Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that is caused by chronic inflammation of the joints or the synovial membrane surrounding the joints [1]. Chronic inflammation can also lead to cardiovascular and pulmonary complications [2]. RA affects between 0.5 and 1 % of adults in the developed world of all ages, but typically targets those between 20 and 45 years of age [3, 4]. Women are three times more likely to develop RA as compared to men [5]. Genetic factors are also involved in the pathogenesis of RA [6].

To acquire substantial clinical remission, it is mandatory to start drug therapy soon after the diagnosis and to enhance the treatment with the disease activity [7, 8]. The Treat-to-Target Recommendations are meant to outline the strategies to reach optimal outcomes of RA [9–11].

In countries like Pakistan, most of the RA patients have access to oral methotrexate (MTX) drug therapy only. It is therefore imperative to study the development of intolerance to MTX among RA patients and its effects on drug compliance.

In the treatment of RA, the two main classes of medications are analgesics such as NSAIDs and disease-modifying anti rheumatic drugs (DMARDs). DMARDs are classified as synthetic DMARDs, e.g. methotrexate, sulfasalazine and leflunomide and newer biologic DMARDs [12].

MTX is the most important and useful DMARD, hence is usually the first-line treatment as it slows or halts the progress of the disease [13]. It must be remembered that MTX has certain side effects which can impair the quality of life [14]. Most common side effects are pertaining to gastrointestinal (GI) tract which are reduced with folic acid supplementation. Anticipatory and associative symptoms can hamper with compliance of the patient to long-term treatment. There are two main mechanisms which play a role in MTX-related GI intolerance. The epithelial cells located in the oral cavity and in the intestine are sensitive to MTX irrespective of folate deficiency. The gastrointestinal epithelium becomes more sensitive with the passage of time due to more and more accumulation of MTX [15]. The second mechanism of MTX intolerance is through stimulation of chemotactic trigger zone (CTZ).

The MISS questionnaire is used as a tool for early detection of MTX intolerance and change of treatment at an early stage to prevent progression of RA.

Materials and methods

One hundred fifty adult females suffering from RA were selected through non-probability sampling for the descriptive study in the Female Rheumatology Department Fauji Foundation Hospital, Rawalpindi, Pakistan, in 2014. All the subjects were diagnosed cases of RA according to the 1987 ACR criterion [16]. All were taking oral MTX as per protocol. Exclusive history was taken to rule out any current or previous drug intolerance [17]. Written/informed consent was taken from all patients. Demographic data constituting of name, sge and duration of MTX use was acquired. Information was secured about the weekly dose of MTX utilized along with parallel use of DMARDs, glucocorticoids, NSAIDs, COX 2 inhibitors, gastroprotective agents and any other medication the patient was taking [18]. All the subjects were using folic acid supplementation with oral MTX.

The MISS questionnaire is a validated tool supported by the American College of Rheumatology and published in 2011 [19]. The MISS Questionnaire embodies five elements: abdominal pain, nausea, vomiting, fatigue and behavioural symptoms. Each symptom is evaluated after intake of MTX, several hours to 1 day before taking MTX (anticipatory) and on thinking about MTX (associative). Behavioural symptoms constitute of restlessness, crying and irritability on taking MTX advancing on to refusal to take MTX [20]. The amplitude of each element was ranked from 0 to 3 being no complaint, mild, moderate and severe respectively. A cut-off score of 6 and above ascertained intolerance. Data collected was entered in SPSS version 21 and analysed. The frequency and percentage for the respective symptoms and the severity of each symptom with respect to MISS score was calculated and tabulated. Confidence interval was kept at 95 %. Null hypothesis was streamlined, accepted and rejected with relation to the results deduced from chi-square test, correlation, statistical significance and correlation coefficient.

Results

Out of the 150 subjects, 50 had MTX intolerance with a MISS score of 6 or above. Thus, the percentage of intolerance came out to be 33.3 % (Fig. 1). The symptoms were then individually analysed to scrutinize their respective potential prevalence and contribution to the intolerance. The results unfolded 44 % of the subjects to have behavioural symptoms followed by abdominal pain 34.66 %, nausea 34 % and fatigue 31.1 %. Only 11.33 % of the subjects had complaint of vomiting (Fig. 2). Frequency and percentage of each element according to severity were calculated as concluded in Table 1.

Fig. 1
figure 1

Percentage of MTX tolerance and intolerance in RA subjects. Intolerance is calculated with patients having a MISS score of 6 or above in the study sample

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Fig. 2
figure 2

Prevalence of intolerance symptoms in RA patients. Figure shows quota of subjects with each symptom diagnostic of intolerance to MTX

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Table 1 Frequency of symptoms prevalent in rheumatoid arthritis subjects graded in the order of severity
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About 6.6 % of the patients were using DMARDS along with MTX. The effect of use of leflunomide and sulfasalazine on MTX intolerance along with statistics of those patients who were not using any DMARDs other than MTX is shown in Fig. 3.

Fig. 3
figure 3

Effect of concurrent use of other DMARDS with MTX on MTX intolerance. p = 0.18 by chi-square test

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The subjects under study were using four different weekly strengths of oral MTX. Those using the highest weekly dose of MTX (20 mg) had supreme intolerance prevailing in 46.2 %. The frequency of intolerance decreased with a decrease in weekly dose being a minimum of 20 % with 7.5 mg (Fig. 4).

Fig. 4
figure 4

Correlation of MTX intolerance with weekly dose utilized to be directly proportional. p = 0.01 by chi-square test with positive correlation coefficient

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Discussion

RA is an irreversible disease, so the main focus of management is to improve the quality of life [21]. The first line of treatment used in RA is MTX.

In developing countries like Pakistan, most of the biologics are not accessible to the general population. So most of the rheumatologists as well as general practitioners stick to conventional DMARDs only. Among them, MTX is the most commonly used. As MTX is easily available, has good tolerance and is relatively inexpensive, its common GI side effects are being neglected. The treat to target approach for RA does not aim for remission or low disease activity only but also for improvement of quality of life. If common side effects are not monitored, patients either stop the medicine themselves without consulting their physicians or start taking complementary and alternative medicine (CAM). So early detection of these side effects is mandatory.

To overcome this hazard and to estimate the level of intolerance in a patient using MTX, MISS has been formulated and validated to assess the prevalence of this intolerance in RA patients [19].

This questionnaire was validated for juvenile idiopathic arthritis patients (JIA). In this study, MTX intolerance was found to be 50.5 % by using the MISS questionnaire.

A similar study carried out among rheumatoid and psoriatic arthritis patients showed 11 % of the patients to be intolerant to MTX out of which 81.3 % had behavioural symptoms, 56.3 % had nausea, 46.9 % had abdominal pain and 31.3 % had vomiting [22].

We used this questionnaire in adult RA patients who were taking MTX in order to assess their type of intolerance. Nevertheless, the MISS questionnaire should be validated for RA patients as well. Once validated, it can be used in routine practice.

This is the first study being done in Pakistan using a standard questionnaire to assess MTX intolerance in RA patients. A similar study was done in the Rheumatology Department of Pakistan Institute of Medical Sciences Hospital, Islamabad, using the same questionnaire in JIA patients showing MTX intolerance of 40 % [23]. Our evaluation points out that 33.3 % of the subjects visiting the Female Rheumatology Department exhibited MTX intolerance according to the MISS questionnaire. Out of which, the most recurring symptom was behavioural, i.e. 44 %, and least noticeable being vomiting, i.e. 11 %. This indicates that one third of the patients using MTX suffer from intolerance. Further stressing on the point, one third of the RA patients using MTX are prone to become non-compliant. In clinical practice, the anticipatory and associative symptoms are usually not asked for. These symptoms if severe can affect the patient’s quality of life or make them abandon the proper treatment. Therefore, all patients using MTX should be monitored and inquired about any symptoms pertaining to intolerance [24].

The study has also brought to our notice that the use of other DMARDs has no effect on the MTX intolerance. A total of 6.6 % of the women with intolerance were consuming DMARDs in conjunction with MTX. The verdict goes in favour of null hypothesis affirming no association of MTX intolerance to the collateral use of DMARDs (p = 0.18).

Those using the highest weekly dose of MTX (20 mg) had supreme intolerance prevailing in 46.2 %. The frequency of intolerance decreased with a decrease in weekly dose being a minimum of 20 % with 7.5 mg. The result goes against null hypothesis corroborating a directly proportional association of MTX intolerance to the weekly dose taken (p = 0.013).

Our study had certain limitations. It was performed on a small sample size of 150 patients in the Female Rheumatology Department of Fauji Foundation Hospital. Therefore, no statistical data to reveal the prevalence of intolerance in male counterparts is available. All patients were using oral MTX so a comparative analysis of intolerance between oral and parenteral use of MTX could not be observed. As all the patients in the study sample were using folic acid, thus the increased level of intolerance due to folic acid deficiency could not be registered. As the patients were not inquired about the relation of symptoms with meal, hence a correlation of MTX intolerance before and after intake of meal was not seen.

To summarize, one can conclude that MTX intolerance has moderate prevalence in RA patients and if left untreated and undetected, it can reduce the compliance for MTX. Counselling should be inculcated in practice for intolerance to MTX as the most prevalent symptom is associative and apt rehabilitation should be done for it. The prescribing dose of MTX should be a matter of concern as higher dosage leads to more intolerance.