Methotrexate dosage and laboratory monitoring in patients with psoriasis and psoriatic arthritis: A retrospective analysis of prescription patterns and financial impact in dermatology and rheumatology settings

Introduction

Methotrexate (MTX) is a cornerstone therapy for psoriasis (PsO) and psoriatic arthritis (PsA), favoured for its efficacy, affordability, and simple administration. This makes it a crucial first-line treatment option, especially in resource-limited settings. However, potential adverse effects such as bone marrow suppression and liver toxicity limit its widespread and long-term use. Early guidelines established for high-dose MTX (≥500 mg/m²) were adapted for the now routinely used low-dose MTX (5-25 mg/week).¹ Dermatologists often refer to the British Association of Dermatologists’ (BAD) guidelines² and Joint American academy of dermatology–National Psoriasis Foundation guidelines(AAD-NPF),³ while rheumatologists follow European Alliance of Associations for Rheumatology (EULAR) guidelines,⁴ American College of Rheumatology (ACR) guidelines,⁵ Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines,⁶ and other regional guidelines for MTX prescription.

PsO and PsA largely share similar inflammatory cascades; however, PsA is more associated with an acute inflammatory response, potentially leading to joint damage and a greater clinical burden. Despite comparable responses to MTX, dermatology and rheumatology guidelines deviate with respect to monitoring strategies. Dermatology guidelines favour a more conservative dosing schedule and rigorous monitoring, while rheumatology guidelines recommend a higher starting dose and more liberal monitoring. This disparity might unintentionally suggest a higher risk of MTX-associated adverse effects in PsO compared to PsA, which may or may not reflect actual outcomes.

We therefore conducted a retrospective chart review and compared prescribing patterns, monitoring, adverse effects and associated financial burden for PsO (treated by dermatologists) and PsA (treated by rheumatologists).

Methods

We conducted an electronic medical record-based retrospective chart review of patients prescribed MTX at the dermatology and rheumatology departments of a tertiary health care centre between 2020 and 2021. After the ethics committee approval, the first 100 consecutive patients from the respective clinics were enrolled in the study. Patients who were on concurrent hepatotoxic or myelotoxic drugs, had less than six months of follow-up for reasons unrelated to the drug or disease, or presented with abnormal baseline liver function tests (LFTs) or hemogram were excluded. Prior to initiating MTX, all participants underwent comprehensive baseline assessments, including complete blood count(CBC), kidney function tests (KFTs), Liver function tests (LFTs), and screening for Human Immunodeficiency Virus, hepatitis B and hepatitis C. A baseline chest radiograph was also obtained. Data collected included demographics, medical histories, MTX dosing, monitoring frequency, adverse events, and resource utilization. The primary outcomes were the frequency and associated cost of laboratory investigations, abnormal laboratory values, and adverse effects.

An abnormal LFT was defined as a more than 2-fold increase in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels from the upper limit of the normal range. Myelosuppression was defined as white blood cells, platelets, neutrophils, or haemoglobin falling below 3,000/mm³, 100,000/mm³, 1,000/mm³, and 10 g/dL, respectively. Abnormal renal function was indicated by serum creatinine >1.4 mg/dL or urea >40 mg/dL.

Results

We analysed the records of 100 PsO patients (46.16 ± 17.91 years old, 55% female) from the dermatology outpatient department and 100 PsA patients (46.62 ± 15.97 years old, 63% female) from the rheumatology outpatient department (p=0.31) [Table 1].

Initiation dosage

The mean starting dose was significantly higher in the PsA group (13.4 ± 3.9 mg/week; range 7.5-20 mg/week) compared to those in the PsO group (9.4 ± 2.9 mg/week; range 5-15 mg/week, p=0.0001). In the PsO group, 7.5 mg/week (35%) and 10 mg/week (39%) were the most frequent initiation doses, while a 15 mg/week (58%) dose was most frequent in the PsA group [Figure 1].

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Figure 1:

Comparison of MTX initiation dosage in the two groups.

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A test dose was defined as an initial methotrexate dose of < 10 mg followed by laboratory monitoring before the second weekly methotrexate dose. Twenty-six PsO patients (7.5 mg most frequent, 76%) and only 2 PsA patients (7.5 mg) were given a test dose, revealing a significant difference in test dose utilization between the groups (p < .00001).

Maintenance dosage

At six months, the mean methotrexate (MTX) maintenance dose was significantly higher in PsA (15.5 ± 5.2 mg/week; range 7.5-25 mg/week) compared to PsO (10.5 ± 3.5 mg/week; range 7.5-15 mg/week p < .00001) [Table 2 and Figure 2].

Table 2: MTX initiation and maintenance dose.

MTX test dose
	Test Dose	No Test Dose	Total	P-value
PsA patients	2	98	100	< .00001*
PsO patients	26	74	100
MTX initiation dose
	Mean (S.D)	Median	Interquartile range	P-value
PsA patients	13.4 (3.86)	15	5	< .00001**
PsO patients	9.39 (2.85)	10	2.5
MTX maintenance dose at 6th month
	Mean (S.D)	Median	Interquartile range	P-value
PsA patients	15.45 (5.20)	15	10	< .00001**
PsO patients	10.45 (3.50)	10	7.5

P-value ≤ 0.05: Significant; * Chi-Square Test **Mann-Whitney Test

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Figure 2:

Comparison of MTX maintenance dosage in the two groups.

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Monitoring

In the PsO group, the mean frequency of laboratory visits was 1.58 times per patient during the first month of treatment, including the baseline CBC, LFT, and KFT evaluation, and primarily at two-week (31%) and four-week (35%) intervals. Subsequently, during the 2^nd and 3^rd month of treatment, a majority of the patients (46% were on 4-weekly laboratory evaluation; 43% patients were on 8-weekly laboratory evaluation between 4^th and 6^th months. The mean total number of laboratory visits during the first six months of treatment for the PsO group was 0.963 laboratory visits per treatment month(Total number of visits, 541.4; Average number of visits per patient, 5.4 ± 1.84) [Figures 3 and 4].

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Figure 3:

Frequency of laboratory visits during 1^st month in the two groups.

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Figure 4:

Frequency of laboratory visits during the maintenance period in the two groups.

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In contrast, during the first month of treatment, a majority (74%) of PsA patients were advised to repeat CBC & LFT every 4 weeks, with the mean number of laboratory visits being 1.08 times per patient. During the 2nd and 3rd month, 30% of patients underwent 8-weekly monitoring, while 38% continued with 4-weekly evaluations, and between the 4^th and 6^th month, the majority (57%) transitioned to 12-weekly monitoring. The mean total number of laboratory visits during the first six months of treatment for the PsA group was 0.62 laboratory visits per treatment month (Total number of visits 373.9; Average number of visits per patient were 3.73 ± 1.37 [Table 3].

Table 3: Laboratory visits, abnormal laboratory results and cost implications in the two groups.

	PsO (treated by dermatologist)	PsA (treated by rheumatologist)
Number of laboratory visits	541.4	373.9
Total treatment months	595	597
Cost of 6 months monitoring*	Rs 4766.08+ 1631.9	Rs 3290.32+ 1207.8
Lab visits per treatment month	0.96	0.62
Number of abnormal lab results	6	8
Number of abnormal lab results per treatment month	0.010	0.013
Number of abnormal lab results per per lab visit	0.011	0.021

* Mann-Whitney test; z-score 7.28252; p value < 0.05

Financial impact

The average cost associated with consultation and laboratory tests (CBC, LFT, serum creatinine) during each visit in our hospital was Rs. 880. The average cost of consultation and laboratory tests over a 6-month period for the PsO group was Rs.4766.08±1631.9, while the same for PsA patients was Rs. 3290.32 ±1207.8, meaning that dermatologist-managed PsO patients incurred 44% higher monitoring costs than rheumatologist-managed PsA patients over six months (p value < 0.05;) (excluding the cost and time involved in travelling) [Table 3].

Discussion

Current monitoring guidelines for MTX are based on historical observations of infrequent but serious adverse events. In this retrospective chart review of 100 PsO and 100 PsA patients receiving low-dose MTX, we found significantly fewer PsA than PsO patients receiving a test dose (2 vs. 26).

The mean starting and maintenance doses at the 6- month follow-up were significantly higher in the PsA group. Comparing various dermatology and rheumatology guidelines reveals that none strongly advocates for a test dose; instead, they recommend initiation at low doses with gradual titration. Under PsO-specific guidelines, BAD guidelines recommends starting at 5-15 mg/week, while AAD-NPF suggests a higher initial dose (7.5-25mg/week). EULAR and ACR guidelines are not specific for PsA but recommend a higher initiation dose (15-25mg/week) as has been detailed and compared in Table 5.

A comprehensive literature review revealed that the test dose and the routine one-week post-initiation laboratory evaluation have minimal impact on treatment decisions in patients with normal renal function.⁷ The rationale for a MTX test dose is to identify acute idiosyncratic or hypersensitive reactions. However, the rarity of these reactions, particularly on initial exposure, and their usual association with higher MTX doses bring into question the utility of the test dose. Additionally, idiosyncratic reactions may not be effectively predicted through test dosing, irrespective of the dose.⁸ Most studies have largely concluded that omitting this evaluation and potentially initiating MTX at higher doses (7.5-20mg/week) may be safe for most patients while elderly people or patients with impaired kidney function may be given a test-dose.^7,9

Interestingly, despite lower dosage regimens, PsO patients had significantly higher laboratory visits during the first six months of MTX therapy compared to PsA patients, resulting in a 44% increase in financial burden & healthcare utilisation. Notably, the frequency of hepatoxicity was comparable in both groups, while leukopenia was observed more in the PsA group, but none of the patients in either group had adverse events resulting in significant hospitalisation.

BAD guidelines suggest more frequent laboratory monitoring (every 2-4 weeks) compared to EULAR/ACR (every 4-8 weeks). However, large-scale retrospective studies have highlighted that the more frequent monitoring advocated in dermatological guidelines may be associated with a higher incidence of abnormal laboratory results and may potentially lead to early withdrawal of MTX.^10,11 Further, based on a large-scale MTX study in connective tissue diseases, the authors concluded that monitoring liver transaminases every 12 weeks is a safe practice as all cases with transaminitis normalised with dose adjustments or drug discontinuation, without any significant liver disease.¹² Furthermore, an Italian Delphi Consensus¹³and EuroGuiDerm guideline¹⁴ on the systemic treatment of psoriasis vulgaris also advocates for a more streamlined approach, suggesting initial laboratory monitoring two weeks after MTX initiation, followed by monthly monitoring for the first 2 months, and then transitioning to a less frequent schedule of every 3 months.¹³ Even in paediatric populations, studies largely advocate against the use of test dose and suggest repeat laboratory investigations only after the first month of treatment and then every 3–4 months.^15,16

Our findings and other similar studies suggest that a more targeted, risk-stratified monitoring strategy, as opposed to a generalised approach, may be appropriate for MTX therapy.¹⁷ Conversely, more frequent monitoring might be warranted for patients exhibiting baseline laboratory abnormalities.¹⁸ This study’s strength lies in demonstrating the non-essentiality of test doses and the increased laboratory monitoring for PsO patients, which translates into higher financial burdens compared to those patients treated by rheumatologists.

Limitations

The single centre, retrospective design, small sample size, and convenience sampling limit the generalisability of our findings. The analysis might not account for any other confounding factors that could influence MTX dosing, monitoring, and outcomes. The exclusion of patients with comorbidities or concurrent medications, such as those using hepatotoxic or myelotoxic drugs, patients with baseline liver or kidney abnormalities could impact the applicability of the results to a broader patient population. Additionally, the study’s focus on a single tertiary care centre may limit its relevance to different healthcare settings, where resource availability and treatment practices may vary. The dosing regimen employed in this study may not fully reflect the variations in dosing strategies used in everyday clinical practice, where flexibility in treatment regimens is often necessary.

Conclusion

This real-world analysis suggests that current routine monitoring practices for methotrexate (MTX) in dermatology, while potentially beneficial for early identification of myelosuppression, may contribute to increased healthcare resource utilisation and financial burden for patients, particularly in resource-poor and developing countries lacking healthcare insurance. Insights from this study and comparison with rheumatology practices and existing literature highlight the potential for designing large-scale, multicentric, non-inferiority studies that could eventually help develop more efficient and streamlined MTX monitoring protocols for dermatology, ultimately improving patient adherence and affordability