Next Article in Journal
A New Detection Method of Oral and Oropharyngeal Squamous Cell Carcinoma Based on Multivariate Analysis of Surface Enhanced Raman Spectra of Salivary Exosomes
Previous Article in Journal
Management of Onsite and Remote Communication in Oncology Hospitals: Data Protection in an Era of Rapid Technological Advances
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 13
Issue 5
10.3390/jpm13050763
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

The Utility of Ultrasound in Evaluating Joint Pain in Systemic Lupus Erythematosus: Looking beyond Fibromyalgia

by
Yeohan Song
1,2,*,
Gabriel Kirsch
1 and
Wael Jarjour
1,2
1
Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
2
Division of Rheumatology and Immunology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2023, 13(5), 763; https://doi.org/10.3390/jpm13050763
Submission received: 12 April 2023 / Revised: 26 April 2023 / Accepted: 27 April 2023 / Published: 28 April 2023
(This article belongs to the Section Methodology, Drug and Device Discovery)
Browse Figures
Review Reports Versions Notes

Abstract

:
Background: Systemic lupus erythematosus (SLE) is a complex autoimmune condition with varied clinical presentations, and musculoskeletal pain is one of the most commonly associated symptoms. However, fibromyalgia (FM) is a prevalent co-existing condition in SLE patients that can also cause widespread pain, and in patients with both conditions, it is often difficult to distinguish the underlying cause of musculoskeletal pain and provide optimal therapy. Methods: A retrospective cohort study was conducted including all adult SLE patients who received musculoskeletal ultrasound (US) examinations for joint pain at the Ohio State University Wexner Medical Center between 1 July 2012, and 30 June 2022. Binary and multiple logistic regression analyses were performed to determine predictors of US-detected inflammatory arthritis as well as improved musculoskeletal pain. Results: A total of 31 of 72 SLE patients (43.1%) had a co-existing diagnosis of FM. In binary logistic regression, a co-existing diagnosis of FM was not significantly associated with US-detected inflammatory arthritis. In multiple logistic regression analysis, clinically detected synovitis was significantly associated with US-detected inflammatory arthritis (aOR, 142.35, p < 0.01), and there was also a weak association with erythrocyte sedimentation rate (ESR) (aOR 1.04, p = 0.05). In separate multiple logistic regression analysis, US-guided intra-articular steroid injection was the only predictor of improved joint pain at follow-up visit (aOR 18.43, p < 0.001). Conclusions: Musculoskeletal US can be an effective modality to detect inflammatory arthritis as well as to guide targeted intra-articular steroid injection to alleviate joint pain in SLE patients with or without FM.

1. Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune condition characterized by autoantibodies and aberrant immune responses involving one or more organ systems that affects more than 3 million people worldwide [1]. Musculoskeletal pain is one of the most commonly reported symptoms associated with this condition, with over 80% of SLE patients experiencing joint pain—often as one of the earliest presenting symptoms [2,3]. While deforming arthropathies such as those seen in Jaccoud arthropathy or rhupus syndrome can occasionally be observed, joint involvement in SLE is typically characterized as an inflammatory arthralgia with non-erosive, non-deforming arthritis [4,5].
The heterogeneous clinical presentation of SLE has led various international working groups and organizations to construct classification criteria to improve characterization of affected patients for research studies, while also updating these criteria to incorporate the adoption of immunologic laboratory tests in clinical practice and to reflect the improved understanding of the observed patterns of organ involvement. Two of the most widely recognized among these, the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, both include measures of joint tenderness among the clinical criteria for SLE [2,6]. However, it is notable that clinically detected joint inflammation had one of the lowest specificities for SLE (43.6%) in the derivation sample for the SLICC classification criteria, suggesting that there can be other potential etiologies of joint pain among these patients [6].
Among these other causes of musculoskeletal pain, fibromyalgia (FM) is a condition characterized by chronic and widespread pain that affects 1–2% of the general adult population [7,8], with an even higher prevalence observed in SLE patients (estimates range from 6% to greater than 20%) [9,10]. Though the etiology of FM remains to be fully elucidated and may be multifactorial, as a chronic pain syndrome, neurochemical studies suggest that the pathophysiology underlying FM involves abnormal pain modulation and central sensitization [11,12,13]. As such, co-existing FM may complicate accurate clinical assessment of musculoskeletal pain in SLE patients. Additionally, with the availability of newer immunosuppressive agents and more robust therapeutic regimens, the life expectancy of SLE patients has increased [14,15] and an increasing number are experiencing osteoarthritis, which represents another potential etiology of musculoskeletal pain [16]. Furthermore, patients with both FM and osteoarthritis have been shown to experience higher perceived joint pain than patients with either condition alone [17], which may also affect the accuracy of clinical joint assessment for synovial inflammation, or synovitis, in these patients.
It has previously been reported that SLE patients without co-existing FM who have sonographic features of inflammatory arthritis in the hands and wrists are more likely to respond to systemic glucocorticoid therapy [18]. While this can provide guidance for adjustments to systemic therapies, in those SLE patients who report joint pain localized to a specific joint and/or also have co-existing FM, it remains to be determined whether a targeted musculoskeletal ultrasound (US) examination accompanied by intra-articular steroid injection can also provide therapeutic benefit and improvement in joint pain, as intra-articular steroid injections can effectively alleviate joint pain from a range of causes, including osteoarthritis [19,20,21], rheumatoid arthritis [22], adhesive capsulitis [23], and potentially crystalline arthropathy [24,25]. In recognition of this, organizations such as the ACR as well as the American Academy of Orthopaedic Surgeons (AAOS) recommend intra-articular steroid injection as a treatment for osteoarthritis and associated joint pain [20,21].
Musculoskeletal US examination of the joints allows further diagnostic examination of the synovial membrane and intra-articular space as well as adjacent bone cortices to assess for the presence of synovitis and erosive changes associated with inflammatory arthritis from any cause, including rheumatoid arthritis and psoriatic arthritis as well as SLE. The sonographic features associated with inflammatory arthritis are well described in consensus definitions from the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) US special interest group and include gray-scale changes detected in B-mode indicating synovial hypertrophy (abnormal hypoechoic, non-displaceable, and poorly compressible intra-articular tissue); joint effusion (increased hypoechoic or anechoic, displaceable, and compressible intra-articular material); tenosynovitis (hypoechoic or anechoic thickened tissue in the tendon sheath observed in orthogonal planes); and bone erosion (intra-articular discontinuity of bone cortices observed in orthogonal planes) [26]. Power Doppler (PD) US has also been used to detect synovial vascularization associated with synovitis [27,28].
Particularly among SLE patients without detectable radiographic changes associated with arthritis, such as bone erosions, previous studies have demonstrated that musculoskeletal US can be a useful tool to detect subclinical synovitis, or early joint inflammation, as well as to confirm the presence of clinically detected synovitis [27,28,29,30,31]. Despite this agreement on the value of musculoskeletal US for this indication, these studies have had varying reports on the significance of associations between sonographic features of inflammatory arthritis in SLE and laboratory tests routinely obtained in clinical practice in the assessment of joint inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as with those that can fluctuate with SLE disease activity, such as anti-double-stranded DNA (anti-dsDNA) and complement component 3 (C3) and complement component 4 (C4) levels, suggesting that these laboratory markers alone are insufficient to determine the presence of subclinical or clinical synovitis [27,31,32]. As SLE patients often have additional conditions associated with musculoskeletal pain, such as FM and osteoarthritis, musculoskeletal US has further potential diagnostic and therapeutic utility in distinguishing inflammatory arthritis from other causes of musculoskeletal pain and in the accurate delivery of targeted intra-articular injections to alleviate joint pain in these patients, which is explored in this study.

2. Materials and Methods

Study design. A retrospective cohort study was conducted including all adult patients (i.e., ≥18 years of age) with a documented diagnosis of SLE from a rheumatologist who received musculoskeletal US examinations for joint pain in an outpatient setting at The Ohio State University Wexner Medical Center between 1 July 2012, and 30 June 2022. Of note, musculoskeletal US examinations were performed in a dedicated clinic by a rheumatologist or sports medicine physician with privileges to perform US-guided arthrocentesis at the Medical Center (US practitioner) separately from the patient’s routine clinic visits with his or her managing rheumatologist. Musculoskeletal US practitioners were required to complete a minimum of 16 h of musculoskeletal US-specific continuing medical education (CME) including didactics and hands-on training, as well as a minimum of 25 supervised US examinations. Musculoskeletal US examinations and intra-articular steroid injections, when performed, were targeted to the single joint where the patient reported the greatest pain. If a patient was examined more than once in the study period, the first US examination was included to maintain independence of observations within the study sample. Exclusion criteria included the following: patients < 18 years of age, those who did not have a diagnosis of SLE prior to the time of musculoskeletal US examination, and those with prior surgical instrumentation of the joint examined by US. Patient medical records fulfilling the above criteria were requested through The Ohio State University Wexner Medical Center Information Warehouse, which were then manually reviewed to confirm study eligibility. Study data were recorded in a de-identified manner to protect patient confidentiality.
Clinical and Laboratory Data. Medical records of eligible patients were reviewed, and demographic (e.g., age and body mass index [BMI] on date of musculoskeletal US, sex, and race) data were recorded. Documentation produced by the patient’s managing rheumatologist preceding the musculoskeletal US examination was then reviewed to determine if there was clinically detected inflammatory arthritis (presence of joint swelling/effusion and/or joint tenderness with ≥30 min of morning stiffness, based on the 2019 EULAR/ACR and 2012 SLICC classification criteria) [2,6], as well as whether the patient had a co-existing diagnosis of FM based on the 2010 ACR diagnostic criteria [33]. Laboratory parameters including anti-dsDNA, C3, C4, ESR, and CRP levels preceding the US examination were then recorded. Based on the procedure note on the date of the musculoskeletal US examination, the presence or absence of US-detected inflammatory arthritis was then recorded as determined by the US practitioner’s evaluation of synovial hypertrophy, joint effusion, tenosynovitis, and bone erosion (Figure 1 and Figure 2). If a joint aspiration and/or intra-articular steroid injection was performed during the musculoskeletal US examination, this was noted. If systemic therapy such as oral or intra-muscular steroids or immunosuppression was started or increased based on the US findings, this was recorded. Finally, the number of days leading up to the follow-up clinic visit with the patient’s managing rheumatologist for re-assessment of joint pain after the musculoskeletal US examination, as well as whether the patient reported improvement in joint pain at the follow-up visit, were also recorded.
Data Analyses. Data were analyzed using SPSS version 28 (IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 28.0. IBM Corp.: Armonk, NY, USA). Descriptive statistics summaries including frequencies and cross-tabulations were used to characterize the data. Correlation matrices were reviewed for statistically significant (α = 0.05, two-tailed tests) associations among potential predictor variables, and significantly correlated variables were excluded to avoid multicollinearity. Binary logistic regression analysis was then used to identify predictor variables associated with the outcome variable (p-value ≤ 0.20), which were then fitted into multiple logistic regression models using the backward elimination method. Predictor variables with p-values less than 0.05 in multiple logistic regression were considered statistically significant, and the strengths of association were interpreted using the adjusted odds ratio (aOR) and 95% confidence interval (CI).

3. Results

3.1. Patient Characteristics

A total of 72 adult SLE patients (66 female, 6 male) received musculoskeletal US examinations for joint pain in the study period, with a median age of 50 years (interquartile range [IQR]: 40–63 years). Of these patients, 31 (43.1%) had a co-existing diagnosis of FM preceding the musculoskeletal US. The patients self-reported their race as the following: 30 (41.7%) were White/Caucasian, 33 (45.8%) were Black/African American, 4 (5.6%) were Asian American, and 4 (5.6%) were Other, with 1 (1.4%) declining to answer. The mean BMI was 32.3 kg/m2 (±SD 9.4 kg/m2). Prior to the musculoskeletal US examination, 6 (8.3%) of the patients were found to have clinically detected synovitis based on the previously described criteria. A summary of the demographic characteristics of SLE patients who had or did not have a co-existing diagnosis of FM is shown in Table 1.
Nearly all SLE patients were on hydroxychloroquine prior to the musculoskeletal US examination, including 29 (93.5%) of the patients with co-existing FM and 37 (90.2%) of those without co-existing FM. Those who were not on hydroxychloroquine were noted to have previously discontinued this medication due to side effects. Additionally, a greater proportion of patients with co-existing FM were on systemic steroids prior to the US examination (45.2% vs. 36.6%; prednisone dose range: 2.5 mg to 20 mg daily), while relatively more patients without co-existing FM were on steroid-sparing immunosuppression (51.2% vs. 32.3%), with mycophenolate and methotrexate being the most common immunosuppressants used (45.2% and 29.0% of all immunosuppression, respectively).

3.2. Laboratory Parameters

Laboratory measures for this cohort of SLE patients with joint pain prior to the US examination included (medians and IQRs): anti-dsDNA (4.0 IU/mL, 4.0–12.0 IU/mL), C3 (131.0 mg/dL, 114.0–144.0 mg/dL), C4 (30.0 mg/dL, 19.0–37.0 mg/dL), ESR (23.5 mm/h, 11.8–49.5 mm/h), and CRP (3.8 mg/L, 1.3–10.3 mg/L). Stratification of these laboratory measures according to whether the patient had FM is presented in Table 2. Among the 31 SLE patients with co-existing FM, 15 (48.4%) had either ESR above the laboratory reference range of 30.0 mm/h or CRP above the reference range of 10.0 mg/L, whereas 18 (43.9%) of the 41 SLE patients without co-existing FM had ESR or CRP above the reference range. Among these patients with either ESR or CRP above the reference range, 21 (63.6%) also had a positive anti-ribonucleoprotein (anti-RNP) antibody, whereas 8 (24.2%) had negative anti-RNP and 4 (12.1%) did not have this tested.

3.3. Ultrasound Examination

Musculoskeletal US examinations were most often performed on a knee joint (20 patients, 27.8%). Twelve patients (16.7%) each had an US examination of a shoulder or hip joint. Eight patients (11.1%) had an US examination of a joint of the hand. Five patients (6.9%) each had an US examination of a wrist or ankle joint. The remaining patients had an US examination of an elbow joint (4 patients, 5.6%) or a foot or sacroiliac joint (3 patients or 4.2% each).
On musculoskeletal US examination, the US practitioners detected the presence of inflammatory arthritis in 8 patients, 5 (62.5%) of whom had synovitis detected on clinical examination. The reported sonographic features of inflammatory arthritis included gray-scale changes indicating both synovial hypertrophy and joint effusion in 7 (87.5%) of these patients and tenosynovitis in 2 patients (25.0%), with PD signal detected in the joints of 3 patients (37.5%). Bone erosions were not detected in any of these patients. Of these SLE patients with US-detected inflammatory arthritis, 3 (37.5%) also had a diagnosis of FM.
During the musculoskeletal US examination, 58 patients (80.6%) received an intra-articular steroid injection, and 9 patients (12.5%) had an aspiration of a joint effusion. Eight patients (11.1%) received additional systemic steroids and/or immunosuppression from their managing rheumatologist upon receiving the US examination report. The median time to follow-up visit with the managing rheumatologist after the US examination was 77 days (IQR: 44–132.5 days).

3.4. Statistical Analysis

Descriptive statistics summaries revealed significant correlations among several potential predictor variables. A significant correlation between BMI and both ESR (r = 0.34, p < 0.01), and CRP (r = 0.43, p < 0.001) was found, as has been previously described in patients with inflammatory arthritis [34]. As ESR and BMI were less significantly associated than CRP and BMI, as also described by other groups [34], BMI and CRP were excluded and ESR was retained to avoid multicollinearity in regression analysis. Additional correlations between C3 and C4 (r = 0.61, p < 0.001), ESR (r = 0.28, p < 0.05), and CRP (r = 0.45, p < 0.001) were noted; therefore, C3 was also excluded and C4 was retained for further regression analysis. Similarly, race was also excluded, as it was significantly associated with ESR based on analysis of variance (F = 7.88, p < 0.001).
On binary logistic regression, age, sex, and co-existing diagnosis of FM were not found to be associated with US-detected inflammatory arthritis (Table 3). Multiple logistic regression analysis of the remaining predictors, including anti-dsDNA, C4, ESR, and clinically detected synovitis, showed clinically detected synovitis had the most significant association with and the highest odds of US-detected inflammatory arthritis in the final model (aOR = 142.35, 95% confidence interval [CI] 6.55–3093.96; p = 0.002), as well as a borderline significant association with ESR levels (aOR = 1.04, 95% CI 1.00–1.08; p = 0.05).
The results of additional binary logistic regression analyses to identify significant predictors of reported improvement in joint pain at the follow-up visit with the managing rheumatologist after musculoskeletal US examination are shown in Table 4. Age, sex, anti-dsDNA, C4, ESR, clinically detected synovitis, and joint aspiration were not found to be associated with improved joint pain after US examination. Multiple logistic regression analysis of the remaining predictors, including co-existing diagnosis of FM, intra-articular steroid injection, and additional systemic steroids and/or immunosuppression based on US findings, showed intra-articular steroid injection was the only predictor significantly associated with improved joint pain at follow-up visit (aOR = 18.43, 95% CI 3.67–92.55; p < 0.001).

4. Discussion

As reported in the United States and globally, SLE patients are predominantly (>85%) female [1,35], which was reflected in the patient sample in this study. Consistent with another study on SLE patients with musculoskeletal pain, the proportion of patients diagnosed with FM in this study was higher than that observed among unselected SLE patient cohorts [18]. In agreement with previous reports on the use of musculoskeletal US in the detection of subclinical and clinical synovitis in SLE patients, anti-dsDNA and complement levels were not found to be significantly associated with the presence of sonographic features of synovitis [31,32].
The results of this study support the association of the sonographic features of inflammatory arthritis with the clinical assessment of synovitis, which remains a well-recognized parameter in both the clinical diagnosis and classification criteria of SLE [2,6]. Care should be taken not to allow a preceding diagnosis of FM to affect the determination of whether inflammatory arthritis is present, particularly among patients with SLE, who have a higher prevalence of co-existing FM [9,10]. This study demonstrates the additional benefit musculoskeletal US can provide for these patients, as particularly among SLE patients who may have multiple causes of pain, diagnostic US can be an effective non-invasive method of corroborating suspected inflammatory arthritis based on the provided history and examination. Additionally, although clinicians should not be overly reliant on laboratory tests and should correlate abnormal findings with the examination, as shown in this study, elevated ESR levels can also potentially provide support for the presence of inflammatory arthritis among SLE patients with joint pain when considered in the appropriate clinical context.
Musculoskeletal US as an imaging modality to improve detection of pre-clinical synovitis in SLE has been well described [27,28,29,30,31]. It has also been reported that in SLE patients without FM, the presence of sonographic features of inflammatory arthritis may help stratify those patients who may benefit from adjustments to systemic therapy, such as intramuscular steroids [18]. However, as demonstrated in this study, there may be additional utility in the targeted use of musculoskeletal US to differentiate inflammatory arthritis from other co-existing causes of musculoskeletal pain in SLE patients, including FM and/or osteoarthritis, and to provide targeted therapeutic intervention in the form of an image-guided intra-articular steroid injection during the examination. This is of particular importance in SLE, which has a well-documented risk of complications such as osteoporotic fractures, avascular necrosis, coronary artery disease, and cataracts that increases with cumulative systemic steroid exposure [36,37].
Among SLE patients with joint pain, use of musculoskeletal US has the additional benefit of providing image guidance for intra-articular steroid injections, which can ensure accurate medication delivery based on real-time anatomic visualization. The targeted delivery of an intra-articular injection into a specific joint has the additional appeal of lower or less rapid systemic absorption compared to oral, intramuscular, or intravenous formulations, as peak serum steroid levels appear to be affected more by the number of joints injected rather than by the dose alone, though individual variability can be observed [38,39]. Additionally, while there has been concern regarding potential risk for osteoarthritis progression, avascular necrosis, and articular collapse following intra-articular steroid injections, a recent study did not demonstrate this association after controlling for baseline osteoarthritis severity and pre-existing avascular necrosis/subchondral insufficiency fracture [40]. However, caution is advised and patient-specific risks should be considered in patients at greater risk of adverse outcomes, such as those who have diabetes mellitus and therefore can experience higher post-injection glycemic levels [41], as well as those already on systemic steroids [38], and those who are anticipating arthroplasty within 3 months, as this increases the risk of periprosthetic joint infection [42]. Furthermore, intra-articular injections should be avoided entirely in patients who have clinical evidence of skin or soft tissue infection overlying the target joint.
In cases where joint pain reported by SLE patients is localized to a specific joint, the presented findings suggest that there may be an additional role for more targeted US assessments of the joints involved, which can provide confirmatory findings of inflammatory arthritis in cases complicated by multiple other potential causes of joint pain and inform decisions on adjustments to systemic therapies. Moreover, during the US examination, accurate image-guided administration of intra-articular steroid medications can provide therapeutic benefit to alleviate the pain experienced by these patients. Furthermore, SLE patients with FM who do not have US-detected features of inflammatory arthritis may also benefit from intra-articular steroid injections to improve joint pain from other causes, as these patients have been shown to have higher perceived pain from other joint pathology such as osteoarthritis [17].
Limitations of this study include the retrospective design of the study and that all patients were treated at a single academic healthcare institution. Due to the retrospective nature of the study, the presence or absence of US-detected inflammatory arthritis was recorded as binary data from the text of the musculoskeletal US examination notes, as the US practitioners did not document standardized scores and for the patients who received intra-articular steroid injections, the corresponding pre-injection US images were not consistently available for review. Outcomes such as patient-reported improvement in musculoskeletal pain were similarly limited to binary data based on the medical documentation. The median follow-up in this study was between 2 and 3 months, which aligns with the reported duration of pain alleviation following intra-articular steroid injections for conditions such as osteoarthritis [21]. Future prospective studies may further characterize the degree of joint inflammation on US using a standardized scoring system and the extent and duration of improvement in pain using scoring systems such as the visual analogue scale (VAS) over a longer follow-up period. Additionally, the minimum institutional training requirement for musculoskeletal US practitioners as detailed in the text may limit the applicability of the findings to other institutions that do not have similar requirements. Future prospective studies may also benefit from a single dedicated US practitioner to examine all recruited subjects to eliminate inter-observer variability. All patients in this study were ≥18 years of age, and findings may not be applicable to younger patient groups. None of the patients in this study had prior surgical instrumentation of the joint examined by musculoskeletal US, as management of post-operative joint pain would be deferred to the operating orthopedist.
Furthermore, as a lack of association between conventional SLE disease activity indices such as the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the European Consensus Lupus Activity Measurement (ECLAM) and sonographic features of inflammatory arthritis has previously been demonstrated, these indices were not included in this study [31]. It has been suggested that these indices are not designed to identify isolated local joint inflammation in the absence of systemic or major organ involvement, indicating the need for an assessment that incorporates imaging modalities, such as musculoskeletal US, to improve detection of subclinical synovitis [31].

5. Conclusions

Musculoskeletal US can be an effective modality to distinguish inflammatory arthritis from other causes of musculoskeletal pain in SLE patients, as well as to guide targeted intra-articular steroid injection for the alleviation of joint pain, regardless of whether these patients have a co-existing diagnosis of FM.

Author Contributions

Conceptualization, Y.S. and W.J.; methodology, Y.S. and W.J.; software, Y.S.; validation, Y.S. and W.J.; formal analysis, Y.S.; investigation, Y.S. and G.K.; resources, Y.S. and W.J.; data curation, Y.S. and G.K.; writing—original draft preparation, Y.S. and G.K.; writing—review and editing, Y.S., G.K. and W.J.; visualization, Y.S.; supervision, Y.S. and W.J.; project administration, Y.S. and W.J.; funding acquisition, W.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research and APC were funded, in part, by the Davis Foundation of The Ohio State University through Fellowship support, to whom the authors express their appreciation.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to de-identification of data collected from the review of medical records. This study was determined to be exempt from IRB review by The Ohio State University Office of Responsible Research Practices (Study Number 2022E0729).

Informed Consent Statement

Patient consent was waived due to the design of the study as a retrospective review of de-identified medical record data.

Data Availability Statement

Requests for data presented in this study should be submitted to the Department of Medical Information Management at The Ohio State University Wexner Medical Center, which controls access to its patient information used for research purposes.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Tian, J.; Zhang, D.; Yao, X.; Huang, Y.; Lu, Q. Global Epidemiology of Systemic Lupus Erythematosus: A Comprehensive Systematic Analysis and Modelling Study. Ann. Rheum. Dis. 2023, 82, 351–356. [Google Scholar] [CrossRef]
  2. Aringer, M.; Costenbader, K.; Daikh, D.; Brinks, R.; Mosca, M.; Ramsey-Goldman, R.; Smolen, J.S.; Wofsy, D.; Boumpas, D.T.; Kamen, D.L.; et al. 2019 European League against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Ann. Rheum. Dis. 2019, 78, 1151–1159. [Google Scholar] [CrossRef] [PubMed]
  3. Leuchten, N.; Milke, B.; Winkler-Rohlfing, B.; Daikh, D.; Dörner, T.; Johnson, S.R.; Aringer, M. Classification Criteria Steering Committee on behalf of the. “Early Symptoms of Systemic Lupus Erythematosus (Sle) Recalled by 339 Sle Patients. Lupus 2018, 27, 1431–1436. [Google Scholar] [CrossRef]
  4. Cervera, R.; Khamashta, M.A.; Font, J.; Sebastiani, G.D.; Gil, A.; Lavilla, P.; Domenech, I.; Aydintug, A.O.; Jedryka-Goral, A.; de Ramon, E.; et al. Systemic Lupus Erythematosus: Clinical and Immunologic Patterns of Disease Expression in a Cohort of 1000 Patients. The European Working Party on Systemic Lupus Erythematosus. Medicine 1993, 72, 113–124. [Google Scholar] [CrossRef] [PubMed]
  5. Ceccarelli, F.; Perricone, C.; Cipriano, E.; Massaro, L.; Natalucci, F.; Capalbo, G.; Leccese, I.; Bogdanos, D.; Spinelli, F.R.; Alessandri, C.; et al. Joint Involvement in Systemic Lupus Erythematosus: From Pathogenesis to Clinical Assessment. Semin. Arthritis Rheum. 2017, 47, 53–64. [Google Scholar] [CrossRef] [PubMed]
  6. Petri, M.; Orbai, A.M.; Alarcon, G.S.; Gordon, C.; Merrill, J.T.; Fortin, P.R.; Bruce, I.N.; Isenberg, D.; Wallace, D.J.; Nived, O.; et al. Derivation and Validation of the Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheum. 2012, 64, 2677–2686. [Google Scholar] [CrossRef]
  7. Bliddal, H.; Danneskiold-Samsoe, B. Chronic Widespread Pain in the Spectrum of Rheumatological Diseases. Best Pract. Res. Clin. Rheumatol. 2007, 21, 391–402. [Google Scholar] [CrossRef] [PubMed]
  8. Walitt, B.; Nahin, R.L.; Katz, R.S.; Bergman, M.J.; Wolfe, F. The Prevalence and Characteristics of Fibromyalgia in the 2012 National Health Interview Survey. PLoS ONE 2015, 10, e0138024. [Google Scholar] [CrossRef]
  9. Torrente-Segarra, V.; Salman-Monte, T.C.; Rua-Figueroa, I.; Perez-Vicente, S.; Lopez-Longo, F.J.; Galindo-Izquierdo, M.; Calvo-Alen, J.; Olive-Marques, A.; Ibanez-Ruan, J.; Horcada, L.; et al. The Prevalence and Clinical Impact of Fibromyalgia in Systemic Lupus Erythematosus. Clin. Exp. Rheumatol 2016, 34 (Suppl. S96), S40–S47. [Google Scholar]
  10. Middleton, G.D.; McFarlin, J.E.; Lipsky, P.E. The Prevalence and Clinical Impact of Fibromyalgia in Systemic Lupus Erythematosus. Arthritis Rheum. 1994, 37, 1181–1188. [Google Scholar] [CrossRef]
  11. Staud, R. Abnormal Pain Modulation in Patients with Spatially Distributed Chronic Pain: Fibromyalgia. Rheum. Dis. Clin. N. Am. 2009, 35, 263–274. [Google Scholar] [CrossRef]
  12. Lautenbacher, S.; Rollman, G.B. Possible Deficiencies of Pain Modulation in Fibromyalgia. Clin. J. Pain 1997, 13, 189–196. [Google Scholar] [CrossRef]
  13. Woolf, C.J. Central Sensitization: Implications for the Diagnosis and Treatment of Pain. Pain 2011, 152, S2–S15. [Google Scholar] [CrossRef]
  14. Doria, A.; Iaccarino, L.; Ghirardello, A.; Zampieri, S.; Arienti, S.; Sarzi-Puttini, P.; Atzeni, F.; Piccoli, A.; Todesco, S. Long-Term Prognosis and Causes of Death in Systemic Lupus Erythematosus. Am. J. Med. 2006, 119, 700–706. [Google Scholar] [CrossRef]
  15. Cervera, R.; Khamashta, M.A.; Font, J.; Sebastiani, G.D.; Gil, A.; Lavilla, P.; Mejia, J.C.; Aydintug, A.O.; Chwalinska-Sadowska, H.; de Ramon, E.; et al. Morbidity and Mortality in Systemic Lupus Erythematosus During a 10-Year Period: A Comparison of Early and Late Manifestations in a Cohort of 1000 Patients. Medicine 2003, 82, 299–308. [Google Scholar] [CrossRef]
  16. Kasturi, S.; Goodman, S. Current Perspectives on Arthroplasty in Systemic Lupus Erythematosus: Rates, Outcomes, and Adverse Events. Curr. Rheumatol. Rep. 2016, 18, 59. [Google Scholar] [CrossRef]
  17. Mahgoub, M.Y.; Elnady, B.M.; Abdelkader, H.S.; Abdelhalem, R.A.; Hassan, W.A. Comorbidity of Fibromyalgia in Primary Knee Osteoarthritis: Potential Impact on Functional Status and Quality of Life. Open Access Rheumatol. 2020, 12, 55–63. [Google Scholar] [CrossRef]
  18. Mahmoud, K.; Zayat, A.S.; Yusof, M.Y.M.; Dutton, K.; Teh, L.S.; Yee, C.S.; D’Cruz, D.; Ng, N.; Isenberg, D.; Ciurtin, C.; et al. Ultrasound to Identify Systemic Lupus Erythematosus Patients with Musculoskeletal Symptoms Who Respond Best to Therapy: The Us Evaluation for Musculoskeletal Lupus Longitudinal Multicentre Study. Rheumatology 2021, 60, 5194–5204. [Google Scholar] [CrossRef]
  19. Katz, J.N.; Arant, K.R.; Loeser, R.F. Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review. JAMA 2021, 325, 568–578. [Google Scholar] [CrossRef]
  20. Kolasinski, S.L.; Neogi, T.; Hochberg, M.C.; Oatis, C.; Guyatt, G.; Block, J.; Callahan, L.; Copenhaver, C.; Dodge, C.; Felson, D.; et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020, 72, 220–233. [Google Scholar] [CrossRef]
  21. American Academy of Orthopaedic Surgeons. Management of Osteoarthritis of the Knee (Non-Arthroplasty) Evidence-Based Clinical Practice Guideline. 2021. Available online: https://www.aaos.org/oak3cpg (accessed on 7 April 2023).
  22. Wallen, M.; Gillies, D. Intra-Articular Steroids and Splints/Rest for Children with Juvenile Idiopathic Arthritis and Adults with Rheumatoid Arthritis. Cochrane Database Syst. Rev. 2006, 2006, CD002824. [Google Scholar] [CrossRef]
  23. Rangan, A.; Hanchard, N.; McDaid, C. What Is the Most Effective Treatment for Frozen Shoulder? BMJ 2016, 354, i4162. [Google Scholar] [CrossRef]
  24. Rosenthal, A.K.; Ryan, L.M. Treatment of Refractory Crystal-Associated Arthritis. Rheum Dis. Clin. N. Am. 1995, 21, 151–161. [Google Scholar] [CrossRef]
  25. Wechalekar, M.D.; Vinik, O.; Schlesinger, N.; Buchbinder, R. Intra-Articular Glucocorticoids for Acute Gout. Cochrane Database Syst. Rev. 2013, 2013, CD009920. [Google Scholar] [CrossRef]
  26. Wakefield, R.J.; Balint, P.V.; Szkudlarek, M.; Filippucci, E.; Backhaus, M.; D’Agostino, M.A.; Sanchez, E.N.; Iagnocco, A.; Schmidt, W.A.; Bruyn, G.A.; et al. Musculoskeletal Ultrasound Including Definitions for Ultrasonographic Pathology. J. Rheumatol. 2005, 32, 2485–2487. [Google Scholar] [PubMed]
  27. Yoon, H.S.; Kim, K.J.; Baek, I.W.; Park, Y.J.; Kim, W.U.; Yoon, C.H.; Cho, C.S. Ultrasonography Is Useful to Detect Subclinical Synovitis in Sle Patients without Musculoskeletal Involvement before Symptoms Appear. Clin. Rheumatol. 2014, 33, 341–348. [Google Scholar] [CrossRef]
  28. Ruano, C.A.; Malheiro, R.; Oliveira, J.F.; Pinheiro, S.; Vieira, L.S.; Moraes-Fontes, M.F. Ultrasound Detects Subclinical Joint Inflammation in the Hands and Wrists of Patients with Systemic Lupus Erythematosus without Musculoskeletal Symptoms. Lupus Sci. Med. 2017, 4, e000184. [Google Scholar] [CrossRef]
  29. Lins, C.F.; Santiago, M.B. Ultrasound Evaluation of Joints in Systemic Lupus Erythematosus: A Systematic Review. Eur. Radiol. 2015, 25, 2688–2692. [Google Scholar] [CrossRef] [PubMed]
  30. Di Matteo, A.; Smerilli, G.; Cipolletta, E.; Salaffi, F.; De Angelis, R.; Di Carlo, M.; Filippucci, E.; Grassi, W. Imaging of Joint and Soft Tissue Involvement in Systemic Lupus Erythematosus. Curr. Rheumatol. Rep. 2021, 23, 73. [Google Scholar] [CrossRef]
  31. Iagnocco, A.; Ceccarelli, F.; Rizzo, C.; Truglia, S.; Massaro, L.; Spinelli, F.R.; Vavala, C.; Valesini, G.; Conti, F. Ultrasound Evaluation of Hand, Wrist and Foot Joint Synovitis in Systemic Lupus Erythematosus. Rheumatology 2014, 53, 465–472. [Google Scholar] [CrossRef]
  32. Mosca, M.; Tani, C.; Carli, L.; Vagnani, S.; Possemato, N.; Sedie, A.D.; Cagnoni, M.; D’Aniello, D.; Riente, L.; Caramella, D.; et al. The Role of Imaging in the Evaluation of Joint Involvement in 102 Consecutive Patients with Systemic Lupus Erythematosus. Autoimmun. Rev. 2015, 14, 10–15. [Google Scholar] [CrossRef] [PubMed]
  33. Wolfe, F.; Clauw, D.J.; Fitzcharles, M.A.; Goldenberg, D.L.; Katz, R.S.; Mease, P.; Russell, A.S.; Russell, I.J.; Winfield, J.B.; Yunus, M.B. The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity. Arthritis Care Res. 2010, 62, 600–610. [Google Scholar] [CrossRef]
  34. George, M.D.; Giles, J.T.; Katz, P.P.; England, B.R.; Mikuls, T.R.; Michaud, K.; Ogdie-Beatty, A.R.; Ibrahim, S.; Cannon, G.W.; Caplan, L.; et al. Impact of Obesity and Adiposity on Inflammatory Markers in Patients with Rheumatoid Arthritis. Arthritis Care Res. 2017, 69, 1789–1798. [Google Scholar] [CrossRef] [PubMed]
  35. Jacobson, D.L.; Gange, S.J.; Rose, N.R.; Graham, N.M. Epidemiology and Estimated Population Burden of Selected Autoimmune Diseases in the United States. Clin. Immunol. Immunopathol. 1997, 84, 223–243. [Google Scholar] [CrossRef]
  36. Zonana-Nacach, A.; Barr, S.G.; Magder, L.S.; Petri, M. Damage in Systemic Lupus Erythematosus and Its Association with Corticosteroids. Arthritis Rheum. 2000, 43, 1801–1808. [Google Scholar] [CrossRef]
  37. Tsai, H.L.; Chang, J.W.; Lu, J.H.; Liu, C.S. Epidemiology and Risk Factors Associated with Avascular Necrosis in Patients with Autoimmune Diseases: A Nationwide Study. Korean J. Intern. Med. 2022, 37, 864–876. [Google Scholar] [CrossRef] [PubMed]
  38. Stout, A.; Friedly, J.; Standaert, C.J. Systemic Absorption and Side Effects of Locally Injected Glucocorticoids. PM R 2019, 11, 409–419. [Google Scholar] [CrossRef]
  39. Armstrong, R.D.; English, J.; Gibson, T.; Chakraborty, J.; Marks, V. Serum Methylprednisolone Levels Following Intra-Articular Injection of Methylprednisolone Acetate. Ann. Rheum. Dis. 1981, 40, 571–574. [Google Scholar] [CrossRef]
  40. Abraham, P.F.; Varady, N.H.; Small, K.M.; Shah, N.; Beltran, L.S.; Kucharik, M.P.; Martin, S.D. Safety of Intra-Articular Hip Corticosteroid Injections: A Matched-Pair Cohort Study. Orthop. J. Sport. Med. 2021, 9, 23259671211035099. [Google Scholar] [CrossRef]
  41. Choudhry, M.N.; Malik, R.A.; Charalambous, C.P. Blood Glucose Levels Following Intra-Articular Steroid Injections in Patients with Diabetes: A Systematic Review. JBJS Rev. 2016, 4, e5. [Google Scholar] [CrossRef]
  42. Kim, Y.M.; Joo, Y.B.; Song, J.H. Preoperative Intra-Articular Steroid Injections within 3 Months Increase the Risk of Periprosthetic Joint Infection in Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. J. Orthop. Surg. Res. 2023, 18, 148. [Google Scholar] [CrossRef]
Jpm 13 00763 g001 550
Figure 1. Musculoskeletal US images of SLE patient without FM reporting right wrist pain, with sonographic features of inflammatory arthritis. (A) Dorsal longitudinal view of the right wrist showing joint effusion with associated power Doppler signal; (B) Dorsal longitudinal view of the right wrist during intra-articular injection, with the needle entering the joint space from the 2 o’clock position (arrows). Depth in centimeters shown on the right of each image.
Figure 1. Musculoskeletal US images of SLE patient without FM reporting right wrist pain, with sonographic features of inflammatory arthritis. (A) Dorsal longitudinal view of the right wrist showing joint effusion with associated power Doppler signal; (B) Dorsal longitudinal view of the right wrist during intra-articular injection, with the needle entering the joint space from the 2 o’clock position (arrows). Depth in centimeters shown on the right of each image.
Jpm 13 00763 g001
Jpm 13 00763 g002 550
Figure 2. Musculoskeletal US images of SLE patient with FM reporting left knee pain, without sonographic features of inflammatory arthritis. (A) Anterior longitudinal view of the left knee showing the non-distended suprapatellar bursa; (B) Anterior transverse view of the left knee during intra-articular injection, with the needle entering the suprapatellar bursa from the 3 o’clock position (arrows) and slightly distending the suprapatellar bursa with injectate. Depth in centimeters shown on the right of each image.
Figure 2. Musculoskeletal US images of SLE patient with FM reporting left knee pain, without sonographic features of inflammatory arthritis. (A) Anterior longitudinal view of the left knee showing the non-distended suprapatellar bursa; (B) Anterior transverse view of the left knee during intra-articular injection, with the needle entering the suprapatellar bursa from the 3 o’clock position (arrows) and slightly distending the suprapatellar bursa with injectate. Depth in centimeters shown on the right of each image.
Jpm 13 00763 g002
Table
Table 1. Demographic characteristics of SLE patients with joint pain stratified by co-existing diagnosis of FM.
Table 1. Demographic characteristics of SLE patients with joint pain stratified by co-existing diagnosis of FM.
SLE with FM
(n = 31)		SLE without FM
(n = 41)
Age 1 (years, median [IQR])48 (40.5–61)50 (40–63)
Sex
 Male (n, %)1 (3.2)5 (12.2)
 Female (n, %)30 (96.8)36 (87.8)
Race 2
 White (n, %)18 (58.1)12 (29.3)
 Black (n, %)11 (35.5)22 (53.7)
 Asian (n, %)1 (3.2)3 (7.3)
 Other (n, %)1 (3.2)3 (7.3)
BMI (kg/m2, mean ± SD)33.9 ± 10.031.1 ± 8.9
1 Age on date of musculoskeletal US examination. 2 One SLE patient without FM declined to self-report race. BMI body mass index, FM fibromyalgia, SLE systemic lupus erythematosus.
Table
Table 2. Laboratory parameters of SLE patients with joint pain stratified by co-existing diagnosis of FM.
Table 2. Laboratory parameters of SLE patients with joint pain stratified by co-existing diagnosis of FM.
SLE with FM
(n = 31)		SLE without FM
(n = 41)
anti-dsDNA (IU/mL)4.0 (4.0–9.5)4.5 (4.0–22.5)
C3 (mg/dL)132.0 (104.0–151.0)130.0 (117.8–140.8)
C4 (mg/dL)28.0 (18.0–33.0)32.0 (25.8–37.3)
ESR (mm/h)23.5 (10.8–44.0)24.5 (12.0–61.5)
CRP (mg/L)2.9 (1.6–9.5)4.3 (1.3–11.1)
Data shown as median, IQR. Anti-dsDNA anti-double-stranded DNA, C3 complement component 3, C4 complement component 4, CRP C-reactive protein, ESR erythrocyte sedimentation rate, FM fibromyalgia, SLE systemic lupus erythematosus.
Table
Table 3. Binary logistic regression of predictor variables for inflammatory arthritis detected on musculoskeletal US examination of SLE patients with joint pain.
Table 3. Binary logistic regression of predictor variables for inflammatory arthritis detected on musculoskeletal US examination of SLE patients with joint pain.
Odds Ratio (95% CI)p-Value
Age1.03 (0.97, 1.08)0.35
Sex0.59 (0.06, 5.83)0.65
anti-dsDNA1.01 (1.00, 1.03)0.06 *
C40.91 (0.83, 0.99)0.03 *
ESR1.02 (0.99, 1.04)0.16 *
Clinical synovitis105.00 (9.16, 1204.08)<0.001 *
Co-existing FM0.77 (0.17, 3.51)0.74
* Predictor variables associated with the outcome variable (p-value ≤ 0.20) were included in multiple logistic regression analysis. Anti-dsDNA anti-double-stranded DNA, C4 complement component 4, ESR erythrocyte sedimentation rate, FM fibromyalgia, SLE systemic lupus erythematosus, US ultrasound.
Table
Table 4. Binary logistic regression of predictor variables for patient reported improvement in pain at follow-up visit after musculoskeletal US examination of SLE patients with joint pain.
Table 4. Binary logistic regression of predictor variables for patient reported improvement in pain at follow-up visit after musculoskeletal US examination of SLE patients with joint pain.
Odds Ratio (95% CI)p-Value
Age1.00 (0.97, 1.04)0.95
Sex1.83 (0.34, 9.79)0.48
anti-dsDNA0.99 (0.98, 1.00)0.22
C41.00 (0.96, 1.03)0.86
ESR1.00 (0.99, 1.02)0.63
Clinical synovitis0.55 (0.10, 2.94)0.48
Co-existing FM2.84 (1.00, 8.07)0.05 *
Intra-articular steroid injection18.43 (3.67, 92.55)<0.001 *
Joint aspiration0.69 (0.17, 2.83)0.60
Additional systemic therapy 10.30 (0.07, 1.38)0.12 *
1 Oral or intra-muscular steroids and/or immunosuppression started or increased based on musculoskeletal US examination findings. * Predictor variables associated with the outcome variable (p-value ≤ 0.20) were included in multiple logistic regression analysis. Anti-dsDNA anti-double-stranded DNA, C4 complement component 4, ESR erythrocyte sedimentation rate, FM fibromyalgia, SLE systemic lupus erythematosus, US ultrasound.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Song, Y.; Kirsch, G.; Jarjour, W. The Utility of Ultrasound in Evaluating Joint Pain in Systemic Lupus Erythematosus: Looking beyond Fibromyalgia. J. Pers. Med. 2023, 13, 763. https://doi.org/10.3390/jpm13050763

AMA Style

Song Y, Kirsch G, Jarjour W. The Utility of Ultrasound in Evaluating Joint Pain in Systemic Lupus Erythematosus: Looking beyond Fibromyalgia. Journal of Personalized Medicine. 2023; 13(5):763. https://doi.org/10.3390/jpm13050763

Chicago/Turabian Style

Song, Yeohan, Gabriel Kirsch, and Wael Jarjour. 2023. "The Utility of Ultrasound in Evaluating Joint Pain in Systemic Lupus Erythematosus: Looking beyond Fibromyalgia" Journal of Personalized Medicine 13, no. 5: 763. https://doi.org/10.3390/jpm13050763

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop