Safety and Efficacy of Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Arthritis | Dermatology | JAMA Dermatology | JAMA Network
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Table 1.  Differences in Baseline Characteristics Between Patients With Psoriasis With and Without Psoriatic Arthritisa
Differences in Baseline Characteristics Between Patients With Psoriasis With and Without Psoriatic Arthritisa
Table 2.  Differential Efficacy of Methotrexate Treatment Between Patients With Psoriasis With and Without Psoriatic Arthritis
Differential Efficacy of Methotrexate Treatment Between Patients With Psoriasis With and Without Psoriatic Arthritis
Table 3.  Summary of Adverse Events
Summary of Adverse Events
Table 4.  Association of Methotrexate With Routine Blood Test Results and Hepatic and Renal Function Analyses
Association of Methotrexate With Routine Blood Test Results and Hepatic and Renal Function Analyses
Table 5.  Association of Alanine Transaminase Level as a Measure of Liver Function With Clinic Characteristics of Psoriasisa
Association of Alanine Transaminase Level as a Measure of Liver Function With Clinic Characteristics of Psoriasisa
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Original Investigation
January 30, 2019

Safety and Efficacy of Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Arthritis

Author Affiliations
  • 1Shanghai Institute of Dermatology, Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
  • 2Institute of Dermatology, Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
  • 3Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
JAMA Dermatol. 2019;155(3):327-334. doi:10.1001/jamadermatol.2018.5194
Key Points

Question  What are the differences in effectiveness and safety of methotrexate for patients with psoriasis with and without psoriatic arthritis?

Findings  In this Chinese cohort study of 107 patients with psoriasis without arthritis and 128 patients with psoriasis with psoriatic arthritis who were undergoing methotrexate therapy, the 90% reduction from baseline Psoriasis Area Severity Index response was significantly lower in the patients with psoriatic arthritis than in the patients without arthritis. In addition, methotrexate-induced adverse events occurred more often in the patients with psoriatic arthritis than in those without psoriatic arthritis.

Meaning  Methotrexate may be more effective and may have fewer adverse effects in patients with psoriasis without concomitant psoriatic arthritis.

Abstract

Importance  It is necessary to determine whether psoriasis responds to methotrexate in the same manner in patients with and without psoriatic arthritis.

Objective  To evaluate the effectiveness and safety of methotrexate in treating patients with psoriasis with and without psoriatic arthritis.

Design, Setting, and Participants  In this prospective, single-arm, interventional study, a total of 235 patients with psoriasis, 107 without psoriatic arthritis and 128 with psoriatic arthritis who were receiving methotrexate therapy from April 1, 2015, to December 31, 2017, were recruited from the outpatient department of a hospital at a large Chinese university. There were no significant demographic or clinical differences between the subgroups with the exception of diabetes.

Interventions  A 12-week course of low-dosage oral methotrexate (7.5-15 mg weekly).

Main Outcomes and Measures  Changes in disease severity, adverse events, blood cell counts, and liver and renal function.

Results  A total of 235 patients with psoriasis (166 male [66.0%]; mean [SD] age, 49.6 [15.1] years) received methotrexate treatment for 12 weeks. The 90% reduction from baseline Psoriasis Area Severity Index response was significantly lower in patients with psoriatic arthritis than in patients without psoriatic arthritis at week 8 (4 0f 128 [3.1%] vs 12 of 107 [11.2%]; P = .02) and week 12 (19 of 128 [14.8%] vs 27 of 107 [25.2%]; P = .049). Furthermore, the incidence of adverse events, including dizziness (12 of 128 [9.4%] vs 1 of 107 [0.9%]; P = .007), gastrointestinal symptoms (32 of 128 [25.0%] vs 13 of 107 [12.1%]; P = .01), and hepatoxicity (34 of 128 [26.6%] vs 16 of 107 [15.0%]; P = .04), was significantly higher in patients with psoriatic arthritis than in patients without psoriatic arthritis. Methotrexate-induced elevation of alanine aminotransferase levels was associated with body mass index (mean [SD] body mass index, 26 [4] in patients with [P = .04] vs 26 [4] in those without [P = .005] psoriatic arthritis) and smoking (17 of 34 [50.0%] in patients with [P = .02] vs 9 of 16 [56.3%] in those without [P = .04] psoriatic arthritis).

Conclusions and Relevance  In this study, methotrexate was well tolerated and effective in treating psoriasis. It was more effective, with fewer adverse effects, in patients with psoriasis who did not have psoriatic arthritis than in patients who presented with both psoriasis and psoriatic arthritis. Therefore, methotrexate can be recommended as first-line treatment for psoriasis without arthritis.

Introduction

Psoriasis is a chronic, immune-mediated inflammatory skin disease caused by the interaction of multiple susceptibility genes and environmental factors that affects 1% to 3% of the population worldwide.1 The prevalence of psoriasis in China is 0.47%.2 Systemic agents available for psoriasis treatment include conventional agents, such as acitretin, cyclosporine, and methotrexate; targeted small-molecule drugs (apremilast); and biologic agents that target distinct proinflammatory cytokines.3 Biologics and small-molecule drugs are more expensive compared with conventional drugs, which limits their widespread use, especially in developing countries. Less than 10% of patients with psoriasis receive biologic agents routinely, even in high-income countries.4

Methotrexate is a folate antagonist5 with anti-inflammatory properties.6-9 Methotrexate has been used as a first-line treatment for moderate to severe psoriasis for more than 50 years.10 We undertook a prospective, single-center, observational study to assess the effectiveness, tolerability, hematotoxicity, and hepatotoxicity of oral methotrexate for the treatment of patients with psoriasis without and with psoriatic arthritis. To our knowledge, a prospective, comparative study of the efficacy and adverse effects of methotrexate in Chinese patients with psoriasis with and without psoriatic arthritis has not yet been performed.

Methods
Study Population and Study Design

This single-center, prospective, single-arm, interventional study was performed at the Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China, from April 1, 2015, to December 31, 2017. Patients 18 years or older were recruited from the outpatient population. Only patients with moderate to severe psoriasis with or without psoriatic arthritis were included in this study. Patients who received therapy with UV light, methotrexate, or other systemic treatments for psoriasis or arthropathy within 1 month of study initiation were excluded. Topical treatments were stopped 1 week before the start of the methotrexate treatment. The European guidelines on contraindications and restrictions on methotrexate use were followed.11 The Medical Ethics Committee of Huashan Hospital, Fudan University, reviewed and approved the protocol, and all patients provided written informed consent. All data were deidentified.

Treatment

The initial oral methotrexate dose was 7.5 to 10 mg once weekly. The dose was increased by 2.5 mg every 2 to 4 weeks to a maximum of 15 mg weekly depending on the patient’s clinical response and adverse effects and results of routine hematologic and blood chemistry tests. Folic acid supplementation was not recommended because it is not available in our clinics. If liver enzyme level elevations were more than 2-fold or less than 3-fold, the methotrexate dose was reduced by 2.5 mg weekly and administered once 2 to 4 weeks later. If the liver enzyme level elevations were more than 3-fold, methotrexate treatment was stopped.12

Effectiveness and Tolerability Assessments

Two certified dermatologists graded the severity and extent of psoriasis using the Psoriasis Area Severity Index (PASI) and body surface area (BSA) scores and tabulated the adverse events. Psoriatic arthritis was assessed using the Classification Criteria for the Study of Psoriatic Arthritis (CASPAR).13 Complete blood cell counts, liver enzyme levels, and renal function were measured at baseline and at weeks 4, 8, and 12.

Statistical Analysis

The data are expressed as means (SDs). The statistical analyses were performed using unpaired t tests, Mann-Whitney tests, unpaired t tests with Welch correction, 1-way analyses of variance with repeated measures, χ2 tests, or Fisher exact tests, as appropriate. Multiple test correction was conducted using the Benjamini-Hochberg procedure. Data analyses were performed using GraphPad Prism software, version 5 (GraphPad Software Inc). P < .05 was considered to be statistically significant.

Results
Disease Duration and Likelihood of Having Diabetes

In total, 248 patients received oral methotrexate, and 235 patients (166 male [66.0%]; mean [SD] age, 49.6 [15.1] years) completed the 12-week study. Five patients dropped out at week 4, and 8 patients dropped out at week 8. No patient withdrew because of adverse effects. Four patients had PASI scores greater than 50 when they dropped out at week 8. The mean (SD) age at disease onset was 36.1 (16.1) years. The mean (SD) disease duration was 13.6 (11.1) years. The mean (SD) baseline PASI score was 13.9 (7.4), and the mean (SD) baseline BSA score was 29.7 (20.8).

Using the CASPAR criteria, 128 patients (54.5%) were diagnosed with psoriatic arthritis. Patients with psoriatic arthritis had a longer duration of psoriasis before entering the study. Furthermore, a significantly higher proportion of patients with psoriatic arthritis had diabetes compared with the 107 patients without psoriatic arthritis. The mean (SD) age (45.2 [17.1] vs 53.3 [12.0] years; P < .001) and age at disease onset (33.2 [16.0] vs 38.3 [15.9] years; P = .008) were significantly higher and the mean (SD) disease duration (11.8 [10.1] vs 15.0 [11.6] years; P = .02) was significantly longer in patients with psoriatic arthritis (Table 1). The number of male patients, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), baseline PASI, BSA score, 50% reduction from baseline PASI score (PASI50), 75% reduction from baseline PASI score (PASI75), mean PASI changes at weeks 8 and 12, incidence of hypertension, and proportions of patients who smoked and consumed alcohol did not differ between the patients with and without psoriatic arthritis.

Effectiveness of Methotrexate in Patients With and Without Psoriatic Arthritis

As indicated in Table 2, the 90% reduction from baseline PASI score (PASI90) response rates were significantly higher in patients without psoriatic arthritis compared with those with psoriatic arthritis at week 8 (12 [1.9%] vs 4 [3.1%]; P = .02) and week 12 (27 [25.2%] vs 19 [14.8%]; P = .049). At week 8, the PASI50 response rates were numerically higher, albeit not statistically significant, in the patients without psoriatic arthritis compared with the patients with psoriatic arthritis (64 [59.8%] vs 61 [47.6%]; P = .07), as were the PASI75 response rates (28 [26.2%] vs 29 [22.6%]; P = .54) and the mean (SD) PASI changes (52.1 [32.7] vs 45.8 [33.0]; P = .12). At week 12, the PASI50 response rates were also numerically higher but not statistically significant in the patients without psoriatic arthritis compared with those with psoriatic arthritis (82 [76.6%] vs 84 [65.6%]; P = .08), as were the PASI75 response rates (54 [50.5%] vs 53 [41.4%]; P = .19) and the mean (SD) PASI changes (648 [33.7] vs 60.1 [31.7]; P = .10).

Methotrexate Treatment–Associated Adverse Events

Table 3 summarizes the adverse events reported during methotrexate treatment, including all adverse effects (92 [39.1%]), methotrexate-associated abnormal hepatic function (61 [26.0%]), and methotrexate-associated cytopenia (17 [7.2%]). In total, 105 patients (44.7%) reported having 1 or more adverse event. The most common reported adverse events were those of the gastrointestinal tract (45 [19.1%]), including nausea and vomiting (20 [8.5%]), dyspepsia (20 [8.5%]), abdominal pain (5 [2.1%]), diarrhea (8 [3.4%]), and oral ulcer (3 [1.3%]), followed by fatigue (29 [12.3%]), dizziness (13 [5.6%]), headache (3 [1.3%]), and hair loss (3 [1.3%]). Methotrexate-associated liver enzyme level elevations occurred in 61 patients (26.0%), including elevated alanine aminotransferase (ALT) level (50 [21.3%]), elevated aspartate aminotransferase (AST) level (29 [12.3%]), elevated direct bilirubin level (11 [4.7%]), and elevated total bilirubin level (8 [3.4%]).

Alanine aminotransferase levels more than 2 times the upper limit of normal were found in 21 patients (8.9%) and AST levels more than 2 times the upper limit of normal in 3 patients (1.3%). The percentage of elevated ALT levels in patients with psoriatic arthritis was significantly higher than that in patients without psoriatic arthritis (34 [26.6%] vs 16 [15.0%]; P = .04). Cytopenia occurred in 17 patients (7.2%), including anemia (9 [3.8%]), leukopenia (6 [3.8%]), neutropenia (4 [1.7%]), and thrombocytopenia (6 [2.6%]). A significantly higher proportion of patients with psoriatic arthritis experienced dizziness (12 [9.4%] vs 1 [0.4%]; P = .007) and gastrointestinal symptoms (32 [25.0%] vs 13 [12.1%]; P = .01) than those without psoriatic arthritis. The total number of adverse events (67 [52.3%] vs 38 [35.5%]; P = .01) and reports of adverse effects (58 [45.3%] vs 34 [31.8%]; P = .04) in patients with psoriatic arthritis were also significantly higher than in patients without arthritis.

Table 4 summarizes the association of methotrexate with hematologic variables and with liver and renal function indicators. Methotrexate was associated with a significantly reduced mean (SD) red blood cell count (from 4.87 [0.43] × 106/μL to 4.67 [0.40] × 106/μL in patients with psoriatic arthritis [P < .001] and from 4.86 [0.47] × 106/μL to 4.67 [0.48] × 106/μL in patients without psoriatic arthritis [P < .001]) (to convert to ×1012 per liter, multiply by 1), white blood cell count (from 6920/μL [1720/μL] to 6240/μL [1650/μL] [P < .001] in patients with psoriatic arthritis and from 7060/μL [1950/μL] to 6610/μL [2070/μL] [P = .009] in patients without psoriatic arthritis) (to convert to ×109 per liter, multiply by 0.001), neutrophil count (from 4450/μL [1390/μL] to 4030/μL [1320/μL] [P = .005] in patients with psoriatic arthritis and 4600/μL [1590/μL] to 4380/μL [1650/μL] [P = .05] in patients without psoriatic arthritis), and hemoglobin level (P < .001) and significantly increased mean corpuscular volume (90.58 [4.45] μm3 to 92.42 [4.44] μm3 [P < .001] in patients with psoriatic arthritis and 91.15 [4.05] μm3 to 93.16 [3.94] μm3 [P < .001] in patients without psoriatic arthritis) (to convert to ×109 per liter, multiply by 0.001), percentage of monocytes (7.09% [1.73%] to 7.49% [1.96%] [P < .001] in patients with psoriatic arthritis and 6.79% [1.73%] to 7.41% [2.20%] [P < .001] in patients without psoriatic arthritis) (to convert to proportion of 1.0, multiply by 0.01), and serum direct bilirubin level (0.20 [0.10] mg/dL to 0.22 [0.09] mg/dL [P = .004] in patients with psoriatic arthritis and 0.21 [0.09] mg/dL to 0.23 [0.09] mg/dL [P = .03] in patients without psoriatic arthritis) (to convert to micromoles per liter, multiply 10.0) from baseline to week 12. A significant increase in neutrophil count (63.52% [8.27%] to 63.90 [7.97%] [P = .63] in patients with psoriatic arthritis and 64.52% [6.94%] to 65.41% [7.12%] [P = .02] in patients without psoriatic arthritis) (to convert to proportion of 1.0, multiply by 0.01) and a decrease in lymphocyte count (26.53% [7.79%] to 25.73% [7.43%] [P = .28] in patients with psoriatic arthritis and 25.98% [6.03%] vs 24.47% [5.99%] [P = .009]) (to convert to proportion of 1.0, multiply by 0.01) were observed from baseline to week 12. The mean values of serum ALT level (30.13 [17.49] U/L at baseline, 40.18 [35.56] U/L at week 8, and 40.90 [36.70] at week 12; P < .001) and AST level (22.51 [8.67] U/L at baseline, 25.46 [12.94] U/L, and 25.84 [12.74] U/L; P = .007) were significantly increased in patients with psoriatic arthritis compared with baseline (to convert ALT and AST to microkatals per liter, multiply by 0.0167). Serum albumin levels (4.56 [0.31] g/dL to 4.62 [0.25] g/dL; P = .02) (to convert to grams per liter, multiply by 10) and the albumin-to-globulin ratio (1.55 [0.30] to 1.61 [0.29]; P = .004) increased significantly, and serum globulin levels (3.04 [0.53] g/dL to 2.96 [0.50] g/dL; P = .01]) (to convert to grams per liter, multiply by 10) decreased significantly from baseline to week 12 in patients with psoriatic arthritis.

Association of Increased Liver Enzyme Levels in Patients With Psoriasis With Smoking and BMI

Fifteen patients with psoriatic arthritis (11.7%) and 15 patients without psoriatic arthritis (14.0%) had elevated ALT levels before they received methotrexate. Consequently, the patients were divided into 3 groups: group 1, patients whose ALT levels were normal before and after treatment; group 2, patients whose ALT levels were elevated before methotrexate treatment; and group 3, patients who experienced methotrexate-associated ALT level elevations. Methotrexate-associated elevation of ALT level was associated with body mass index (mean [SD] body mass index, 26 [4] in the patients with psoriatic arthritis [P = .04] and 26 [4] in those without arthritis [P = .005]) and smoking (17 [50.0%] in the patients with arthritis [P = .02] and 9 [56.2%] in those without arthritis [P = .04]). The mean (SD) baseline BSA scores in groups 2 and 3 patients with psoriatic arthritis were significantly higher than those in group 1 patients with psoriatic arthritis (37 [31] and 38 [27] vs 27 [21]; P = .046). The mean (SD) BSA changes in group 2 and 3 patients with psoriatic arthritis (35 [53] and 49 [41] vs 62 [39]; P =  .048) and patients without psoriatic arthritis (35 [56] and 51 [55] vs 71 [34]; P = .005) were significantly lower than those in group 1 patients at week 12. Patients with psoriatic arthritis in group 2 received a lower mean (SD) cumulative methotrexate dose than those in group 1 (124 [29] mg vs 135 [22] mg), but no statistically significant differences were observed (P = .15) (Table 5).

Discussion

The effectiveness and safety of methotrexate therapy in patients with and without psoriatic arthritis were compared in a prospective, single-arm, interventional study. Significantly more patients with psoriatic arthritis presented with diabetes at baseline. Similar findings have been reported by Coto-Segura et al,14 and increased levels of adipokines that drive insulin resistance in patients with psoriatic arthritis may provide an explanation for this observation.15 Our results demonstrated that 50% of patients without and 41% of patients with psoriatic arthritis achieved PASI75 responses after 12 weeks, which concurs with the findings reported by Boehncke and Schön.16 Other investigators have reported that the PASI75 response rate can vary from 24% to 73% during 12 to 24 weeks,17-24 depending on the methotrexate dose, the time when the response is measured, and the study’s design. Statistical differences in PASI90 response at weeks 8 and 12 were observed between patients with and without psoriatic arthritis, which can be better explained by the fact that psoriatic arthritis occurs later in psoriasis and a long-standing disease may be harder to control.25

More patients with psoriatic arthritis reported dizziness and nausea or vomiting compared with patients without psoriatic arthritis. This difference might also be related to genetic factors.26 Sampaio-Barros et al27 described 8.8% of patients with ankylosing spondylitis receiving methotrexate treatment who reported dizziness, which is consistent with 9.4% of patients with psoriatic arthritis in our study who also experienced dizziness. Overall, 105 patients (44.7%) reported methotrexate-associated adverse events, which were mostly mild or moderate, and none of the patients dropped out of the study because of severe adverse events.

Methotrexate-associated abnormal hepatic function was observed in 61 patients (26.0%), which was similar to previously reported incidence rates of 15% to 50%.20 Moreover, abnormal hepatic function was more severe in patients with psoriatic arthritis than in those without psoriatic arthritis. Smoking and increased BMI are important risk factors in patients with psoriasis with ALT level elevations. Associated with significantly lower methotrexate polyglutamate 3 concentrations in red blood cells, smoking increases the basal metabolic rate in patients with rheumatoid arthritis and may affect drug metabolism.28 No difference in the percentage of smoking was observed between patients with vs without psoriatic arthritis, but the mean BMI was higher in those with vs without psoriatic arthritis, which might be one reason why methotrexate-induced liver enzyme elevations were more frequent in patients with psoriatic arthritis. A previous study29 also reported that obesity and diabetes were significant risk factors for liver injury, which is consistent with our observation. However, the mechanism of hepatotoxicity remains to be elucidated.

Methotrexate-associated myelosuppression was similar in patients with and without psoriatic arthritis. The lack of use of concomitant folic acid might be related to the hematologic laboratory changes observed in this study. However, the rate of cytopenia (2.6%) was similar to previously reported methotrexate-related myelosuppression rates of 2% to 10.2%.30,31 Mean corpuscular volume elevations and hemoglobin level decreases have been ascribed to the inhibition of folic metabolism during methotrexate therapy.32 The increase in neutrophils induced by methotrexate in patients without psoriatic arthritis might be associated with infection. Monocyte levels increased significantly after methotrexate treatment, but the mechanism is unclear33; methotrexate has previously been reported to act as a strong differentiation factor for immature and undifferentiated monocytic cells in vitro.34 Furthermore, methotrexate treatment boosts systemic monocyte generation.35 Additional studies are needed to identify the stimulatory factors involved in this process.

Limitations

The limitations of this study are its short intervention course (12 weeks) and its single-center setting. Gastrointestinal tract adverse events might have been overestimated because no folic acid supplementation was prescribed.

Conclusions

Our study demonstrated that methotrexate was well tolerated by Chinese outpatients with psoriasis. Methotrexate appeared to be more effective and had fewer adverse effects in patients without psoriatic arthritis compared with those with psoriatic arthritis. Although multicenter trials with larger sample size are needed to confirm these results, our findings suggest that methotrexate can be recommended as first-line treatment for psoriasis without arthritis.

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Article Information

Accepted for Publication: November 15, 2018.

Published Online: January 30, 2019. doi:10.1001/jamadermatol.2018.5194

Correction: This article was corrected on March 13, 2019, to fix a data error in Table 1 and an additional data error in Table 2.

Corresponding Authors: Jinhua Xu, MD, PhD (xjhhsyy@163.com), and Xuejun Zhang, MD, PhD (ayzxj@vip.sina.com), Shanghai Institute of Dermatology, Department of Dermatology, Huashan Hospital, Fudan University, No. 12 Middle Wumunuqi Rd, Shanghai 200040, China.

Author Contributions: Drs Yan and Y. Zhang contributed equally to this article. Drs Yan and Y. Zhang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yan, Fang, Zheng, X. Zhang, J. Xu.

Acquisition, analysis, or interpretation of data: Yan, Y. Zhang, Han, Huang, Z. Zhang, Yawalkar, Chang, Q. Zhang, Jin, Qian, Li, Wu, Q. Xu.

Drafting of the manuscript: Yan, Y. Zhang, Han, Z. Zhang.

Critical revision of the manuscript for important intellectual content: Yan, Y. Zhang, Huang, Fang, Zheng, Yawalkar, Chang, Q. Zhang, Jin, Qian, Li, Wu, Q. Xu, X. Zhang, J. Xu.

Statistical analysis: Yan, Y. Zhang, Fang.

Obtained funding: Yan, Fang, Zheng, X. Zhang.

Administrative, technical, or material support: Yan, Y. Zhang, Han, Huang, Z. Zhang, Fang, Zheng, Chang, Q. Zhang, Jin, Qian, Li, Wu, Q. Xu, J. Xu.

Supervision: Yan, Zheng, Yawalkar, X. Zhang, J. Xu.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by grant 81773322 from the National Natural Science Foundation of China.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Weilin Pu, PhD, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China, provided guidance in statistics, and Yang Zhao, PhD, Shanghai International Studies University, Shanghai, China, provided guidance in language. They were not compensated for their help.

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