A 5 YEARS REVIEW OF RHEUMATOID ARTHRITIS …jknj.moh.gov.my/jsm/day2/OP2 - A 5 Years Review of Rheumatoid... · Section 2: Literature Review • A study conducted by Sanchez et al

P R E S E N T E D B Y :

O O I Y E E S H I N

P E G A W A I F A R M A S I U 4 8

M A H A N U M Z , S O L E H A H R , C H O Y M . C , C H O N G S . L & O O I Y . S

D E P A R T M E N T O F P H A R M A C Y , H O S P I T A L S U L T A N I S M A I L , J A L A N P E R S I A R A N M U T I A R A E M A S

U T A M A , T A M A N A U S T I N , 8 1 1 0 0 J O H O R B A H R U , M A L A Y S I A .

A 5 YEARS REVIEW OF RHEUMATOID ARTHRITIS PATIENTS TREATED WITH

METHOTREXATE: MAXIMUM TOLERATED DOSE AND ADVERSE DRUG EVENTS

Section 1: Introduction


• The prevalence of Rheumatoid Arthritis (RA) in adult population of developed countries is estimated to be 0.5% to 1%. 1

• Methotrexate (MTX) is usually first line therapy in moderate to severe RA.2

• MTX toxicity affects various systems, including gastrointestinal (GI), hematologic, skin, pulmonary, central nervous and renal. 3, 4

1 Helmick, C. G., Felson, D. T., Lawrence, R. C., Gabriel, S., Hirsch, R., Kwoh, C. K., et al. (2008). Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I. Arthritis & Rheumatism,58(1), 15-25.

2 Pincus, T., Yazici, Y., Sokka, T., Aletaha, D., & Smolen, J. S. (2003). Methotrexate as the" anchor drug" for the treatment of early rheumatoid arthritis. Clinical and experimental rheumatology, 21(5; SUPP 31), S179-S185.

3 Gaies, E., Jebabli, N., Trabelsi, S., Salouage, I., Charfi, R., Lakhal, M., & Klouz, A. (2012). Methotrexate side effects: review article. J Drug Metab Toxicol, 3(125), 2.

4 Rau, R., & Herborn, G. (2004). Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clinical and experimental rheumatology, 22, S83-S94.


Combined therapy of MTX with disease-modifying anti-rheumatic drugs (DMARDs) is known to increase adverse reactions affect the time to discontinuation of MTX.

The only concomitant DMARD which was found to be associated with MTX withdrawal is Leflunomide as MTX may enhance the adverse reaction of Leflunomide hence increased risk of both hematological and hepatological toxicity 5.

To our knowledge, no studies have been carried out in Asian RA patients to investigate MTX tolerability and its adverse events. Therefore, this study aimed to identify the dose and time to development of adverse drug reactions in a sample of Malaysian RA patients treated with MTX, as well as to assess whether patient’s body mass index (BMI) is related to the maximum tolerated dose (MTD) of MTX.

5 Sánchez, G., Castro, J. S., Al Snih, S., Blanco, L. P., Esteva, M. H., MacGregor, E. G., ... & Rodríguez, M. A. (2007). Durability of

treatment with methotrexate in Venezuelan patients with rheumatoid arthritis. Rheumatology international, 27(6), 531-536.

Section 2: Literature Review

Section 2: Literature Review

• A study conducted by Sanchez et al. on Venezuelan patients with RA revealed that 29.7% of subjects terminated MTX treatment due to the incidence of adverse reactions. 5

• A study conducted by Kinder et al. revealed that 206 RA patients stopped MTX due to the incidence of an adverse reaction. 6

• The average dose on stopping MTX was 10.7mg (range 2.5-25mg), while the probability of patients remaining on MTX treatment 5 years after starting treatment was 0.74. 6

• According to Hoekstra et al., side effects of MTX were associated with BMI. 7

5 Sánchez, G., Castro, J. S., Al Snih, S., Blanco, L. P., Esteva, M. H., MacGregor, E. G., ... & Rodríguez, M. A. (2007). Durability of treatment with methotrexate in Venezuelan patients with rheumatoid arthritis. Rheumatology international, 27(6), 531-536.

6 Kinder, A. J., Hassell, A. B., Brand, J., Brownfield, A., Grove, M., & Shadforth, M. F. (2005). The treatment of inflammatoryarthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology, 44(1), 61-66.

7 Hoekstra, M., Van Ede, A. E., Haagsma, C. J., van de Laar, M. A. F. J., Huizinga, T. W. J., Kruijsen, M. W. M., & Laan, R. F. J. M. (2003). Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Annals of the rheumatic diseases, 62(5), 423-426.

3 . 1 G E N E R A L O B J E C T I V E

3 . 2 S P E C I F I C O B J E C T I V E S

Section 3: Research Objectives

Section 3.1 : General Objective

The main objective of the research is to evaluate time and dose to the discontinuation of MTX due to

adverse events, as well as to investigate the maximum tolerated MTX dose-BMI relationship for RA patients in rheumatology clinic, Hospital Sultan

Ismail, Johor Bahru (HSIJB).

1. To evaluate the time leading to the discontinuation of MTX due to development of adverse reactions in RA patients.

2. To evaluate the proportion of RA patients with adverse reactions attributable to MTX.

3. To evaluate the MTD of MTX where adverse reactions develop, as well as to analyze the relationship and association in between MTD of MTX and occurrence of adverse reactions in RA patients.

4. To evaluate the association between MTD of MTX and BMI in RA patients.

Section 3.2 : Specific Objectives

4 . 1 S T U D Y D E S I G N

4 . 2 S T U D Y P O P U L A T I O N

4 . 3 I N C L U S I O N C R I T E R I A

4 . 4 E X C L U S I O N C R I T E R I A

4 . 5 S A M P L E S I Z E A N D S A M P L I N G M E T H O D

4 . 6 D A T A C O L L E C T I O N F O R M

4 . 7 D A T A C O L L E C T I O N P R O C E D U R E

4 . 8 S T A T I S T I C A L A N A L Y S I S M E T H O D

Section 4: Methodology


4.1 Study Design

Retrospective cohort study based on data extracted from patients’ medical records in Total Hospital Information System (THIS), HSIJB.

4.2 Study Population

Adult RA patient treated with MTX from 2008 until 2012 in rheumatology clinic, HSIJB

4.3 Inclusion Criteria

RA patients who are treated with MTX

4.4 exclusion criteria

None

4.5 Sample size and sampling method

All patients who meet the inclusion criteria in year 2008 to 2012 were included in this study using universal sampling method



4.6 Data Collection Form

Patient’s demographic information as well as clinical characteristics, such as age, gender, ethnicity, height and body weight were extracted.

BMI was calculated for each patient.

THIS was accessed to obtain the data such as duration of treatment with MTX, initial dose of MTX, MTD of MTX, concomitant therapy which include past or current use of other DMARDs or non-steroidal anti-inflammatory drugs (NSAIDs), and adverse effects.


No Age Gender Race Height

(cm)

Body

weight

(kg)

BMI Date

start on

MTX

Initial

dose of

MTX (mg)

Date

stop

on

MTX

Max. dose

of MTX

(mg)

Reason

for

stopping

MTX

Concomitant

therapy

Remarks

4.6 Data Collection Form

4.7 Data Collection Procedure

Patients who were diagnosed with RA and on MTX were identified Total Hospital

Information System (THIS)

The relevant patient’s medical records were retrieved from THIS

Patients who defaulted follow up and with incomplete medical

records were contacted and interviewed to obtain

the required data

All the required data extracted from THIS or through interview were

recorded in the data collection form

4.8 Statistical Analysis Method

• All the extracted data were analyzed using SPSS Software version 16.0

• Categorical results were presented in the form of frequency tables

• Numerical results were expressed as mean ±standard deviation

1. To evaluate the time leading to the discontinuation of MTX due to the incidence of adverse events in RA patients

2 groups

MTX only

MTX + Leflunomide

Kaplan-Meier method

Log-rank test

2. To evaluate the proportion of RA patients with adverse reactions attributable to MTX

Analysis was done in terms of percentage


3. To evaluate the MTD of MTX where adverse reactions develop, as well as to analyze the relationship and association between MTD of MTX and occurrence of adverse reactions in RA patients

Logistic regression

Spearman’s correlation

4. To evaluate the association in between MTD of MTX and BMI in RA patients

o Spearman’s correlation


Section 5 : Results

Section 5: Results

A total of 434 RA patients seek treatment in HSIJB from January 2008 to December 2012.

only 377 patients met the inclusion criteria

111 patients (29.4%) still receiving MTX treatment .

225 patients (59.7%) were previously on MTX but discontinued

40 patients (10.6%) had received Leflunomide + MTX

41 patients (10.9%) were censored patients

Variables Mean ± SD n (%)

Age 55.1 ± 11.1

Height (m) 1.57 ± 0.08

Weight (kg) 64.0 ± 16.8

Gender

Female 318 (84.4)

Male 59 (15.6)

Ethnicity

Malay 132 (35.0)

Chinese 145 (38.5)

Indian 95 (25.2)

Others 5 (1.3)

BMI

< 18.5 31 (8.2)

18.6 – 25.0 161 (42.7)

25.1 – 30.0 104 (27.6)

> 30.1 81 (21.5)

Table 1Baseline characteristics of patients (n = 377).

Variables Mean ± SD n (%)

MTX 337 (89.4%)

MTX + Leflunomide 40 (10.6%)

MTX MTD (mg)

2.5 0 (0.0)5.0 4 (1.1)7.5 43 (11.4)10.0 10 (2.7)

12.5 4 (1.1)

15.0 103 (27.3)

17.5 5 (1.3)

20.0 192 (50.9)

22.5 2 (0.5)

25.0 13 (3.4)

27.5 0 (0.0)

30.0 1 (1.3)

Table 1 (cont)Baseline characteristics of patients (n = 377).

Survival curves showed a steady decrease in continuation of MTX treatment from 70% at 12 months of therapy to 10% at 60 months.

However, using the log rank test, the difference between both curves was statistically insignificant (P = 0.158).

Kaplan-Meier Survival Curve

Figure 1 Figure show Kaplan-Meier survival curves for MTX treatment survival in

patients treated with MTX alone and in patients with MTX plus Leflunomide

MTX + Leflunomide

MTX

Time (months)

Table 2Adverse reactions developed in each RA patients (n = 377).

Adverse reactions Total number of

patients, n (%)

Causing discontinuation

of MTX, n (%)Gastrointestinal 170 (45.1) 138 (36.6)

Abnormal liver enzymes 117 (31.0) 103 (27.3)

Nausea 30 (8.0) 18 (4.8)

Vomiting 11 (2.9) 10 (2.7)

Diarrhea 4 (1.1) 3 (0.8)

Abdominal pain 2 (0.5) 1 (0.3)

Oral ulcer 2 (0.5) 0 (0.0)

Gingivitis 1 (0.3) 0 (0.0)

Others 23 (6.1) 8 (2.1)

Lung 70 (18.6) 46 (12.2)

Cough 57 (15.1) 34 (9.0)

Dyspnea 7 (1.9) 6 (1.6)

Pneumonitis 7 (1.9) 6 (1.6)

Skin 13 (3.4) 8 (2.1)

Pruritus 5 (1.3) 3 (0.8)

Rash 4 (1.1) 1 (0.3)

Skin lesion 4 (1.1) 4 (1.1)

Hematological 11 (2.9) 9 (2.4)

Leucopenia 11 (2.9) 8 (2.1)

Anemia 1 (0.3) 1 (0.3)

Thrombocytopenia 1 (0.3) 1 (0.3)

Fever 4 (1.1) 0 (0.0)

Miscellaneous 78 (20.7) 38 (10.1)

Dose of MTX (mg) Total number of

patients, n (%)

Causing

discontinuation of

MTX, n (%)

2.5 – 5.0 4 (1.1) 0 (0.0)

7.5 – 10.0 53 (14.0) 37 (9.8)

12.5 – 15.0 107 (28.4) 72 (19.1)

17.5 – 20.0 197 (52.2) 100 (26.5)

22.5 – 25.0 15 (4.0) 13 (3.4)

27.5 – 30.0 1 (0.3) 1 (0.3)

Table 3Dose of MTX where adverse reactions develop in each RA patients (n = 377).

Section 5: Results

Table 4

Kolmogorov-Smirnova test for normality

Criteria for normality: p values >0.05

Statistic Sig.

MTD of MTX .299 .000

BMI .089 .000

Table 5 Logistic Regression Analysis of Relationship between the MTD of MTX and occurrence of adverse reactions in RA patients (n = 377).

*OR was found out to be < 1 (0.503)

MTD of MTX ↑, adverse reactions ↓, however this isstatistically insignificant at p > 0.05 (0.069)

Independent

variable

B S.E. Wald df Sig. Exp (B) /

Odds

MTD of MTX

Constant

-.687

1.308

.377

.356

3.318

13.475

1

1

.069*

.000

.503*

3.700

Section 5: Results

Table 6Spearman’s Rho Correlation Analysis of Association between the MTD of MTX and the occurrence of adverse reactions in RA patients (n = 377).

* Spearman result ( rho, r = -0.101) indicate a poor negative

correlation between MTD of MTX and Adverse reactions. This correlation is statistically insignificant. (p, 0.065 > 0.05)

MTD of MTX Adverse reactions

MTD of MTXCorrelation CoefficientSig (2-tailed)N

1.000

.

377

-.101*

.065*

336

Adverse reactionsCorrelation CoefficientSig (2-tailed)N

-.101*

.065*

336

1.000

.

336

Section 5: Results

Table 7Spearman’s Rho Correlation Analysis of Association between the BMI and MTD of MTX in RA patients (n = 377).

MTD of MTX BMI

MTD of MTXCorrelation CoefficientSig (2-tailed)N

1.000

.

377

-.032*

.537*

377

BMICorrelation CoefficientSig (2-tailed)N

-.032*

.537*

377

1.000

.

377

Section 5: Results

* Spearman result ( rho, r = -0.032) indicate a poor negative correlation between MTD of MTX and BMI. This correlation is statistically insignificant. (p, 0.537 > 0.05)

Section 6: Discussion


The survival analysis of continuity of MTX treatment in RA patients follow up under rheumatology clinic HSIJB has shown the likelihood of patients remaining on MTX decrease from 70% at 12 months to 10% at 60 months.

The occurrence of adverse reactions was the most common reason for treatment interruption in most of the patients.

Sánchez et al – Combined therapy with Leflunomide may influence the duration of MTX treatment. 5

However, our study does not show the same trend as Sánchez et al.

Difference between survival curves of MTX alone and MTX plus Leflunomide treatment was showed to be statistically insignificant. P= 0.158

MTX plus leflunomide treatment shows a better survival rate compared to treatment with MTX alone.

This result may be affected by various factors, including patients’ disease state and comorbid conditions, as well as precriber’s prescribing preferences.

Disproportionate number of patients on MTX + Leflunomide (40) vs patients on MTX alone (337) may also affect the accuracy and reliability of the result.

5. Sánchez, G., Castro, J. S., Al Snih, S., Blanco, L. P., Esteva, M. H., MacGregor, E. G., ... & Rodríguez, M. A. (2007). Durability of treatment with

methotrexate in Venezuelan patients with rheumatoid arthritis. Rheumatology international, 27(6), 531-536


In most studies, the occurrence of adverse reactions with MTX treatment was reported to be as high as 80-90%, which cause the discontinuity of treatment in 40-50% patients 8-10

Kinder et al., 206 out of 551 RA patients were reported to discontinue MTX treatment due to the occurrence of adverse reactions 6.

Aletaha et al., 42% of 593 patients discontinued MTX treatment due to the development of adverse reaction 11

In our study, 69.5% of patients had developed adverse reactions, which was the cause for 59.7% of treatment withdrawal.

Although most of the adverse reactions are relatively mild and reversible and discontinuation of treatment may not be necessary, our study found some discontinuation of MTX treatment which were under patients’ request or physician’s order, resulting in the slightly higher rate of MTX withdrawal compared to previous studies

8. Alarcóan, G. S., Tracy, I. C., & Blackburn, W. D. (1989). Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis & Rheumatism, 32(6), 671-676

9. Kremer, J. M., & Lee, J. K. (1986). The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis & Rheumatism, 29(7), 822-831

10. Rau, R., Schleusser, B., Herborn, G., & Karger, T. (1998). Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. The Journal of rheumatology, 25(8), 1485-1492

11. Aletaha, D., Kapral, T., & Smolen, J. S. (2003). Toxicity profiles of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. Annals of the rheumatic diseases, 62(5), 482-486


The European League Against Rheumatism (EULAR) suggest that MTX at higher weekly doses (20-30 mg) is more effective compared to MTX at lower weekly doses (7.5-15 mg) 12

In our study, 84.9% of patients were able to tolerate MTX dose of > 10 mg, where 49.3% of patients discontinued MTX treatment due to the occurence of adverse reactions.

To our knowledge, there are no studies that suggest the relationship between the dose of MTX and the occurrence of adverse reactions. Our study has shown that the association in between MTD of MTX and the occurrence of adverse reactions was statistically insignificant.

The categorization of the MTX dose to ≤ 10 mg and > 10 mg may be one of the reasons affecting the results.

12. Smolen, J. S., Landewé, R., Breedveld, F. C., Dougados, M., Emery, P., Gaujoux-Viala, C., et al. (2010). EULAR recommendations for the management of

rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Annals of the rheumatic diseases, 69(6), 964-975


We observed that RA patients follow up under rheumatology clinic HSIJB were not seemed to be able to tolerate MTX dose as high as patients in European countries.

In the study conducted by Hoekstra et al., hepatotoxicity occurred in 20% of patients with a BMI of 30-35 compared to patients with a BMI of 20-25 (8%) 7 .

However, the above-mentioned study only shows relationship in between adverse reactions and BMI. Study suggesting the definite relationship in between MTD of MTX and BMI could not be found.

In our study, despite statistically insignificant, we found poor negative correlation in between the MTD of MTX and BMI.

The results obtained may be affected by the categorization of the MTX dose which are ≤ 10 mg and > 10mg in our study.

7. Hoekstra, M., Van Ede, A. E., Haagsma, C. J., van de Laar, M. A. F. J., Huizinga, T. W. J., Kruijsen, M. W. M., & Laan, R. F. J. M.

(2003). Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Annals of the

rheumatic diseases, 62(5), 423-426


Section 7: Limitations

Section 7: Limitations

One potential limitation in this study is that MTX discontinuation is based on the judgement of the rheumatologist / supervising doctors and does not imply that thresholds for adverse reactions (e.g. liver function tests and etc.) have been exceeded.

The maximum dose of MTX recorded in patient’s medical record may be the adequate therapeutic dose for some patients which may not represent the actual MTD of MTX for those patients.

Longer follow-up period may be required to represent a clearer picture of MTX treatment survival rate.

This study also does not exclude patients being on combination DMARDs (except patient on MTX+Leflunomide) or having further second-line therapy added in. Hence, other medications predisposing to certain adverse reactions of MTX are not considered.

Section 8: Conclusion

Section 8: Conclusion

This study demonstrated that long term treatment with MTX is unfavorable in our study population, with the probability of patients remaining on MTX 5 years after starting treatment being 10%.

The frequency of adverse reactions and their influence on MTX withdrawal were similar with other studies.

The MTD of MTX varies among individuals and was showed to have statistically insignificant association with adverse reactions and also BMI.

Section 9: Future Research

Section 9: Future Research

A prospective study involving data collection for a longer period of time would be recommended to accurately estimate the survival rate of MTX treatment.

A different categorisation of the MTX dose, e.g. < 15 mg and ≥ 15mg may give a different result as compared to the categorisation in the current study.

The relationship between patient’s BMI and the occurrence of adverse reaction due to MTX treatment may be evaluated.

Further study can be conducted to evaluate the cost-effectiveness of MTX treatment in RA patients as well.

Acknowledgement

Thanks to efforts contributed by:

Dr Loh Yet Lin - HSI Consultant of Rheumatology

Pn. Roslita binti Alivi - HSI Head of Clinical Pharmacy

Unit

Pn. Nur Hazalina Md Salleh – HSI Head of

Ambulatory Pharmacy Unit

Ms Tan Pui San & Dr Yong - Clinical Research Center

HSAJB

Thank you

Documents

A 5 YEARS REVIEW OF RHEUMATOID ARTHRITIS …jknj.moh.gov.my/jsm/day2/OP2 - A 5 Years Review of Rheumatoid... · Section 2: Literature Review • A study conducted by Sanchez et al