Introduction

Rheumatoid arthritis (RA) is an autoimmune disease in which inflammation of the cells lining the synovium produces pain, swelling, and progressive erosion of the synovial joints [1].

Methotrexate (MTX) is the current cornerstone of pharmacological management for most patients with rheumatoid arthritis (RA). The 2015 ACR recommendations for the use of disease-modifying anti-rheumatic drugs (DMARDs) in RA support the use of MTX as the first-line therapy for most patients [2]. Similarly, according to recent EULAR recommendations for management of RA based on broad systematic literature review, MTX should be part of the first treatment strategy for patients with active RA [3].

Methotrexate has been tried intra-articularly and has been shown to be effective as reported in various trials [4]. Repeated intra-articular injections of MTX result in a decrease of local as well as systemic inflammatory signs in RA [5]. Intra-articular MTX therapy results in a strong decrease of SF-granulocyte counts. This effect may be due to the impairment of IL-8-mediated chemotaxis by decreased IL-8 synthesis in synovial fluid mononuclear cells [6].

Musculoskeletal ultrasonography (US) on B-mode has demonstrated greater sensitivity than clinical assessment for detecting synovitis and tenosynovitis in RA target joints [7, 8].

US on Doppler mode detects pathological synovial blood flow, which reflects joint inflammatory activity. An important capability aspect is that US-detected subclinical synovitis, mainly synovial Doppler signal, has shown predictive value in relation to radiographic damage progression and disease flare or relapse [9, 10].

Patients

One hundred RA patients attending the outpatient clinic of Rheumatology and Rehabilitation Department, Faculty of Medicine, Zagazig University, were selected for the study from May 2013 to January 2014. All patients included in the study were fulfilling the following inclusion criteria: (1)fulfilling 2010 American college of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis [11], (2) DAS28 ESR < 2.6, (3) arthritis in one or two medium-sized joints (wrists, elbows, and ankles) resistant to systemic DMARDs including methotrexate.

Patients known to have diabetes mellitus, hepatitis C, or B infection were excluded from the study. Patients with joint sepsis or bleeding disorders are also excluded. All patients were on their conventional systemic DMARDs including methotrexate without any modification of doses. None of the patients included in the study received biologic therapy. Patients were randomized using a simple randomization method into two groups: group 1 (methotrexate group): 56 patients (38 females and 18 males) in which 84 joints (32 ankles, 28 wrists and 24 elbows) were injected intra-articularly under complete aseptic technique by 10 mg of methotrexate without dilution in the targeted joint on a weekly basis for 8 weeks. The total received dose for the single joint was 80 mg MTX per 8 weeks and the maximum total received dose for a patient was 160 mg MTX per 8 weeks. Group 2 (steroid group) included 44 patients (34 females and 10 males) in which 70 joints (26 ankles, 24 wrists, and 20 elbows) were injected under complete aseptic technique once by Triamcinolone acetonide (kenacort) 40 mg. All injections were done guided by ultrasonography.

This study was approved by ethics committee of our university and all patients give written consent for injections after explaining the side effects.

Clinical and laboratory evaluation

All patients were subjected to full history taking including the duration of disease and duration of morning stiffness (MS) and drug therapy, general musculoskeletal examination. Visual analogue scale (VAS) for pain in the targeted joints was measured using a 10-cm horizontal scale with ten possible scores. Tenderness and swelling in the targeted joints were graded on a semiquantitative scale from 0 to 3. A clinical evaluator was blinded to the type of local injections. All patients were investigated as regards ESR, CRP, rheumatoid factor, CBC, liver functions, hepatitis markers, and kidney functions at weeks 0, 8, and 20.

Ultrasonographic examination

Ultrasonographic examination of the targeted joints was performed with a 5–12-MHz linear probe (medison R3) on the same days of clinical assessments. The method of US examination was according to the guidelines published by Backhaus et al. [12]. Synovitis was defined according to the published OMERACT definitions [13]. Synovitis on gray-scale US was evaluated using a semiquantitative 4-grade scale of 0–3, where 0 = absence of synovial thickening, 1 = mild synovial thickening, 2 = moderate synovial thickening, and 3 = marked synovial thickening. An ultrasonographer was blinded to the clinical parameters and the type of local injection.

Power Doppler ultrasonography

Synovial blood flow was evaluated in the same joints. Active synovitis was defined with power Doppler signals. Intra-articular power Doppler signal was graded semiquantitatively using a 4-grade scale of 0–3, where 0 = absence of signal, no intra-articular flow, 1 = mild, 1 or 2 vessels (including 1 confluent vessel) for small joints and 2–3 signals for large joints (including 2 confluent vessels), 2 = moderate confluent vessels in < 50% of the synovium, and 3 = marked vessel signals in > 50% of the synovium [14].

Clinical, ultrasonographic, and power Doppler US evaluation was done before the first injection (W0), after 2 months (W8), and after 5 months (W20).

Statistical analysis

All data were collected, tabulated, and statistically analyzed using SPSS 20.0 for windows (SPSS Inc., Chicago, IL, USA). Quantitative data were expressed as the mean ± SD and qualitative data were expressed as absolute frequencies (number) and relative frequencies (percentage). Independent sample Student’s t test was used to compare between the two groups of normally distributed variables while one-way repeated measures ANOVA was used to compare between more than two matched groups of continuous data. Friedman’s test was used to compare between more than two matched groups of ordinal data. Cochran Q test was used to compare between more than two matched groups of dichotomies data. Percent of categorical variables were compared using the chi-square test (χ 2). All tests were two sided. p value < 0.05 was considered statistically significant (S), p value < 0.001 was considered highly statistically significant (HS), and p value ≥ 0.05 was considered statistically insignificant (NS).

Results

One hundred patients with RA was divided into two groups (Table 1): group (1): 56 patients (38 females and 18 males), their mean age was 35.2 ± 5.02 years and the disease duration was 4.23 ± 3.06 years and 36 patients (64.2%) had positive rheumatoid factor; and group (2): a total of 44 patients (34 females and 10 males), their mean age was 37.3 ± 3.7 years and the mean duration of disease was 3.7 ± 2.9 years and 28 patients (63.6%) had rheumatoid factor positive.

Table 1 Demographic and clinical characteristics of both groups
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Clinical parameters (VAS for pain, tenderness, and swelling) improved significantly in both groups between baselines (W0) and 2 months later (W8) (Tables 2, 3, and 4). While the improvement of clinical parameters continued in the methotrexate group up to 3 months later W20, in the corticosteroid group, there was no significant differences between clinical parameters at W0 and clinical parameters at W20.

Table 2 Clinical parameters of both groups before, after 8 weeks, and 20 weeks of follow-up
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Table 3 Clinical parameters of both groups before, after 8 weeks, and 20 weeks of follow-up
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Table 4 Clinical parameters of both groups before, after 8 weeks, and 20 weeks of follow -up
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In both groups gray US and power Doppler US showed that synovial thickness and intra-articular power signals was reduced significantly between (W0 and W8) (Tables 5 and 6). In the methotrexate group, there was an insignificant increase in synovial thickness between W8 and W20, while there was a significant increase in power Doppler signals between W8 and W20, p < 0.05 (Tables 3 and 4). In the corticosteroid group, there was a significant increase in both synovial thickening and power Doppler signals between W8 and W20.

Table 5 Grades of synovial thickness detected by gray ultrasonography before and after injection
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Table 6 Power Doppler grades before and after injection
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As regards side effects, two participants in the MTX group reported multiple oral ulcerations during the study, one participant in the same group reported post-injection nausea, and three participants in the corticosteroid group reported post-injection flare of arthritis. In both groups, there were no significant differences in renal and liver functions after injections in both groups.

Figures 1 and 2 show the grades of Doppler ultrasound activity of the two groups and show that at 20 weeks, there were more activity in Doppler in group 2.

Fig. 1
figure 1

Grades of Doppler ultrasound activity of methotrexate intra-articular injection group

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Fig. 2
figure 2

Grades of Doppler ultrasound activity of corticosteroid intra-articular injection group. Figures 1 and 2 showed that at 20 weeks, there were more activities in Doppler in group 2

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Figures 3 and 4 show the grades of synovial thickness detected by gray ultrasound of the two groups, showing different grades of synovial thickness between the two groups at 20 weeks.

Fig. 3
figure 3

Grades of synovial thickness detected by gray ultrasound of methotrexate intra-articular injection group

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Fig. 4
figure 4

Grades of synovial thickness detected by gray ultrasound of corticosteroid intra-articular injection group. Figures 3and 4 showing different grades of synovial thickness between two groups at 20 weeks

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Supplementary Figures 5, 6, and 7 show the power Doppler images.

Discussion

The results reported suggest that intra-articular methotrexate has a more prolonged anti-inflammatory effect than intra-articular corticosteroids. This anti-inflammatory effect appeared clinically as improvement in VAS for pain and as decreases in the grades of tenderness and swelling and confirmed laboratory (by the decrease in ESR and CRP) and ultrasonographically (by the decrease in grades of synovial thickness as detected by gray-scale US and the decrease in power Doppler activities as detected by power Doppler US (PDUS)). While in the MTX group, this anti-inflammatory was persistence up to 32 weeks and in the corticosteroid group, the anti-inflammatory effects continued only for 8 weeks.

The improvement of clinical parameters and gray-scale parameters is in agreement with a study done by Iagnocco and colleagues [4]; their patients were treated with IA knee injections of MTX 10 mg every 7 days for 8 weeks. An increase of the mean value of maximal knee flexion angle and a reduction of the mean values of ESR and VAS between W9 and W17 were demonstrated. US evaluation showed significant reduction of synovial thickness and joint effusion. They concluded that repeated intra-articular injections of MTX resulted in a decrease of local as well as systemic inflammatory signs.

The superior clinical effects of repeated intra-articular MTX in comparison with intra-articular corticosteroids presented in these results also agree with a study done by Gao and colleagues [6]on patients with RA and knee effusions in the two groups; the first group were treated with up to six intra-articular injections of 10 mg MTX every 3 to 7 days and the control group received a single IA injection of 40 mg corticosteroids. They found also that the intra-articular granulocyte counts and IL-8 levels decreased in all MTX-treated patients on days 10–13 and stayed low in those patients after 13 weeks.

This agreed with the results of Blyth and colleagues [15] who found that the addition of 600 mg rifampicin or 50 mg methotrexate gave more pain relief after injection of the rheumatoid knee with 20 mg triamcinolone hexacetonide (TH). The improvement was detected clinically and themographically.

Our results agreed also with that of Tqweem and colleagues [16] who reported improvement in pain, swelling, flexion, and ESR after injecting with MTX 12.5 mg twice but he did not study how long this improvement lasted.

Many studies confirmed the role of power Doppler US in monitoring the response to therapy in RA [17]. In 2006, Filippucci and colleagues monitored treatment with adalimumab for 2 weeks with power Doppler US and demonstrated a rapid decrease in synovial pathological flow after treatment. In [18] 2008, Naredo and colleagues found sensitivity of change in PDUS in 28 joints of RA patients on anti-TNF therapy, showing a correlation with the improvement in DAS-28 and a predictive value for radiological progression.

Peter P and Bhasin S [19] found that PDUS correlates significantly with clinical findings and inflammatory markers. It has the ability to detect subclinical synovitis not detected by clinical assessment. So it can be used to predict that the efficacy of intra-articular MTX injection will end shortly which has to be confirmed in a more longitudinal studies.

The presented results are in contrary with many early studies like those with Hall and colleagues [20], which did not detect any clinical effects to intra-articular methotrexate. However, these early studies used a single MTX injection, which may be not enough to give clinical effects.

The present study confirm the safety of intra-articular MTX injection that presented in earlier studies [4, 5], with only two patients reported oral ulcers and one patient reported nausea which may be related to a minor systemic absorption. It may be of interest that while three patients in the corticosteroid group reported a post-injection flare, none of our patients in the methotrexate group reported such side effects.

To our knowledge, this the first study to confirm the effect of intra-articular MTX in synovial joints other than the knee joint which may encourage physicians to consider repeated intra-articular MTX injection as an option in treatment of resistant synovitis that does not respond to systemic therapy including systemic MTX.

While it seems that intra-articular MTX is cost-effective, this was not one of the targets of our study and we did not calculate the costs of injections for the different participants with different insurance systems. This should be discussed in further studies.

In conclusion, the present report shows that repeated intra-articular MTX injection resulted in a decrease in degree of synovitis of medium-sized joints in RA patients both clinically and by power Doppler US, while the clinical effects and decrease in synovial thickness by gray US continue after 6 months. The power Doppler signals tend to increase after 6 months. On the other hand, both synovial thickness and power Doppler signals tend to increase in steroid-injected joints after 3 months.