Sorokina L, Kaneva M, Artamonov A, Gordeeva N, Chikova I, Kostik M. Clinical and laboratory features of juvenile idiopathic arthritis with wrist involvement: Results of a retrospective cohort study. World J Clin Pediatr 2024; 13(3): 91656 [DOI: 10.5409/wjcp.v13.i3.91656]
Corresponding Author of This Article
Mikhail Kostik, MD, PhD, Professor, Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Lytovskaya 2, Saint-Petersburg 194100, Russia. kost-mikhail@yandex.ru
Research Domain of This Article
Rheumatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Lyubov Sorokina, Maria Kaneva, Artem Artamonov, Irina Chikova, Mikhail Kostik, Hospital Pediatry, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Natalia Gordeeva, Department of Consulting and Diagnostic, Saint-Petersburg Children’s Hospital #2, n.a. Saint Mary Magdalene, Saint Petersburg 199004, Russia
Mikhail Kostik, Research Laboratory of Autoimmune and Autoinflammatory Diseases, Almazov National Medical Research Center, Saint-Petersburg 197341, Russia
Author contributions: Kostik MM and Sorokina LS contributed to conceptualization, writing—review and editing; Kostik MM and Chikova IA contributed to methodology; Artamonov AK contributed to software, resources, and data curation; Artamonov AK, Kaneva MA, and Gordeeva NA contributed to validation; Sorokina LS contributed to formal analysis; Kaneva MA contributed to investigation and visualization; Kostik MM contributed to writing—original draft preparation, funding, supervision, and project administration; All authors have read and agreed to the published version of the manuscript.
Supported byMinistry of Science and Higher Education of the Russian Federation, No. 075-15-2022-301.
Institutional review board statement: The protocol of the study was approved by the local Ethical Committee of Saint Petersburg State Pediatric Medical University (#11/10 from 23.11.2020).
Informed consent statement: Informed consent was obtained from all subjects involved in the study.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
STROBE statement: The authors have read the STROBE Statement—a checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—a checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mikhail Kostik, MD, PhD, Professor, Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Lytovskaya 2, Saint-Petersburg 194100, Russia. kost-mikhail@yandex.ru
Received: January 1, 2024 Revised: June 16, 2024 Accepted: June 26, 2024 Published online: September 9, 2024 Processing time: 241 Days and 11.1 Hours
Abstract
BACKGROUND
Previous studies in the pre-biological era showed an association of wrist inflammation in juvenile idiopathic arthritis (JIA) with progressive disease course, polyarticular involvement and failure of methotrexate treatment.
AIM
To describe features of JIA, associated with wrist arthritis.
METHODS
Data from about 753 JIA patients were included in this retrospective cohort study. The clinical and laboratory features of patients with and without wrist involvement were analyzed.
RESULTS
Wrist involvement was found in oligoarthritis (5.8%), RF(−)/RF(+) polyarthritis (44.9%/15.0%), enthesitis-related arthritis (17.7%), and systemic (58.6%) JIA categories. Unilateral wrist involvement was typical for oligoarthritis patients, bilateral involvement was either equal to that of unilateral involvement or was more frequent in other categories. Wrist arthritis was found to be associated with female sex, a low incidence of uveitis, and more indications of systemic inflammation, including elevated levels of C-reactive protein, erythrocyte sedimentation rate, and platelets, as well as involvement of the cervical spine, temporomandibular, shoulder, elbow, metacarpophalangeal, proximal interphalangeal, distal interphalangeal, hip, ankle, and tarsus arthritis. The number of patients with hip osteoarthritis and hip replacement was also higher. Wrist arthritis was associated with a lower probability of achieving remission [hazard ratio (HR) = 1.3 (95%CI: 1.0-1.7), P = 0.055], and a higher probability of being treated with biologics [HR = 1.7 (95%CI: 1.3-2.10, P = 0.00009)].
CONCLUSION
Wrist arthritis in JIA patients is a marker of a severe disease course, characterized by more intensive inflammation, unfavorable outcomes, and. requiring more intensive treatment with early administration of biologics. Close monitoring of wrist inflammation with ultrasound and MR assessment with early biological treatment might improve the outcomes.
Core Tip: Wrist arthritis has specific symptoms, such as muscle weakness, paresthesia, limited fist function, limited pinch grip, joint deviation, aesthetic complaints, and difficulties in writing, drawing, and working with a knife, pencil, laptop, or other device. The frequency of wrist involvement in juvenile idiopathic arthritis categories was 5.8% in oligoarthritis, 44.9% in RF(−), 15.0% in RF( +) polyarthritis, 17.7% in enthesytis-related arthritis, and 58.6% in systemic. Wrist arthritis was associated with higher inflammation, specific joint involvement (cervical spine, temporomandibular, shoulder, elbow, metacarpophalangeal, proximal interphalangeal, distal interphalangeal, hip, ankle, and tarsus), a lower probability of achieving remission, and a higher probability of being treated with biologics.
Citation: Sorokina L, Kaneva M, Artamonov A, Gordeeva N, Chikova I, Kostik M. Clinical and laboratory features of juvenile idiopathic arthritis with wrist involvement: Results of a retrospective cohort study. World J Clin Pediatr 2024; 13(3): 91656
Juvenile idiopathic arthritis (JIA) is the most frequent chronic pediatric rheumatic disease and has joint involvement with different prognoses, treatment, and outcomes[1]. Recent data from two national databases indicate that the incidence of JIA in Germany ranges from 34 (29–41) to 60 (53–67) per 100000 patients and the prevalence ranges from 133 (122–145) to 168 (157–179) per 100000 patients. According to the current classification, JIA presents with different categories depending on the number of active joints, the presence of systemic features, and immunological features[1]. The pathogenesis of various JIA categories ranges from autoinflammatory for systemic to autoimmune for RF (+) polyarthritis[3,4]. Treatment includes nonsteroid anti-inflammatory drugs (NSAID), intra-articular corticosteroids, nonbiological (methotrexate, sulfasalazine, leflunomide), and biological disease-modifying antirheumatic drugs (DMARD), and inhibiting various cytokines including tumor necrosis factor and interleukins 1, 6, and 17a[5]. JIA categories, the number of active joints, and specific joint involvement have been described many times as markers of disease course, prognosis, and treatment outcomes[6,7]. Knees, ankles, and wrists are joints that are frequently involved in JIA[6]. Wrist arthritis affects about 25% of JIA patients at the onset of the disease and increases to 40% of patients over the next 5 years[8]. Wrist arthritis can be diagnosed both clinically and with imaging tools. The main clinical signs are pain and swelling with early loss of range of motion[9]. In some patients, wrist arthritis can have a silent course with only limitation of motion detected and subsequent muscle atrophy by the rheumatologist. Sometimes the main complaints are related to weak grip during sports exercises or difficulty with writing. Schoolchildren need more time and breaks during writing. Imaging modalities may show signs of wrist involvement depending on the tool and arthritis duration[10]. Ultrasound and magnetic resonance imaging (MRI) may find effusion and synovial hyperplasia in the early stages and bone marrow edema in MRI, especially in clinically nonmanifest wrist synovitis[11,12]. In some cases with arthritis of the fingers, wrist effusion and bone marrow edema may be found in the absence of clinically evident wrist arthritis[13]. Bone erosions and bone loss are markers of advanced wrist arthritis that might be detected with MRI, computed tomography, or plain X-ray. images[14,15]. Several radiological scores have been applied in JIA and adult rheumatoid arthritis based on plain wrist X-rays[16-18]. Early diagnostic evaluation of wrist arthritis is needed to prevent functional disability and joint damage[19]. The severity of wrist arthritis prompted the American College of Rheumatology (ACR) to include it, along with arthritis of the hip joint and cervical spine, in a separate group in which the use of biological drugs as the first line of DMARD treatment with or without methotrexate may be recommended[20]. We performed our study to describe the clinical features of the patients with wrist arthritis.
MATERIALS AND METHODS
Study design and patient selection
We retrospectively analyzed data from the medical histories of 753 patients between the ages of 2 and 17 who were treated at Saint Petersburg State Pediatric Medical University from 2006-2016. Diagnosis of JIA was made according to the International League of Associations for Rheumatology criteria[21]. The inclusion criteria were: (1) All categories of JIA[21]; (2) A minimum of two observations during at least 2 years in our center; and (3) Wrist arthritis was diagnosed clinically with swelling or pain with limitation of motion. In doubtful cases, the presence of arthritis was confirmed by joint ultrasound (effusion, synovial hyperplasia, and increased Doppler signals from the synovial membrane, erosions) or MRI (effusion, synovial enhancement, erosions). Children with and without wrist arthritis were compared, and having unilateral and bilateral involvement was investigated.
Data collection
Patient evaluation included: (1) Demographic characteristics: Onset age, sex, JIA duration, JIA category, uveitis; (2) Joint assessment: Active joint count, specific joint involvement. In patients with hip involvement, we evaluated the number with hip osteoarthritis and those for whom hip arthroplasty was done; (3) Markers of laboratory and immunological activity. including hemoglobin, white blood cell count, platelets, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), HLA B27 antigen, and rheumatoid factor (RF); (4) Treatment options including the number of patients who received NSAIDs or oral, high-dose intravenous, or intra-articular injections of glucocorticosteroids in any joints and the cumulative doses, biological and nonbiological DMARDs and the time before biologic administration; and (5) Disease outcomes including achievement of remission and time until remission, developing a significant flare (i.e. the flare, followed by change of the current treatment).
Statistical analysis
The sample size was not calculated initially. Statistical analysis was performed with the STATISTICA, version 10.0 (StatSoft Inc., Tulsa, OK, United States). All continuous variables were checked for normality. by the Kolmogorov–Smirnov test. Quantitative variables were reported as medians (Me) and percentiles (25%, 75% for continuous variables, and as absolute frequencies and percentages for categorical variables. Pearson's χ2 test or Fisher's exact test in the expected frequencies < 5 was used to compare categorical variables. Two quantitative variables were compared using the Mann–Whitney test. The ability of each variable to discriminate patients with wrist arthritis from those without it was evaluated by sensitivity and specificity analysis, and area under the receiver operating characteristic curve were calculated with 95% confidence intervals (CI), and odds ratio (OR) for the detection the best cutoff of continuous variables. Higher values of OR of variables interfere with discriminatory ability. We used the “best” threshold for our data’s receiver operating characteristic curve analysis. Survival analysis in each group, with JIA outcomes (treatment with biologics, achievement of the remission) as the event of interest, was estimated the Kaplan–Meier method. The log rank test compared survival curves. Factors significantly associated with the time of JIA outcomes were then tested in a Cox proportional hazards regression model, calculating the hazard ratio (HR) with a 95%CI. A P value of < 0.05 was considered statistically significant.
RESULTS
The patients’ demography
The median age at study inclusion was 12.3 (7.9; 16.5) years, had a slight predominance of girls (60.7%) and a relatively long duration of the disease before inclusion [4.3 (1.9; 7.5)] years. The distribution of the JIA categories was oligoarthritis 27.1%, RF-positive and RF-negative polyarthritis 35.2%, psoriatic arthritis 5.3%, enthesitis-related arthritis 24.7%, and systemic arthritis 7.7%. Uveitis was detected in 15.4% of the patients. ANA positivity was 46.1% and RF-positivity was 5.4%.
A total of 86.5% were treated with NSAIDs, 41.7% received intra-articular corticosteroid injections, 20.2% received oral corticosteroids, and 17.9% received pulse therapy. The main nonbiological DMARD was methotrexate in 76.1% of the patients. Sulphasalazine, leflunomide, and cyclosporine A were given to 18.2%, 9.2%, and 46.6% of the patients, respectively. Biological treatment was given to 46.6% of the patients and 64.4% of them achieved remission. A subsequent flare was experienced by 18.3% of the patients.
Characteristics of JIA patients with wrist involvement
Wrist arthritis was present in 204 (27.1%) of the patients, 121 (59.3%) had bilateral, and 83 patients (40.7%) had unilateral wrist involvement. The frequency of wrist involvement in JIA categories was 5.8% in oligoarthritis, 44.9% in RF(−) and 15.0% in RF(+) polyarthritis, 17.7% in enthesytis-related arthritis, and 58.6% in systemic. Wrist arthritis frequently affected girls along with less frequent development of uveitis. Patients with wrist arthritis were shorter and had a smaller body mass index.
Patients with wrist arthritis had more signs of systemic inflammation, i.e. higher CRP, ESR, and platelets, and lower hemoglobin levels. Wrist involvement was associated with arthritis involvement of the cervical spine, temporomandibular, shoulder, elbow, metacarpophalangeal, proximal interphalangeal, distal interphalangeal, hip, ankle, and tarsus joints. The number of patients with hip osteoarthritis and hip replacement was also higher in those with JIA and the time before hip osteoarthritis was longer compared with patients with wrist arthritis. Patients with wrist arthritis required more immunosuppressive treatment with oral and intravenous corticosteroids and had a higher rate of treatment and a higher corticosteroid cumulative dose, more frequent. methotrexate, leflunomide, and cyclosporine A treatment, and less frequent use of sulfasalazine.
Despite the higher proportion of patients with wrist arthritis treated with biologics (predominantly tumor necrosis factor alpha inhibitors), the probability of remission was lower (the percentage of patients who achieved remission was lower and the time to the remission was longer), but flares were rare in patients who achieved remission. The data are shown in Table 1.
Table 1 Comparative characteristics of patients with juvenile idiopathic arthritis with and without wrist arthritis.
Parameters
Whole group, n = 753
Wrist arthritis, yes, n = 204
No wrist arthritis, n = 549
P value
Demography
Sex, females
457 (60.7)
149 (73.0)
308 (56.1)
0.00002
JIA onset age in years Me (25%-75%)
6.0 (3.0-10.4)
5.1 (2.8-9.4)
6.3 (3.0-10.7)
0.064
JIA duration in years Me (25%-75%)
4.3 (1.9-7.5)
5.3 (2.9-8.9)
3.7 (1.7-7.1)
0.00004
Age of the inclusion in the study, Me (25%-75%)
12.3 (7.9-16.5)
13.1 (8.7-17.0)
12.0 (7.4-16.3)
0.032
JIA category
0.000001
Oligoarthritis
204 (27.1)
12 (5.9)
192 (35.0)
Polyarthritis
265 (35.2)
119 (58.3)
146 (26.6)
Psoriatic arthritis
40 (5.3)
6 (2.9)
34 (6.2)
Enthesitis-related arthritis
186 (24.7)
33 (16.2)
153 (27.8)
Systemic arthritis
58 (7.7)
34 (16.7)
24 (4.4)
Uveitis
116 (15.4)
15 (7.4)
101 (18.4)
0.0002
Anthropometry
Height, %, Me (25%-75%)
137 (111-157)
43.1 (17.8-74.4)
56.1 (26.9-78.0)
0.022
Height, SD, Me (25%-75%)
0.11 (-0.7-0.8)
-0.15 (-1.0-0.7)
0.17 (-0.6. 0.9)
0.038
Weight in kg, Me (25%-75%)
31.5 (19.0-50.0)
28.0 (19.5-46.5)
33.0 (19.0-51.5)
0.385
Body mass index, SD, Me (25%-75%)
0.04 (-0.8-0.9)
-0.23 (-1.1-0.8)
0.09 (-0.7-0.9)
0.037
Laboratory
ANA-positivity
212/460 (46.1)
55/126 (43.7)
157/334 (47.1)
0.713
HLA B27-positivity
100/308 (32.5)
21/75 (28.0)
79/233 (33.9)
0.530
RF-positivity
22/406 (5.4)
7/118 (5.9)
15/288 (5.2)
0.377
ESR, mm/h, Me (25%-75%)
8.0 (3.0-20.0)
12.0 (5.0-29.5)
7.0 (3.0-17.0)
0.000002
C-reactive protein in mg/L, Me (25%-75%)
1.4 (0.2-8.0)
3.3 (0.2-19.5)
1.0 (0.0-6.0)
0.00003
White blood cells as × 109/L, Me (25%-75%)
7.1 (5.8-9.4)
7.4 (6.0-9.9)
7.0 (5.8-9.2)
0.056
Platelets as × 109/L, Me (25%-75%)
311 (255-388)
342 (278-433)
302 (253-373)
0.00006
Hemoglobin in g/L, Me (25%-75%)
124 (116-132)
121 (105-128)
126 (118-134)
0.000001
Joint involvement
Wrist arthritis, unilateral
204 (27,1)
83 (40.7)
-
-
Active joints, Me (25%-75%)
6 (3-12)
14 (8-25)
4 (2-8)
0.0000001
Cervical spine
101 (13.4)
62 (30.4)
39 (7.1)
0.0000001
TMJ
43 (5.7)
23 (11.3)
20 (3.6)
0.00006
SCJ
12 (1.6)
6 (2.9)
6 (1.1)
0.072
Shoulder
56 (7.4)
38 (18.6)
18 (3.3)
0.0000001
Elbow
120 (15.9)
74 (36.5)
46 (8.4)
0.000001
MCP
164 (21.8)
96 (47.1)
68 (12.4)
0.000001
PIP
192 (25.5)
109 (53.4)
83 (15.1)
0.000001
DIP
70 (9.3)
37 (18.1)
33 (6.0)
0.0000001
Hip
153 (20.3)
55 (27.0)
98 (17.9)
0.006
Hip osteoarthritis
48/153 (31.4)
24/55 (43.6)
24/98 (24.5)
0.014
Hip prosthetics
16/153 (10.5)
11/55 (20.0)
5/98 (5.3)
0.005
Time before hip osteoarthritis, Me (25%-75%)
5.0 (2.4-9.4)
5.7 (4.5-11.7)
2.3 (1.5-5.9)
0.0009
Sacroiliac
71 (9.4)
15 (7.4)
56 (10.2)
0.232
Knee
535 (72.8)
141 (69.1)
394 (71.9)
0.454
Ankle
323 (42.9)
122 (59.8)
201 (36.6)
0.0000001
Subtalar
62 (8.2)
21 (10.3)
41 (7.5)
0.210
Tarsus
43 (5.7)
20 (9.8)
23 (4.2)
0.003
MTP
98 (13.0)
31 (15.2)
67 (12.2)
0.278
Interphalangeal foot
94 (12.8)
31 (15.2)
63 (11.5)
0.170
Treatment and outcomes
NSAID
651 (86.5)
172 (84.3)
479 (87.3)
0.295
Any joints IACI
314 (41.7)
77 (37.8)
237 (43.2)
0.180
Oral GCS
152 (20.2)
78 (38.2)
74 (13.5)
0.0000001
GCS pulse therapy
135 (17.9)
67 (33.0)
68 (12.4)
0.0000001
Any GCS treatment
445 (59.1)
142 (69.6)
303 (55.2)
0.0003
Cumulative dose of GCS in mg, Me (25%-75%)
2650 (1000-5000)
3000 (1000-6000)
1750 (900-4000)
0.048
Methotrexate
573 (76.1)
174 (85.3)
399 (72.7)
0.0003
Sulphasalazine
137 (18.2)
28 (13.7)
109 (19.9)
0.053
Leflunomide
7 (9.2)
6 (2.9)
1 (0.2)
0.0005
Cyclosporine A
53 (7.0)
26 (12.8)
27 (4.9)
0.0002
Biologics
351 (46.6)
125 (61.3)
226 (41.2)
0.000001
Time before biologics in years, Me (25%-75%)
4.2 (1,9-7.8)
3.9 (1.5-8.0)
4.3 (2.0-7.6)
0.464
Remission
485 (64.4)
118 (57.8)
367 (66.9)
0.022
Time before remission in years, Me (25%-75%)
3.2 (1.5-6.6)
4.1 (1.8-7.9)
3.0 (1.4-6.1)
0.002
Flare
138 (18.3)
28 (13.7)
110 (20.1)
0.046
Unifactorial analysis revealed that female sex, systemic JIA category, active joints > 9, increased ESR and CRP, and involvement of the specific joints and immunosuppressive treatment with methotrexate, systemic corticosteroids and biologics. were predictors associated with wrist arthritis. The data are in the Table 2.
Table 2 Factors associated with wrist involvement in juvenile idiopathic arthritis patients.
Parameter
Se
Sp
OR (95%CI)
P value
Sex, female
43.9
73.0
2.1 (1.5-3.0)
0.00002
Systemic JIA
16.7
95.6
4.4 (2.5-7.6)
0.0000001
Uveitis
89.1
26.4
0.43 (0.21-0.91)
0.0002
Active joints > 9
69.6
81.1
9.8 (6.8-14.1)
0.000001
Height ≤ 39%
47.1
65.0
1.7 (1.1-2.5)
0.011
BMI ≤ -0.3 SD
49.7
64.1
1.8 (1.2-2.6)
0.004
CRP > 5.9 mg/L
41.0
76.0
2.2 (1.5-3.1)
0.00001
ESR > 11 mm/h
50.5
67.1
2.1 (1.5-2.9)
0.00002
Platelets > 292 × 109/L
71.9
46.6
2.2 (1.5-3.1)
0.00001
Cervical spine
30.4
92.9
5.7 (3.7-8.9)
0.0000001
TMJ involvement
11.3
96.4
3.2 (1.7-6.0)
0.00006
Shoulder involvement
18.6
96.7
4.1 (2.3-7.4)
0.0000001
Elbow involvement
36.5
91.6
6.3 (4.1-9.5)
0.000001
MCP involvement
47.1
87.6
6.3 (4.3-9.1)
0.000001
PIP involvement
53.4
84.9
6.7 (4.6-9.5)
0.000001
DIP involvement
18.1
94.0
3.5 (2.1-5.7)
0.0000001
Hip involvement
27.0
83.4
1.7 (1.2-2.5)
0.006
Hip osteoarthritis involvement
43.6
75.5
2.4 (1.2-4.8)
0.014
Hip prosthetics involvement
20.0
94.8
4.7 (1.5-14.2)
0.005
Time before hip osteoarthritis > 3.2 years
95.7
57.1
29.3 (3.3-260.1)
0.0001
Ankle involvement
59.8
63.4
2.6 (1.9-3.6)
0.0000001
Tarsus involvement
9.8
95.8
2.5 (1.3-4.6)
0.003
Treatment with oral GCS
38.2
86.5
4.0 (2.7-5.8)
0.0000001
GCS pulse therapy
33.0
87.5
3.5 (2.4-5.1)
0.0000001
Any GCS treatment
69.6
44.8
3.6 (2.6-5.0)
0.0003
Methotrexate
91.6
16.4
6.7 (3.9-11.5)
0.0003
Biologics
61.3
58.8
2.3 (1.6-3.1)
0.000001
No remission
42.2
66.8
1.5 (1.1-2.0)
0.022
Time before remission > 3.1 years
61.0
53.3
1.8 (1.3-2.5)
0.0006
No flare
86.3
20.1
1.6 (1.01-2.5)
0.046
Comparison of children with unilateral and bilateral wrist arthritis revealed the following differences. Unilateral involvement was more frequently observed in oligoarthritis (4.9% vs 1.0%), was about equal in enthesitis-related arthritis (9.1% vs 8.6%), and rare in RF-negative (16.2% vs 28.7%), and RF-positive polyarthritis (5.0% vs 10.0%) and in systemic arthritis (19.0% vs 39.7%). The number of patients with uveitis was two times higher in those with unilateral involvement, but the difference was not significant. Laboratory abnormalities included a higher proportion of ANA-positive patients and a lower level of CRP in patients with unilateral wrist involvement. Patients with unilateral wrist involvement required fewer immunosuppressive drugs and had outcomes (remission, flares) similar to those of patients with bilateral involvement. The data are shown in Table 3.
Table 3 Comparative characteristics of patients with juvenile idiopathic arthritis with unilateral or bilateral wrist involvement.
Parameters
Unilateral, n = 83
Bilateral, n = 121
P value
Demography
Sex, female
65 (78.3)
84 (69.4)
0.160
JIA onset age in years Me (25%-75%)
5.4 (2.9-10.0)
5.0 (2.8-8.9)
0.578
JIA duration in years Me (25%-75%)
4.8 (2.5-7.9)
5.9 (3.0-10.0)
0.231
Age of the inclusion in the study in years, Me (25%-75%)
11.7 (8.4-17.3)
13.7 (8.8-17.0)
0.368
Uveitis
9 (10.8)
6 (5.0)
0.114
Laboratory
ANA-positivity
31/54 (57.4)
24/72 (33.3)
0.031
HLA B27-positivity
11/33 (33.3)
10/42 (23.8)
0.362
RF-positivity
2/50 (4.0)
5/68 (7.4)
0.720
ESR in mm/h, Me (25%-75%)
11.0 (4.0-30.0)
12.5 (5.0-26.0)
0.746
C-reactive protein in mg/L, Me (25%-75%)
1.5 (0.2-11.6)
4.4 (0.4-36.0)
0.027
White blood cells as × 109/L, Me (25%-75%)
7.4 (6.1-9.4)
7.5 (6.0-10.6)
0.416
Platelets as × 109/L, Me (25%-75%)
345 (291-419)
335 (263-448)
0.905
Hemoglobin in g/L, Me (25%-75%)
121 (107-128)
121 (105-129)
0.880
Joint involvement
Active joints, Me (25%-75%)
9 (6-13)
23 (12-34)
0.0000001
Cervical spine
12 (14.5)
50 (41.3)
0.00004
TMJ
4 (4.8)
19 (15.7)
0.016
SCJ
2 (2.4)
4 (3.3)
0.710
Shoulder
5 (6.0)
33 (27.3)
0.0001
Elbow
14 (17.1)
60 (49.6)
0.000002
MCP
29 (34.9)
67 (55.4)
0.004
PIP
36 (43.4)
73 (60.3)
0.017
DIP
10 (12.1)
27 (22.3)
0.062
Hip
12 (14.5)
43 (35.5)
0.0009
Hip osteoarthritis
4/12 (33.3)
9/43 (20.9)
0.371
Hip prosthetics
2/12 (16.7)
9/43 (20.9)
0.744
Time before hip osteoarthritis, Me (25%-75%)
8.2 (4.4-11.7)
5.2 (4.7-10.2)
0.972
Sacroiliac
5 (6.0)
10 (8.3)
0.547
Knee
43 (51.8)
98 (81)
0.000009
Ankle
33 (39.8)
89 (73.6)
0.000001
Subtalar
4 (4.8)
17 (14.1)
0.033
Tarsus
4 (4.8)
16 (13.2)
0.047
MTP
10 (12.1)
21 (17.4)
0.300
Interphalangeal foot
11 (13.3)
20 (16.5)
0.522
Treatment and outcomes
NSAID
72 (86.8)
100 (82.6)
0.429
Any joints IACI
42 (50.6)
35 (28.9)
0.002
Oral GCS
23 (27.7)
55 (45.5)
0.010
GCS pulse therapy
23 (27.7)
44 (36.4)
0.182
Any GCS treatment
60 (40.7)
82 (59.3)
0.490
Cumulative dose of GCS in mg, Me (25%-75%)
3000 (1000-6000)
3000 (1135-5625)
0.668
Methotrexate
72 (92.8)
102 (84.3)
0.628
Sulphasalazine
12 (14.5)
16 (13.2)
0.801
Leflunomide
1 (1.2)
5 (4.1)
0.235
Cyclosporine A
5 (6.0)
21 (17.4)
0.017
Biologics
41 (49.4)
84 (69.4)
0.004
Time before biologics in years, Me (25%-75%)
5.0 (1.8-8.2)
3.67 (1.1-7.7)
0.187
Remission
48 (57.8)
70 (57.9)
0.998
Time before remission in years, Me (25%-75%)
3.8 (1.8-7.4)
4.2 (1.7-8.6)
0.471
Flare
11 (13.3)
17 (14.1)
0.871
Cox regression analysis found that wrist arthritis was a predictor of a severe disease course. Patients with wrist arthritis had a lower probability of achieving remission (log rank test P = 0.001; HR = 1.3 (95%CI: 1.0-1.7), P = 0.055, Figure 1A), not using biologics (log rank test P = 0.0003; HR = 1.7 (95%CI: 1.3-2.10, P = 0.00009, Figure 1B). Patients with unilateral wrist arthritis had a lower probability of not using biologics (log rank test, P = 0.032; HR = 1.6 (95%CI: 1.03-2.58), P = 0.035).
Figure 1 Survival analysis and Cox proportional hazards regression models.
A: Cumulative probability of the achievement of the remission in juvenile idiopathic arthritis (JIA) patients with and without wrist arthritis; B: Cumulative probability of requirement in biological treatment in JIA patients with and without wrist arthritis. HR: Hazard ratio.
DISCUSSION
In this study, wrist arthritis was found to be a marker of a severe JIA course. Wrist arthritis was associated with systemic and polyarticular JIA categories, intensive systemic inflammation, an increased number of active joints, higher risk of developing hip osteoarthritis, hip arthroplasty, and intensive treatment. The frequency of wrist involvement ranged from 17%-50% and depended on the distribution of JIA categories in the population and the duration of JIA[6-7]. Several studies have shown an increased frequency of wrist involvement during the disease course[8]. Ulnar and radial deviation of the wrist are the most frequent joint deformities in JIA patients, ranging from 28.6%-50%[22-24]. During a 5 year follow-up observation period, the frequency of wrist involvement increased from 24% at onset to 40%[8]. At the onset of the JIA there were no differences in the frequency of wrist involvement in the persistent-oligo compared to that in polyarticular JIA (19% and 33%, P = 0.272) but in 5 years the difference was significant at 22% vs 51%, P = 0.024). Several studies have positioned wrist involvement is as a marker of poor outcomes in JIA[25,26].
Routine clinical assessment of the wrist joint is less reliable than imaging methods, especially MRI, which allow the detection of subclinical synovitis and bone marrow edema[27-29]. The wrist joint was used for the development of a pediatric-targeted MRI scoring system to assess disease activity and damage in juvenile idiopathic arthritis[30]. In JIA patients, synovial thickening and enhancement are particularly present at three anatomical sites, and this information is useful for navigation through MRI of the wrist in search of JIA disease activity[31]. Sometimes clinical examination does not reveal synovitis that is detected by MRI or ultrasound[32-34]. Thermography is a promising tools for detecting mild wrist synovitis, especially if accompanied by ultrasound assessment[35]. MRI scoring was shown to have a poor correlation with laboratory markers of inflammation but it has a strong correlation with the number of swollen joints, physician's global disease activity, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS71), confirming the utility of the wrist as a surrogate marker of the total burden of disease activity[30,36,37].
Dynamic contrast-enhanced MRI of the wrist in children with JIA is a relatively new diagnostic tool for the identification of active wrist synovitis[38]. Recently, reference values of sonographic cartilage thickness, bone-capsular distance, and tendon diameter at several joints, including the wrist and hand were provided[39]. The preliminary CARRA MSUS scoring system for assessing arthritis of the pediatric elbow, wrist, and finger joints was recently launched[40]. In the absence of clinically symptomatic inflammation of. the wrist in pediatric patients, contrast-enhanced magnetic resonance imaging revealed juvenile idiopathic arthritis-relevant MRI characteristics that require follow-up observation to determine the clinical significance of this finding[41].
Along with pain, stiffness, and swelling, patients with wrist arthritis may have a set of complaints, e.g., muscle weakness, paresthesia, limited fist function, limited pinch grip, any joint deviation, aesthetic complaints, difficulties in writing, drawing, working with knives, pencils, laptops or other devices[42]. Children with JIA and wrist involvement had higher joint reposition errors than healthy controls for each direction and poorer results than healthy controls in the single hand Purdue Pegboard test, two hand Purdue Pegboard test, hand grip strength, and lateral pinch strength[43]. Some patients needed hand or wrist braces or splints[44].
The abovementioned hand- or wrist-related symptoms were present in 69% of patients, 55% in the hands and. 49% in the wrists. The dominant side was affected most patients (63%) compared to the nondominant hand (53%)[44]. Wrist impairment (predominantly restricted motion) was noted in 30% of the JIA patients, mostly in the dominant hand[44]. Wrist- and hand-related symptoms were mostly observed in RF-negative polyarthritis, compared to other JIA categories[44]. Discrepancies between wrist-related complaints and physical fundings were observed in several studies, but the data are contradictory[44,45]. Handwriting problems related to pain are frequently reported by a majority of schoolchildren[42]. Noninvasive testing of hand grip strength with a dynamometer was found to be an independent predictor of disease activity, disability, and quality of life in JIA patients[46].
Wrist involvement was reported to be a clinical biomarker of poor disease prognosis in nonsystemic JIA with plasma biomarkers[47,48]. Bilateral wrist involvement was a marker of poor response to methotrexate therapy[49]. Patients with wrist involvement may have initial treatment with biologicals with or without methotrexate, according to the current ACR recommendations[20]. Tocilizumab may decrease radiographic progression in systemic and polyarticular JIA according to the adapted Sharp-van der Heijde and Poznanski scoring methods[50]. Wrist arthroscopy with synovectomy is considered an option for patients refractory to medical management[51,52]. Early monitoring of wrist involvement with clinical, functional (dynamometer, writing), and radiological (MRI and ultrasound) evaluation can find the subgroup of patients with likely poor outcomes and require earlier initiation of biological treatment. Close monitoring with early medical intervention with physiotherapy and occupational therapy support can improve the outcomes of wrist arthritis.
Limitations
The study has several limitations. The retrospective study cohort, missing data, and differing duration of arthritis influenced the study results. Routine clinical assessment of joints may have decrease the number of active joints and influenced study results. The absence of a standardized imaging protocol may have led to missing some cases of wrist arthritis. The above mentioned limitations may have led to underestimation of the study results.
CONCLUSION
Wrist arthritis in JIA patients was a marker of a severe disease course, characterized by more intensive inflammation with unfavorable outcomes, requiring more intensive treatment with early administration of biologics. Close monitoring of the inflammation in the wrist with ultrasound and magnetic resonance assessment with early biological treatment might improve the outcomes.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Rheumatology
Country of origin: Russia
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade D
P-Reviewer: Arumugam VA S-Editor: Liu JH L-Editor: Filipodia P-Editor: Guo X
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