Joint ultrasound baseline abnormalities predict a specific long-term clinical outcome in systemic lupus erythematosus patients

Abstract

Objective

To describe long-term clinical and serological outcome in all systemic lupus erythematosus (SLE) domains in SLE patients with hand arthralgia (HA) and joint ultrasound (JUS) inflammatory abnormalities, and to compare them with asymptomatic SLE patients with normal JUS.

Methods

SLE patients with HA who presented JUS inflammatory abnormalities (‘cases’) and SLE patients without HA who did not exhibit JUS abnormalities at baseline (‘controls’) were included. All SLE clinical and serological domain involvement data were collected. End follow-up clinical activity and damage scores (systemic lupus erythematosus disease activity index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR)) were recorded. JUS inflammatory abnormalities were defined based on the Proceedings of the Seventh International Consensus Conference on Outcome Measures in Rheumatology Clinical Trials (OMERACT-7) definitions. Statistical analyses were carried out to compare ‘cases’ and ‘controls’.

Results

A total of 35 patients were recruited. The ‘cases’, n = 18/35, had a higher incidence of musculoskeletal involvement (arthralgia and/or arthritis) through the follow-up period (38.9% vs 0%, p = 0.008) and received more hydroxychloroquine (61.1% vs 25.0%, p = 0.034) and methotrexate (27.8% vs 0%, p = 0.046) compared to ‘controls’, n = 17/35. Other comparisons did not reveal any statistical differences.

Conclusions

We found SLE patients with arthralgia who presented JUS inflammatory abnormalities received more hydroxychloroquine and methotrexate, mainly due to persistent musculoskeletal involvement over time. JUS appears to be a useful technique for predicting worse musculoskeletal outcome in SLE patients.

Keywords

Systemic lupus erythematosus musculoskeletal involvement joint ultrasound

Introduction

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder. Musculoskeletal (MS) involvement is known to be one of the most common features of SLE, which encompasses arthralgia, arthritis, tenosynovitis and non-erosive deforming arthropathy (Jaccoud’s arthropathy). The incidence of arthritis at disease onset ranges from 69% to 97% during the disease course.¹ SLE-related arthritis has been classically defined as a ‘non-erosive arthropathy’, although an erosive pattern similar to rheumatoid arthritis (RA) has also been observed in <5% of SLE patients.^2–4 This rate becomes higher when imaging techniques such as magnetic resonance imaging and joint ultrasound (JUS) are applied.⁵ SLE patients often complain of inflammatory hand arthralgia (HA), despite the lack of any such signs during their physical examinations.^4,6,7

JUS, aided by power doppler (PD), is widely used in other inflammatory rheumatic diseases such as RA and psoriatic arthritis (PsA). Indeed, it has proven to be a useful non-invasive imaging technique for assessing inflammation of the synovial tissue, tendon, bone and adjacent structures. JUS has shown greater sensitivity in detecting inflammatory abnormalities in asymptomatic joints of SLE patients compared to physical examination, suggesting the presence of underlying subclinical inflammatory activities.^4,7–10 Our group previously observed the presence of JUS inflammatory abnormalities in those patients who complained of inflammatory HA.⁷

It has also been posited that SLE patients with ‘arthritis and/or arthralgia’ at disease onset experience longer diagnosis delays than those in whom SLE onset is based on other clinical manifestations. With such delays, SLE patients would be expected to have worse clinical outcomes than those diagnosed during earlier stages.¹¹ Whether these patients experience worse outcomes due to the presence of ‘arthritis and/or arthralgia’ by itself has yet to be confirmed.

We aimed to follow-up all symptomatic SLE patients who presented JUS abnormalities in order to describe long-term clinical and serological outcomes across all SLE domains, and to compare them with asymptomatic SLE patients with normal JUS.

Methods

Selected SLE patients from our previous cross-sectional work⁷ were followed-up in a clinical practice lupus unit setting and were included in the present study. For the initial clinical study, 58 consecutive SLE patients (those who fulfilled ≥4 American College of Rheumatology (ACR) 1982 criteria) were divided into two groups: ‘cases’ (patients with inflammatory hand arthralgia and normal physical examinations) and ‘controls’ (patients lacking the former) and were analysed by performing bilateral hand and wrist power doppler ultrasound. In the present study, we selected a subgroup from the previous study; SLE patients with inflammatory HA who exhibited JUS abnormalities (‘cases’) and those SLE patients without HA and morning stiffness who did not present JUS abnormalities at baseline (‘controls’). JUS abnormalities were defined based on the Proceedings of the Seventh International Consensus Conference on Outcome Measures in Rheumatology Clinical Trials (OMERACT-7) definitions.¹²

A prospective observational data collection for the above-mentioned SLE patients was performed in a clinical practice setting at Hospital del Mar, Barcelona, Spain. We reviewed all clinical charts and collected baseline socio-demographics and clinical features data: age, gender, JUS findings and date of JUS. The clinical variables collected during the follow-up were disease evolution (described as predominance joint/systemic involvement during follow-up); baseline visit date; presence (yes/no) and type of arthritis; prednisone intake and dosage (yes/no; maximum dosage and current dosage in milligrams or prednisone equivalent); SLE-related synthetic disease-modifying antirheumatic drugs (DMARD) (hydroxychloroquine, azathioprine, metotrexate, leflunomide, mycophenolate mofetil, rituximab, belimumab or others); disease and damage severity scores, including SLE disease activity index (SLEDAI)¹³ and Systemic Lupus International Collaborating Clinic/ACR damage index (SLICC/ACR);¹⁴ and disability based on the modified health assessment questionnaire (mHAQ).¹⁵

In addition, each patient was asked to rate their own degree of ‘fatigue’ using the 0–100 mm visual analogue scale (VAS) (0 = no fatigue and 100 = intense fatigue)¹⁶ and ‘hand pain’ using the 0–100 mm VAS (0 = no pain and 100 = intense pain).

Blood tests from our reference laboratory were regularly performed to assess SLE serological markers (36), including anti-DNAds using the CLIF method (Crithidia luciliae), antinuclear antibodies (ANA) (0–1/40 UI/mL) and complements C3 (0–90 mg/dL) and C4 (0–10 mg/dL). Other serological variables included the presence/absence of antiphospholipid autoantibodies (either anticardiolipin IgG/IgM, anti-b2-glycoproteine IgG/IgM or lupus anticoagulant), cyclic citrullinated peptide antibody (CCPA) (0–1), rheumatoid factor (01–20 U/ml), anti-Ro (0.1–1) and anti-Smith antibodies (anti-Sm) (0.1–1), if applicable.

All participants gave their informed consent, in accordance with the Declaration of Helsinki.

Results

Thirty-five SLE patients (18 ‘cases’ and 17 ‘controls’) were included, with a mean follow-up time of 5.8 ± 1.1 and 6.0 ± 1.4 years, respectively. All were women, and no differences related to age and/or disease follow-up time were observed between both groups.

The ‘cases’ presented predominantly musculoskeletal involvement (arthralgia and/or arthritis) during the entire follow-up period (38.9% vs 0%, p = 0.008) compared with the ‘controls’, and a significant trend in the presence of fatigue (62.6 ± 34.8 vs 40.5 ± 26.0, p = 0.051) was also observed in ‘cases’ compared to ‘controls’.

Statistical analysis showed significant differences in the type of treatments prescribed during follow-up. ‘Cases’ more frequently received hydroxychloroquine (61.1% vs 25.0%, p = 0.034) and methotrexate (27.8% vs 0%, p = 0.046) compared to ‘controls’; no differences between the other therapies nor with corticosteroids (nor maximum corticosteroids dosages) were observed.

At baseline, ‘cases’ showed a higher SLEDAI score (3.1 ± 2.5 vs 1.5 ± 1.0, p = 0.036) compared with ‘controls’.

No significant associations with the other clinical variables were found. All studied variables are shown in Table 1.

Table 1

Sociodemographic, clinical and serological data of SLE patients

Variable	Controls (n = 17)	Cases (n = 18)	p-value
Age (years)	42.1 ± 16.6	37.7 ± 15.7	0.422
Follow-up time (years)	5.8 ± 1.1	6.0 ± 1.4	0.135
Arthritis (day of visit)
No	15 (93.8%)	17 (94.4%)	1.000
Yes	1 (6.3%)	1 (5.6%)	1.000
Predominance of joint involvement during follow-up
No	16 (100%)	11 (61.1%)	0.008
Yes	0 (0%)	7 (38.9%)	0.008
Arthritis
No	12 (80.0%)	8 (47.1%)	0.055
Yes	3 (20.0%)	9 (52.9%)	0.055
Arthralgia
No	6 (40.0%)	3 (17.6%)	0.243
Yes	9 (60.0%)	14 (82.4%)	0.243
Predominance of systemic involvement during follow-up
No	9 (56.3%)	11 (61.1%)	0.774
Yes	7 (43.8%)	7 (38.9%)	0.774
Lupus nephritis
No	11 (78.6%)	16 (100%)	0.090
Yes	3 (21.4%)	0 (0%)	0.090
SLEDAI (baseline)	1.5 ± 1.0	3.1 ± 2.5	0.036
SLEDAI (end of follow-up)	3.3 ± 3.3	4.7 ± 4.4	0.384
SLICC	0.9 ± 1.7	0.5 ± 0.7	0.695
mHAQ	0.1 ± 0.2	0.4 ± 0.6	0.313
VAS fatigue (mm)	40.5 ± 26.0	62.6 ± 34.8	0.051
VAS hand pain (mm)	20.9 ± 22.8	38.7 ± 31.9	0.146
Corticosteroids
No	11 (68.8)	12 (66.7%)	0.897
Yes	5 (31.3%)	6 (33.3%)	0.897
Current prednisone (mg)	2.6 ± 4.2	3.4 ± 5.7	0.825
Maximum prednisone dosage (mg)	13.4 ± 19.7	18.5 ± 17.0	0.136
Hidroxicloroquine
No	12 (75.0%)	7 (38.9%)	0.034
Yes	4 (25.0%)	11 (61.1%)	0.034
Azathioprine
No	14 (87.5%)	13 (72.2%)	0.405
Yes	2 (12.5%)	5 (27.8%)	0.405
Methotrexate
No	16 (100%)	13 (72.2%)	0.046
Yes	0 (0%)	5 (27.8%)	0.046
Micophenolic Acid
No	13 (81.3%)	18 (100%)	0.094
Si	3 (18.8%)	0 (0%)	0.094
Rituximab
No	16 (100%)	16 (88.9%)	0.487
Si	0 (0%)	2 (11.1%)	0.487
Belimumab
No	16 (100%)	17 (94.4%)	1.000
Yes	0 (0.0%)	1 (5.6%)	1.000
Antiphospholipid antibodies
No	8 (53.3%)	11 (61.1%)	0.653
Yes	7 (46.7%)	7 (38.9%)	0.653
CCPA
No	14 (93.3%)	17 (94.4%)	1.000
Yes	1 (6.7%)	1 (5.6%)	1.000
RF
No	11 (73.3%)	15 (83.3%)	0.674
Yes	4 (26.7%)	3 (16.7%)	0.674
Anti-Ro
No	9 (60.0%)	13 (72.2%)	0.458
Yes	6 (40.0%)	5 (27.8%)	0.458
Chritidia luciliae antibodies
No	11 (73.3%)	11 (61.1%)	0.458
Yes	4 (26.7%)	7 (38.9%)	0.458
Anti-Sm
No	12 (80.0%)	10 (76.9%)	1.000
Yes	3 (20.0%)	3 (23.1%)	1.000

n (%)/mean ± SD

Comparisons performed with χ² test or Fisher’s exact test.

Discussion

We found SLE patients who presented inflammatory HA with JUS abnormalities had a higher incidence of musculoskeletal involvement and received more hydroxychloroquine and methotrexate than patients lacking HA and normal JUS during a long-term follow-up (6 years).

To the best of our knowledge, this is the longest observational follow-up period conducted in SLE patients who presented arthralgia symptoms.

Several previous studies^4,9,10 showed that JUS is a useful technique for evaluating the presence of inflamed synovial tissue in SLE patients, as in other inflammatory diseases. Although Dreyer et al.⁴ described a higher number of JUS abnormalities in SLE patients with HA, synovitis was also shown by US in almost 50% of asymptomatic patients. Yoon HS et al.⁹ also demonstrated that JUS was useful for detecting joint abnormalities even in SLE patients whose symptoms had yet to appear.

We previously reported that patients who complained of inflammatory hand arthralgia with abnormal JUS not only experienced a more severe disease course, but also showed both higher SLEDAI scores and anti-DNAds titres.⁷ Therefore, JUS might be useful for better assessing and defining musculoskeletal SLE involvement in symptomatic patients.

In the present study, we observed permanent predominantly musculoskeletal manifestations (arthralgia or arthritis) in those patients with JUS abnormalities at basal evaluation. These patients also showed a statistical trend towards greater fatigue during follow-up, without any other significant statistical associations with other clinical variables. It is well known that fatigue is one of the most prevalent symptoms in SLE, since it is present in up to 90% of all patients.¹⁶ Whether this fatigue is related to the presence of a specific musculoskeletal involvement has yet to be determined.

No correlation was found between the development of non-musculoskeletal systemic symptoms or the presence of lupus nephritis and the presence of JUS abnormalities, as previously suggested by Kaplan et al.¹⁷ The latter research group suggested that SLE patients with arthritis were less likely to develop nephritis than those without it. We found all lupus nephritis patients (n = 3) within the control group. Most likely due to the small number of patients no statistical significant differences were found, however. Moreover, the association between JUS abnormalities and co-existence of arthritis has yet to be defined.

To the best of our knowledge, there are no previous reports describing the differences in treatment burdens vis-à-vis JUS abnormalities in SLE. Our results showed that symptomatic patients with abnormal JUS needed more specific DMARDs, such as hydroxychloroquine and methotrexate. When assessing SLE patients, physicians should be aware that mild symptoms such as ‘arthralgia’, even with a normal physical examination, can be associated with worse SLE outcomes. We do recommend careful assessments of the ‘arthralgia’ pattern using available imaging techniques such as JUS, in order to establish the type of involvement and its relationship to SLE activity. We found these patients were ultimately more likely to receive more specific DMARDs throughout their disease course as they presented higher activity, based on the expert diagnoses of clinicians.

Our work does have some limitations: the small sample of patients and the inability of the study design to evaluate other joints abnormalities commonly found to be within the most involved site by other authors.¹⁰

In conclusion, patients who complain of inflammatory HA with joint abnormalities, as assessed by JUS, were more likely to receive treatment with hydroxichloroquine and methotrexate than those who did not. JUS appears to be a useful technique for detecting joint involvement in SLE patients. Moreover, it appears accurate in predicting predominantly musculoskeletal involvement and worse clinical outcomes in symptomatic SLE patients. Further studies comparing the long-term outcomes in SLE patients with JUS abnormalities should be performed, in order to better ascertain whether JUS might serve as a helpful predictor of clinical outcomes in SLE patients.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Khamashta

Vilardell

. Lupus eritematoso eistémico 3a edición. Barcelona: Editorial Caduceo Multimedia, pp. 99–114.

Ball

Bell

. Lupus arthritis – do we have a clinically useful classification? Rheumatology (Oxford) 2012; 51: 771–779.

Richter Cohen

Steiner

Smolen

Isenberg

. Erosive arthritis in systemic lupus erythematosus: analysis of a distinct clinical and serological subset. Br J Rheumatol 1998; 37: 421–424.

Dreyer

Jacobsen

Juul

Terslev

. Ultrasonographic abnormalities and inter-reader reliability in Danish patients with systemic lupus erythematosus – a comparison with clinical examination of wrist and metacarpophalangeal joints. Lupus 2015; 24: 712–719.

Ostendorf

Scherer

Specker

Mödder

Schneider

. Jaccoud's arthropathy in systemic lupus erythematosus: differentiation of deforming and erosive patterns by magnetic resonance imaging. Arthritis Rheum 2003; 48: 157–165.

Ball

Gibson

Bell

Rooney

. Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus. Lupus 2014; 23: 46–56.

Torrente-Segarra

Lisbona

Rotés-Sala

. Hand and wrist arthralgia in systemic lupus erythematosus is associated to ultrasonographic abnormalities. Joint Bone Spine 2013; 80: 402–406.

Mosca

Tani

Carli

. The role of imaging in the evaluation of joint involvement in 102 consecutive patients with systemic lupus erythematosus. Autoimmun Rev 2015; 14: 10–15.

Yoon

Kim

Baek

. Ultrasonography is useful to detect subclinical synovitis in SLE patients without musculoskeletal involvement before symptoms appear. Clin Rheumatol 2014; 33: 341–348.

10.

Iagnocco

Ceccarelli

Rizzo

. Ultrasound evaluation of hand, wrist and foot joint synovitis in systemic lupus erythematosus. Rheumatology (Oxford) 2014; 53: 465–472.

11.

Ozbek

Sert

Paydas

Soy

. Delay in the diagnosis of SLE: the importance of arthritis/arthralgia as the initial symptom. Acta Med Okayama 2003; 57: 187–190.

12.

Cheung

Kong

Chew

. Achieving consensus in ultrasonography synovitis scoring in rheumatoid arthritis. Int J Rheum Dis 2014; 17: 776–781.

13.

Ward

Marx

Barry

. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J Rheumatol 2000; 27: 664–670.

14.

Gladman

Goldsmith

Urowitz

. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 2000; 27: 373–376.

15.

Milligan

Hom

Ballou

Persse

Svilar

Coulton

. An assessment of the Health Assessment Questionnaire functional ability index among women with systemic lupus erythematosus. J Rheumatol 1993; 20: 972–976.

16.

Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria for Fatigue. Measurement of fatigue in systemic lupus erythematosus: a systematic review. Arthritis Rheum 2007; 57: 1348–1357.

17.

Kaplan

Ginzler

Feldman

. Arthritis and nephritis in patients with systemic lupus erythematosus. J Rheumatol 1991; 18: 223–229.