammatory signs is used to define a cure [9]. Second, compared to DFO [10], microbiological data on deep tissue specimens, which have important implications in choosing antimicrobials, are scarce for SRO. Deep-tissue sampling is rarely performed in SRO [7, 11]. Although bone culture and biopsy are the gold standards for diagnosing osteomyelitis, clinical and imaging findings are often used as substitutes [11, 12]. Third, unlike in DFO, aggressive surgical interventions such as amputation are often averted in SRO because of vasculopathy, and its role remains uncertain [4]. To address these gaps, we aimed to explore the definition of treatment success and optimal management of patients with SRO at a reference center for SSc.
The objectives of our study were to (1) describe the changes in clinical symptoms, signs, and laboratory data before and after treatment to explore the criteria for treatment success in patients with SRO; (2) evaluate the concordance between superficial and deep tissue cultures; and (3) investigate the role of prolonged antimicrobial and surgical therapy.
Methods
Study design, setting, and participants
This single-center retrospective study was conducted at The University of Tokyo Hospital (UTH) in Japan. UTH has a Scleroderma Center comprising a multidisciplinary team that provides comprehensive care to patients with SSc [13]. We included all individuals with positive SSc-related autoantibody test results who were 18 years or older during the study period from April 2005 to March 2022 at UTH. SSc-related autoantibodies include anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA polymerase III, and anti-U1-ribonucleoprotein (RNP) antibodies [1] and have been consistently measured in patients at our referral center with clinical suspicion of SSc.
In this study, SRO was diagnosed as per the following criteria: (1) the patient fulfilled the 2013 American College of Rheumatology (ACR) /European League Against Rheumatism (EULAR) classification criteria of SSc [14]; (2) the patient had clinical presentations suspicious for osteomyelitis of the extremities at the same time or after receiving the diagnosis of SSc; (3) the patient underwent magnetic resonance imaging (MRI) of the extremities; and (4) MRI findings were consistent with osteomyelitis. Using the ACR/EULAR SSc criteria in 2013 [14], we excluded patients with anti-U1-RNP antibodies who had mixed connective tissue disease in the absence of SSc. At UTH, treating physicians consistently ordered MRI for patients suspected of having osteomyelitis unless they had a contraindication for MRI. Patients with osteomyelitis at other sites such as vertebral osteomyelitis were excluded. If the patients experienced SRO more than once during the study period, only the first episode was included in the analyses. After a diagnosis of osteomyelitis was made based on clinical and MRI findings, the patients received therapy in either an inpatient or outpatient setting. Infectious disease (ID) consultations were available at the request of the treating physician.
Variables, data sources, and measurement
We collected the baseline characteristics of the study participants, including demographics, comorbidities, medications, clinical manifestations, autoantibodies, laboratory, microbiological, and pathologic data, and imaging findings through electronic health records. The timing of SSc diagnosis was ascertained according to documentation in the medical records, and the time of osteomyelitis diagnosis was determined as the day of the index MRI. We also collected data on ID consultations, duration of antimicrobial therapy, and surgical interventions. Surgical interventions included (1) amputation and (2) non-amputation-surgical interventions, including aspiration and drainage of deep tissue. Given the poor definition of treatment success for SRO, treatment outcomes in our study included mortality, white blood cell counts, C-reactive protein levels, and local signs (i.e., gangrene, redness, swelling, warmth, pus drainage, and wound dehiscence) at 3, 6, and 12 months after the initiation of treatment and these details were retrieved from the medical records.
Statistical analyses
First, to assess the accuracy of the microbiological diagnosis, we calculated the sensitivity and specificity of superficial swab cultures using bone culture as a standard test. Second, to explore the useful markers for treatment success, we evaluated the agreement of post-treatment improvement between local signs and symptoms and C-reactive protein levels using kappa statistics. Third, univariable analyses were performed to assess the association between treatment outcomes and (1) prolonged antimicrobial therapy (i.e., duration > 42 days) or (2) surgical interventions. In this analysis, we did not conduct a multivariable analysis due to the small sample size. Instead, we incorporated comparisons of confounders, such as medications for digital ulcers and systemic immunosuppressants between the groups, to illustrate the patient background. The Chi-squared test, Fisher’s exact test, or Mann-Whitney U test were performed as appropriate, with statistical significance defined as a two-tailed P < 0.05. For the analysis of SRO treatment, we excluded patients who were followed up without systemic antimicrobial therapy. We performed either the Fisher’s exact test or the chi-squared test for categorical variables, as appropriate, using Stata version 16 software (StataCorp, College Station, TX, USA).
Patient consent statement
This study was approved by the Institutional Review Board of The University of Tokyo Hospital (approval number 2023107NI, approval day September 11, 2023). Given the retrospective nature of the study, the requirement for patient consent was waived in accordance with the Declaration of Helsinki. This study was performed in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Results
Baseline characteristics of the study population
During the study period, 2,126 patients tested positive for at least one SSc-related autoantibody, 50 (2.4%) of whom had features of osteomyelitis in the MRI of the extremities. The chart review confirmed that three patients (3/50,6.0%) underwent MRI for arthritis, digital ischemia, and dactylitis and did not have clinical presentations suspicious for osteomyelitis of the extremities. Thus, 47 patients (47/2,126:2.2%) with positive SSc-related autoantibodies developed osteomyelitis of the extremities. After excluding one patient who did not satisfy the 2013 ACR/EULAR classification criteria, we identified 46 patients with SRO. In total, 49 episodes of SRO occurred, and the first episode in each patient was included in the present study (Fig. 1). The median age at the development of SRO was 66.5 years (interquartile range: 54.5–77.3 years), and 44 participants (95.7%) were female. Eleven (23.9%) participants were past or current smokers. Regarding the type of SSc, 18 (39.1%) had diffuse cutaneous SSc, and 18 had limited cutaneous SSc. The median modified Rodnan total skin thickness score was 5.5 (interquartile score: 2.0-14.3) [15], and 28 patients (60.9%) were on immunosuppressive therapy (Table 1). Among the overall cohort of 2,126 patients with SSc-related autoantibodies, those who developed osteomyelitis of the extremities were more likely to have anti-topoisomerase I antibodies than those who did not (36.2% vs. 19.8%, respectively; P < 0.01) (Online Resource 1).
Fig. 1.
Flow diagram of study participants. Note: Abbreviations: SSc, systemic sclerosis; SRO, systemic sclerosis-related osteomyelitis; ACR, American College of Rheumatology; EULAR, European League Against Rheumatism. aSSc-related autoantibodies included anti-centromere antibodies, anti-topoisomerase I (Scl-70) antibodies, anti-RNA polymerase III antibodies, and anti-U1-ribonucleoprotein (RNP) antibodies
Table 1.
Baseline characteristics of patients with systemic sclerosis-related osteomyelitis at enrollment
| Variables | Total (n = 46) |
|---|---|
| Patient demographics | |
| Age, median, (IQR) years | 66.5 (54.5–77.3) |
| Female sex | 44 (95.7) |
| History of smoking | 11 (23.9) |
| Characteristics of systemic sclerosis | |
| Cutaneous subset | |
| Diffuse cutaneous systemic sclerosis | 18 (39.1) |
| Limited cutaneous systemic sclerosis | 18 (39.1) |
| Unidentified | 10 (21.7) |
| Autoantibodies | |
| Anti-centromere antibody | 25 (54.3) |
| Anti-topoisomerase I antibody | 17 (37.0) |
| Anti-U1RNP antibody | 13 (28.3) |
| Anti-RNA polymerase III antibody | 1 (2.2) |
| Modified Rodnan total skin thickness score, median, (IQR) (n = 30)b | 5.5 (2-14.3) |
| Digital ulcers (n = 45)b | 43 (95.6) |
| Raynaud’s phenomenon (n = 40)b | 38 (95.0) |
| Pitting scars (n = 24)b | 19 (79.2) |
| Telangiectasia (n = 29)b | 20 (69.0) |
| Nail fold bleeding (n = 34)b | 20 (58.8) |
| Comorbidities | |
| Gastroesophageal reflux disease | 27 (58.7) |
| Interstitial lung disease | 20 (43.5) |
| Ischemic heart disease | 12 (26.1) |
| Pulmonary hypertensiona | 8 (17.4) |
| Scleroderma renal crisis | 2 (4.3) |
| Hypertension | 14 (30.4) |
| Peripheral artery disease | 12 (26.1) |
| Chronic kidney disease | 14 (30.4) |
| History of malignancy | 6 (13.0) |
| Cerebrovascular disease | 5 (10.9) |
| Diabetes | 4 (8.7) |
| Stasis dermatitis | 1 (2.2) |
| Other collagen vascular diseases | |
| Sjögren syndrome | 8 (17.4) |
| Systemic lupus erythematosus | 6 (13.0) |
| Rheumatoid arthritis | 3 (6.5) |
| Antiphospholipid syndrome | 3 (6.5) |
| Vasculitis | 2 (4.3) |
| Polymyositis/dermatomyositis | 2 (4.3) |
| Medications | |
| Non-immunosuppressants | |
| Proton pump inhibitors | 46 (100.0) |
| Prostacyclin analogs | 30 (65.2) |
| Endothelin receptor antagonists | 24 (52.2) |
| Serotonin receptor antagonists | 19 (41.3) |
| Phosphodiesterase inhibitors | 18 (39.1) |
| Calcium channel blockers | 15 (32.6) |
| Warfarin | 7 (15.2) |
| Direct oral anticoagulants | 3 (6.5) |
| Nitrates | 2 (4.3) |
| Soluble guanylate cyclase agonists | 2 (4.3) |
| Any immunosuppressants | 28 (60.9) |
| Glucocorticoids | 27 (58.7) |
| Calcineurin inhibitors | 3 (6.5) |
| Mizoribine | 3 (6.5) |
| Mycophenolate mofetil | 2 (4.3) |
| Intravenous immunoglobulin | 2 (4.3) |
| Azathioprine | 1 (2.2) |
| Methotrexate | 1 (2.2) |
| Intravenous cyclophosphamide | 1 (2.2) |
| Rituximab | 1 (2.2) |
| Tocilizumab | 1 (2.2) |
Note: Data are presented as a number (%) unless otherwise specified
Abbreviations: IQR, interquartile range
aPulmonary hypertension was defined as either mean pulmonary artery pressure ≥ 20mmHg measured by right heart catheterization or right ventricular systolic pressure ≥ 50mmHg measured by cardiac echography
bSome data were missing in the health record
Clinical manifestations and laboratory and microbiological characteristics of SRO
The time between the diagnosis of SSc and SRO varied considerably, ranging from 251 days to 35 years; 35 (76.1%) of the 46 study participants were diagnosed with SRO five years after the diagnosis of SSc. Twenty-two patients (47.8%) had toe osteomyelitis and 21 (45.7%) had finger osteomyelitis. The most common manifestation was local gangrene (n = 33, 71.7%), followed by local redness (n = 22, 47.8%), and local swelling (n = 19, 41.3%) (Online Resource 2). Only 11 patients (23.9%) had fever. The median white blood cell counts and C-reactive protein (CRP) level at the diagnosis of osteomyelitis were 5.9
103/µL (normal range: 3.3–8.6
103/ µL) and 0.40 mg/dL (normal range: 0.0–0.3 mg/dL), respectively. Bone biopsy was performed in eight patients (17.4%), of whom seven (87.5%) had a pathological diagnosis of osteomyelitis and one (12.5%) had an indeterminate result (Table 2).
Table 2.
Clinical, laboratory, and imaging characteristics of systemic sclerosis-related osteomyelitis
| Variables | Total (n = 46) |
|---|---|
| Clinical manifestations | |
| Time from the diagnosis of systemic sclerosis to osteomyelitis | |
| Within 1 year | 4 (8.7) |
| 1–5 year | 7 (15.2) |
| More than 5 years | 35 (76.1) |
| Infection site | |
| Toe | 22 (47.8) |
| Finger | 21 (45.7) |
| Foot | 3 (6.5) |
| Fever | 11 (23.9) |
| Local gangrene | 33 (71.7) |
| Local redness | 22 (47.8) |
| Local swelling | 19 (41.3) |
| Local warmth | 14 (30.4) |
| Pus drainage | 13 (28.3) |
| Bone exposure | 9 (19.6) |
| Laboratory data at enrollment | |
White blood cells level, median, (IQR)  103/µL |
5.9 (4.7–8.1) |
| CRP level, median, (IQR) mg/dL | 0.40 (0.11–1.43) |
| Imaging studies | |
| CT findings consistent with osteomyelitis (n = 4) | 1 (25.0) |
| Cultures | |
| Positive blood cultures (n = 11) | 3 (27.3) |
| Positive superficial swab cultures (n = 36) | 31 (86.1) |
| Positive cultures of deep tissue other than bone (n = 12) | 10 (83.3) |
| Positive bone culture (n = 8) | 8 (100.0) |
| Pathology | |
| Bone histopathology consistent with osteomyelitis (n = 8) | 7 (87.5) |
Note: Abbreviations: IQR, interquartile range; CRP, C-reactive protein; CT, computerized tomography
Regarding microbiological testing, blood cultures were drawn from 11 patients (23.9%), and three (6.5%) had bacteremia. Superficial swabs and bone cultures were submitted in 36 (78.2%) and eight (17.4%) patients, respectively, and the proportions of positive results were 86.1% (n = 31) and 100% (n = 8), respectively (Table 3). Bone cultures from eight patients showed that the most common organism was Staphylococcus aureus (n = 5, 62.5%). Pseudomonas aeruginosa was the second most commonly detected organism in superficial swab cultures (n = 4, 11.4%), followed by Enterococcus faecalis and Escherichia coli but was not detected in bone cultures. In seven patients who underwent both swab and bone cultures, the overall sensitivity of swab cultures was 71.4% for detecting at least one species and 28.6% for detecting all species from bone cultures.
Table 3.
The sensitivity and specificity of superficial swab culture for bone culture on microbiological results
| Organisms | Bone culture (n = 8)a |
Swab culture (n = 36) |
Validity of swab cultureb | |
|---|---|---|---|---|
| sensitivity | specificity | |||
| Gram-positive organisms | ||||
| Staphylococcus aureus | 5 (62.5) | 19 (52.8) | 75.0% | 66.7% |
| Streptococcus spp. | 1 (12.5) | 3 (8.3) | 0% | 0% |
| Enterococcus faecalis | 1 (12.5) | 4 (11.4) | 100% | 100% |
| Gram-negative organisms | ||||
| Escherichia coli | 1 (12.5) | 4 (11.4) | 100% | 100% |
| Pseudomonas aeruginosa | 0 | 5 (13.9) | 0% | 0% |
| Obligate anaerobes | ||||
| Bacteroides spp. | 1 (12.5) | 2 (5.6) | 100% | 100% |
| Total | 8 (100) | 31 (86.1) | ||
| Detection of ≥ 1 species from bone culture | 71.4% | N/Ac | ||
| Detection of all species from bone culture | 28.6% | N/Ac | ||
Note: Data are presented as a number (%) unless otherwise specified
Abbreviations: N/A, not applicable
aOrganisms recoverd from bone culture included Moraxella species (n = 1), Peptoniphilus harei (n = 1), Proteus hauseri (n = 1), and Candida glabrata (n = 1)
bValidity was calculated using data in seven participants who examined both bone and swab culture
cSpecificity was unavailable because all bone cultures were positive
Subsequent clinical course of patients not receiving antimicrobial therapy
Of the 46 study participants who were initially suspected of having osteomyelitis clinically, six (13.0%) were followed up without antimicrobial therapy. One patient was in the end-of-life stage. Another patient remained stable without antimicrobial therapy after confirming the negativity of bone culture. The other four patients did not receive antimicrobial therapy because of the subsequent spontaneous improvement of local signs and symptoms. No patient developed a relapse during the follow-up period.
Management and post-treatment clinical course of SRO
Among the study participants, 40 (87.0%) received antimicrobial therapy and were left for further analysis. The median duration of antimicrobial therapy was 47.5 days (interquartile range: 26.5–83.5 days). An ID consultation within 7 days of SRO diagnosis was performed in 28 patients (62.2%). Four patients (10.0%) underwent amputation, six (15.0%) underwent non-amputation-surgical interventions, and 30 (75.0%) received antimicrobial therapy alone.
Local inflammatory signs improved over time, with 84.8% and 100% of the patients showing no local signs or symptoms at three months and 12 months, respectively. Although the proportion of remaining open wounds also decreased gradually, 32.1% (9/28) of the patients still had open wounds after 12 months. In 23 patients with initially elevated CRP levels, the agreement between the subsequent reduction in CRP levels and the improvement of these local findings was largely poor, with the kappa statistics ranging from 0 to 0.31 (Online Resource 3). Five patients (12.5%) died within the follow-up period of one year after the diagnosis of SRO, of whom one died of progressive heart failure while receiving antimicrobial therapy for SRO. The other four died of SRO-unrelated causes, such as acute coronary syndrome. When comparing short course (≤ 42 days) vs. prolonged antimicrobial therapy (≥ 43 days), there was no statistically significant difference in the proportion of patients receiving surgical interventions or residual local manifestations (Table 4).
Table 4.
The management and outcomes of study participants receiving antimicrobial therapy in patients with systemic sclerosis-related osteomyelitis
| Variables | Total (n = 40) |
Antimicrobial therapy | P value | |
|---|---|---|---|---|
| Duration ≤ 42 days (n = 19) |
Duration ≥ 43 days (n = 21) |
|||
| Underlying medication use | ||||
| Prostacyclin analogs | 27 (67.5) | 12 (63.2) | 15 (71.4) | 0.58 |
| Endothelin receptor antagonists | 21 (52.5) | 10 (52.6) | 11 (52.4) | 0.99 |
| Phosphodiesterase inhibitors | 16 (40.0) | 5 (31.3) | 11 (52.4) | 0.09 |
| Serotonin receptor antagonists | 15 (37.5) | 7 (36.8) | 8 (38.1) | 0.93 |
| Calcium channel blockers | 13 (32.5) | 8 (42.1) | 5 (23.8) | 0.22 |
| Any immunosuppressants | 26 (65.0) | 12 (63.2) | 14 (66.7) | 0.82 |
| Management | 0.68 | |||
| Amputation in addition to systemic antimicrobial therapy | 4 (10.0) | 1 (5.3) | 3 (14.3) | |
| Surgical debridement in addition to systemic antimicrobial therapy | 6 (15.0) | 3 (15.8) | 3 (7.0) | |
| Systemic antimicrobial therapy alone | 30 (75.0) | 16 (84.2) | 14 (66.7) | |
| Outcomes a | ||||
| Resolution of local inflammationb | ||||
| 3 months after the initiation of treatment | 28/33 (84.8) | 12/14 (85.7) | 16/19 (84.2) | 1.00 |
| 6 months after the initiation of treatment | 31/32 (96.9) | 12/13 (92.3) | 19/19 (100.0) | |
| 12 months after the initiation of treatment | 28/28 (100.0) | 12/12 (100.0) | 16/16 (100.0) | |
| Wound closure | ||||
| 3 months after the initiation of treatment | 7/33 (21.2) | 4/14 (28.6) | 3/19 (15.8) | 0.42 |
| 6 months after the initiation of treatment | 13/32 (40.6) | 5/13 (38.5) | 8/19 (42.1) | 1.00 |
| 12 months after the initiation of treatment | 19/28 (67.9) | 9/12 (75.0) | 10/16 (62.5) | 0.69 |
Note: Data are presented as a number (%) unless otherwise specified
Abbreviations: IQR, interquartile range
aOutcome data of patients who died (n = 5) or were transferred to other hospitals during the follow-up period (n = 7) were missing
bSigns of local inflammation include gangrene, redness, swelling, warmth, and pus drainage
The reasons for undergoing surgical intervention in 10 patients (10/40, 25.0%) included refractoriness to antimicrobial therapy (n = 7), abscess formation (n = 2), and a lower likelihood of subsequent re-epithelization (n = 1). Although not statistically significant, those who underwent surgical intervention tended to have wound closure earlier than others (Table 5).
Table 5.
The association between surgical therapy and the duration of antimicrobial therapy and clinical outcomes in patients with systemic sclerosis-related osteomyelitis
| Variables | Surgical intervention (n = 10) |
No surgical intervention (n = 30) |
P value |
|---|---|---|---|
| Underlying medication use | |||
| Prostacyclin analogs | 7 (70.0) | 20 (66.7) | 0.85 |
| Endothelin receptor antagonists | 6 (60.0) | 15 (50.0) | 0.58 |
| Phosphodiesterase inhibitors | 6 (60.0) | 10 (33.3) | 0.14 |
| Serotonin receptor antagonists | 2 (20.0) | 13 (43.3) | 0.19 |
| Calcium channel blockers | 1 (10.0) | 12 (40.0) | 0.08 |
| Any immunosuppressants | 4 (40.0) | 22 (73.3) | 0.06 |
| Management | |||
| Duration of antimicrobial therapy within a year of the diagnosis, (IQR) daysa | 42 (35–76) | 47.5 (14-93.8) | 0.45 |
| Outcomes b | |||
| Resolution of local inflammationc | |||
| 3 months after the initiation of treatment | 7/9 (77.8) | 21/24 (87.5) | 0.60 |
| 6 months after the initiation of treatment | 8/9 (88.9) | 23/23 (100.0) | |
| 12 months after the initiation of treatment | 6/6 (100.0) | 22/22 (100.0) | |
| Wound closure | |||
| 3 months after the initiation of treatment | 3/9 (33.3) | 4/24 (16.7) | 0.36 |
| 6 months after the initiation of treatment | 5/9 (55.6) | 8/23 (34.8) | 0.43 |
| 12 months after the initiation of treatment | 5/6 (83.3) | 14/22 (63.6) | 0.63 |
Note: Data are presented as a number (%) unless otherwise specified
Abbreviations: IQR, interquartile range
aLonger than one year-course of antimicrobial therapy was calculated as 365 days
bOutcome data of patients who died (n = 5) or were transferred to other hospitals during the follow-up period (n = 7) were missing
cSigns of local inflammation include gangrene, redness, swelling, warmth, and pus drainage
Discussion
In this retrospective study, we identified 47 patients with osteomyelitis among > 2,000 patients with positive SSc-related autoantibodies. Both local inflammatory signs and wound dehiscence resolved over time in many patients receiving therapy. However, wound closure followed the resolution of local signs, which suggests the improvement of local inflammation, among others, as a useful clinical criterion for treatment success. The sensitivity and specificity of superficial swab cultures for bone cultures were not consistently high. The duration of the antimicrobial therapy was highly variable. Surgical interventions were performed infrequently; however, no association between surgical intervention and delayed wound healing was demonstrated. These findings may guide the diagnostic and therapeutic approach to SRO, where relevant previous reports are scarce.
Similar to DFO [8], the absence of a definition of treatment success may be a major obstacle to exploring an appropriate approach for SRO. Potential surrogate markers include the resolution of local inflammation, wound healing, improvement of biomarkers, or a combination of these factors [8]. We collected serial data on these factors up to a year later, revealing that the signs of local inflammation and wound dehiscence improved over time and that the resolution of local inflammation preceded wound healing. In contrast, inflammatory biomarkers such as white blood cell counts and C-reactive protein levels were mostly within or near the normal range even before treatment, presumably because of the local inflammatory nature of SRO. These findings suggest that improvement in local inflammatory signs, rather than blood biomarkers, may be a good indicator of SRO treatment success.
There were some interesting findings regarding the microbiological and antimicrobial therapies of SRO in this study. First, S. aureus was the most common causative organism based on bone culture. This is consistent with the results of previous studies, although the microbiological data in these studies were based on superficial swab cultures [7, 16]. Second, the true involvement of P. aeruginosa in deep tissue was not common, in contrast to superficial swab culture results. Empiric antimicrobial therapy with antipseudomonal coverage can be reserved for selected patients with chronic digit osteomyelitis, depending on local epidemiology [17]. In addition, similar to DFO [10], superficial swab cultures may be of little value in estimating the true causative organisms of SRO, which supports the importance of evaluating deep tissue cultures before empirically escalating antimicrobial coverage when patients with SRO do not respond to the initial antimicrobial therapy. Third, prolonged antimicrobial therapy was not associated with improved local symptoms or wound healing. The benefit of antimicrobial therapy for longer than six weeks has not been established in DFO [18, 19] and prolonged antimicrobial therapy may not be necessary for SRO.
The need for surgical intervention for chronic osteomyelitis remains controversial. Observational studies have reported that 17–97% of patients with DFO were successfully treated with medical therapy alone, despite the presence of confounding by indication [8, 20]. Similarly, in this study on SRO, improvement of local inflammatory signs was documented in nearly 70% of the patients treated with medical therapy alone. The SRO-specific reason for avoiding surgery may be the concern that ischemic and fibrotic changes in soft tissue related to SSc hamper the natural wound-healing process [4]. However, surgery was not associated with wound dehiscence in this study. Instead, patients who underwent surgical intervention tended to have earlier wound closure than those who received medical therapy alone. Consistent with recommendations in previous narrative reviews [21, 22], surgical intervention may be an option in selected patients with SRO, especially those who have an insufficient response to initial antimicrobial therapy.
The prevalence of SRO among patients with SSc in this study was 2.2%, which is lower than that reported in previous studies (7.7–15.8%) [5–7]. It is impossible to compare these numbers directly because the definitions of SRO differ. Nevertheless, given the genetic predisposition to SSc [23], differences in ethnicity may partially explain the differences in the prevalence of SRO. Furthermore, recent progress in SSc pharmacotherapy such as the advent of endothelin receptor antagonists, may affect the development of digital ulcers [24], thereby preventing SRO. In addition, the proportion of patients with anti-topoisomerase I antibodies was higher among those with osteomyelitis than among those without osteomyelitis, in line with a previous study [7]. However, these aspects require further investigation.
The present study had certain limitations. First, the study size was relatively small, owing to the low prevalence of osteomyelitis in our cohort and the lack of statistical power to address the associations between the treatment strategy and subsequent outcomes. Likewise, bone culture tests were infrequently performed, warranting further studies to determine the precise sensitivity and specificity of superficial swab cultures. However, we identified patients with SRO among over 2,000 patients with SSc, which was larger than that reported in previous studies [5, 7]. Second, SRO was defined based on clinical presentation and MRI findings, and very few patients had pathological confirmation. However, although pathological confirmation is generally preferred [12], deep-tissue diagnoses are infrequently available in patients suspected of having SRO, as seen in this study. To reduce the chance of false positivity in the MRI findings, we ascertained that the patients had clinical presentations compatible with SRO. Third, the study findings related to clinical outcomes need to be interpreted with caution as there may be confounding factors, which are inherent to the retrospective nature of the study. Future studies with a large sample size are warranted to determine the optimal duration of antimicrobial therapy and to identify the population that would benefit the most from surgical interventions. Fourth, the microbiological epidemiology of the causative organisms and their resistance may be center-specific, although our findings are largely consistent with those of previous studies on other types of chronic osteomyelitis [10, 17].
In summary, the diagnostic and management approaches for SRO are highly heterogeneous, probably due to the lack of major guidelines. Response to antimicrobial therapy should be evaluated based on improvements in local inflammation, and prolonged therapy may not be necessary. For patients who do not respond to medical therapy, obtaining a deep tissue culture to identify the true causative organisms and surgical intervention may be safe and effective options in selected cases. While more research is necessary, these measures may be the first step toward the optimal management of SRO.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
T.M., K.O., and H.S. designed the study. T.M., K.O., H.S., and S.T. obtained data. T.M., K.O., and H.S. interpreted the data. T.M. drafted the manuscript. S.S. and T.T. supervised the study. All the authors critically reviewed the manuscript and approved the submitted version.
Funding
Open Access funding provided by The University of Tokyo.
This work was supported in part by the JSPS KAKENHI Grant Number JP 23K16252 (KO).
Data availability
Data are not publicly available due to ethical considerations but are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
KO received lectures and medical advice honoraria from Thermo Fisher Scientific; Becton, Dickinson and Company; Eiken Chemical Co.; and Kyorin Pharmaceutical Co.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Koh Okamoto, Email: kokamoto-tky@umin.ac.jp.
Hayakazu Sumida, Email: sumida-tky@umin.ac.jp.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are not publicly available due to ethical considerations but are available from the corresponding author upon reasonable request.