Abstract

J

Ś

, J

S

Side Effects of Methotrexate Treatment in Patients

With Rheumatoid Arthritis

Działania niepożądane metotreksatu w trakcie terapii chorych

na reumatoidalne zapalenie stawów

Department of Rheumatology and Internal Medicine Silesian Piasts University of Medicine, Wrocław, Poland

Adv Clin Exp Med 2008, 17, 4, 387–394 ISSN 1230−025X

ORIGINAL PAPERS

© Copyright by Silesian Piasts University of Medicine in Wrocław

Abstract

Background.Methotrexte (MTX) is the most commonly prescribed disease−modifying anti−rheumatic drug. Howe− ver, toxicity is an important drawback of MTX therapy.

Objectives.The objective of this study was to determine the long−term safety of low−dose MTX in the treatment of rheumatoid arthritis (RA) and to evaluate the spectrum, severity, and frequency of adverse effects in clinical practice.

Material and Methods.One hundred forty patients with RA (119 women, 21 men) treated with MTX who were hospitalized in rheumatology departments or were rheumatologists’ outpatients between 2002 and 2007 were included in the observation group. Patients who had been taking MTX for at least 6 months or had developed ad− verse reactions earlier were analyzed. The median age of the RA patients was 54 years. The duration of RA ranged from 0.3−35 years and the median dose of MTX used was 15 mg/week.

Results.One hundred five patients had a complete laboratory evaluation and clinical examination. Adverse effects (AEs) occurred in 54 patients (51.4%), but only 20 (19%) of the patients discontinued MTX permanently. Five stopped MTX therapy temporarily and four had a lower dose of MTX but did not stop the treatment completely. The median time after onset was six months. During the study the most common adverse events were gastrointe− stinal symptoms in 33 patients (31%). In this patient population the most common side effects leading to MTX withdrawal were hepatotoxicity and pulmonary and hematological toxicity. The potential risk factors for AEs we− re age > 65 yr and polypharmacy.

Conclusion.Side effects were often observed in the group of patients treated with MTX, but they rather rarely cau− sed cessation of therapy. The side effects occurred more often in older patients. Most gastrointestinal symptoms de− creased after dividing the dose and after changing from oral to parenteral administration (Adv Clin Exp Med 2008, 17, 4, 387–394).

Key words:methotrexate, polyarteritis rheumatoidea, toxicity.

Streszczenie

Wprowadzenie. Metotreksat (MTX) jest najczęściej stosowanym lekiem modyfikującym przebieg choroby w le− czeniu reumatoidalnego zapalenia stawów (r.z.s.). Jednymi z najczęstszych powodów zaprzestania terapii są dzia− łania niepożądane występujące w czasie terapii.

Cel pracy. Ocena występowania objawów niepożądanych podczas terapii MTX u pacjentów z r.z.s. leczonych w poradni reumatologicznej lub hospitalizowanych na oddziale reumatologicznym.

Materiał i metody. 140 pacjentów (119 kobiet i 19 mężczyzn) oddziału i przychodni reumatologicznej chorują− cych na r.z.s. leczonych MTX w latach 2002–2007 było obserwowanych głównie pod kątem występowania dzia− łań niepożądanych. Końcowa analiza została przeprowadzona u chorych, którzy co najmniej przez 6 miesięcy by− li leczeni MTX lub wcześniej wystąpiły u nich działania niepożądane. Średni wiek chorych wynosił 54 lata. Czas od rozpoznania r.z.s. wynosił 4 miesiące – 35 lat. Średnia dawka MTX wynosiła 15 mg raz w tygodniu.

Although new disease−modifying anti− rheumatic drugs (DMARDs) have been intro− duced, MTX is still considered the gold standard in rheumatoid arthritis (RA) therapy. When low doses of MTX are used, adverse effects often occur. These effects usually emerge within the first six months of therapy. Twenty to thirty percent of patients discontinue treatment within the first year of therapy. The reasons are usually adverse effects and, less often, no therapeutic effect. The side− effect rates during long−term therapy reported by different authors fall between 37 and 96%. Among the factors predisposing to MTX toxicity are higher age, renal and hepatic impairment, drugs affecting MTX’s pharmacokinetics, alcohol abuse, and dia− betes (in some studies) [1, 2].

Material and Methods

One hundred forty patients with RA (119 women and 21 men) who were hospitalized in rheumatology departments or were rheumatolo− gists’ outpatients between 2002 and 2007 were included in the prospective observational study. All met RA diagnostic criteria according to the ARA guidelines of 1987. The analysis was performed on patients who had been taking MTX for at least six months or had developed adverse reactions earlier. The mean age was 54 years. The time since RA diagnosis ranged from 3 months to 35 years. The MTX doses were 10–20 mg once weekly, the mean dose being 15 mg a week. MTX was used alone in 75 patients and in combination with other drugs in 30 patients. It was combined most often with sul− fasalazin (9 patients), cyclosporine (8), and lefluno− mide (6). Sixty−four patients (61%) used glycocor− ticosteroids (2.5–15 mg prednisolone) as part of their therapeutic regimen. Fifty−nine patients (56%) received non−steroidal anti−inflammatory drugs (NSAIDs). All patients received 5–15 mg of folic acid weekly. The DAS28 value was used for RA activity and disease course assessment.

Results

The final analysis was performed on 105 patients who had been taking MTX for at least six months or had developed adverse reactions

earlier. Not all the clinical and laboratory data were available for the other 35 patients because they did not come regularly to control visits. Adverse effects were seen in 54 (51.4%) patients and in 20 (19%) cases they were reason for drug discontinuation. The mean time of onset of adverse effects was 4 months and varied from sev− eral hours to 42 months. The most frequent adverse effects were gastrointestinal symptoms and hematological abnormalities. The most com− mon reasons for discontinuation were hematologi− cal complications, i.e. leukopenia in two patients and pancytopenia in two patients, liver enzyme elevation in four, and interstitial lung diseases in four cases (Table 1). Eight patients (7.6%) devel− oped life−threatening adverse effects, including leukopenia in two cases, pancytopenia in two cases, pneumonia in two cases, and acute leukemia and breast cancer in one case each. Three patients (2.8%) died during the follow−up period. The causes of death were respiratory and circulatory failure, leukopenia associated with bacterial pneu− monia, and acute leukemia. All the patients who died were over 70 years old and had highly active disease when MTX was introduced (DAS28>6) and high levels of rheumatoid factor and anti−cit− rulline antibodies. Two of them suffered addition− ally from ischemic heart disease and hypertension. All received at least five other drugs in addition to MTX, including NSAIDs and steroids. The patient with respiratory and circulatory failure died three months after MTX discontinuation. She had been receiving steroids then. The patient who died of pneumonia had a history of prior pneumonia. The role of MTX in the above deaths could not be clearly discerned.

Gastrointestinal−related adverse effects were found in 33 patients (31%). These included most often dyspepsia and nausea, which occurred on the day of drug administration and lasted from several to 72 hours. There was one case of diarrhea the day after MTX administration. These effects were mild and only in five cases were they reasons for discontinuation. Elevated liver enzymes were found in eight patients (7.6%). In four of them the ALT values normalized in the control examination and they were allowed to continue on MTX. In the other four (three of whom were over 65 years old), the liver enzyme elevation warranted therapy dis−

niami niepożądanymi, które zmusiły do zaprzestania terapii były: wzrost enzymów wątrobowych, powikłania płuc− ne i hematologiczne. Wzrost częstości objawów niepożądanych był związany z wiekiem powyżej 65 lat i stosowa− niem jednocześnie wielu leków.

Wnioski.Objawy niepożądane występują często w czasie leczenia MTX, ale relatywnie rzadko są powodem za− przestania terapii. Częściej występują one w starszych grupach wiekowych. Większość działań niepożądanych ze strony przewodu pokarmowego zmniejszała się po podzieleniu dawki na dwie części w odstępach 12−godzinnych lub po zmianie podawania z drogi doustnej na pozajelitową (Adv Clin Exp Med 2008, 17, 4, 387–394).

continuation. All four used at least four other drugs in addition to MTX. One patient developed liver enzyme elevation > 2 ×ULN (upper limit of normal) after two months of therapy and the others after 16, 20, and 24 months of therapy. All patients denied alcohol abuse.

Hematological complications (leukopenia and thrombocytopenia) occurred in four patients (3.8%): in three patients who were over 65 years of age and in one patient who was 53. In one case the onset of adverse effects was after 1 month and in the others after 14, 24, and 42 months. All used at least five other drugs in addition to MTX. The MTX dose varied from 15–25 mg/week. The patients with pancytopenia also revealed signs of vasculitis, and one patient also had renal failure and amyloidosis. Three patients developed pneumonia or bronchitis, of whom one died of respiratory and circulatory failure secondary to pneumonia.

Pulmonary complications occurred in six patients (5.7%). In four of them, additional exam− inations revealed signs of restrictive respiratory failure and decreased partial pressure of oxygen in the blood. MTX therapy was discontinued due to interstitial changes and fibrosis found in chest X−rays and computer tomography. Three patients had histories of smoking and prior bronchitis and pneumonia.

In a 70−year−old patient, acute leukemia occurred after four months of therapy. She initial− ly had highly active disease (DAS28 = 7.91), a high anti−CCP level of 82.76 RU/ml, and ane− mia. In addition, she had ischemic heart disease and osteoporosis with pathological fractures. The patient died after two months despite therapy. Breast cancer was found in a 65−year−old patient who had been using 15 mg of MTX once weekly for four years. Mastectomy with subsequent chemo− and radiotherapy was commenced.

MTX therapy is known to increase suscepti− bility to infections. One patient from the study group developed herpes zoster. One dose of MTX was then skipped and acyclovir was introduced. After resolution, two doses of MTX 7.5 mg were administered during the two subsequent weeks and then a 15−mg dose once weekly was reintroduced. In four patients (3.8%) the so−called post−dosing reaction occurred within 24 hours following MTX administration, which included muscular pains, stiffness, fatigue, and drowsiness. These reactions did not require cessation of therapy. In 6 patients (5.7%) at least two adverse effects occurred simul− taneously, most often dyspepsia and headaches or dyspepsia and increased hair loss.

The influence of comorbidities and the use of other drugs on the development of adverse effects was also analyzed (Tables 2, 3). Adverse effects occurred more often in patients with more active

disease, amyloidosis, vasculitis, or ischemic heart disease. No increased cumulative adverse effect rate was found when a combination of two DMARDs was used in the observed group. Elevated liver enzymes were found in two patients who were also using leflunomide and pancytope− nia occurred after a month of therapy in one patient who was taking cyclosporine. There were similar percentages of patients on NSAIDs and steroids in both groups with and without adverse effects. All the patients who developed life−threat− ening adverse effects had been using NSAIDs and steroids concomitantly. Sixty percent of the patients who presented increased rates of adverse effects and 69% of those who discontinued MTX therapy due to adverse effects had been using at least four other drugs. The mean number of drugs taken by patients without adverse effects was 3.7 and by those with adverse effects 4.3.

In the patients on MTX, the effects of age, duration of disease, stage of RA, and disease activ− ity on the occurrence of adverse effects were deter− mined. The cumulative number of adverse effects was analyzed due to the limited population size. Adverse effects were found to occur significantly more often in elderly patients and those with more active disease. The mean age of the patients who discontinued therapy due to adverse effects was 63 and of those who continued on the drug 56 years. Adverse effects occurred in 65% of the patients with DAS28 > 5.1 and in 39% with DAS28 < 5.1 at the beginning of MTX therapy.

Discussion

Long−term therapy with MTX is possible thanks to its high effectiveness and relatively good tolerability. According to various authors, 55–81.8% of patients continued treatment after 2 years, 46–62% after 5 years, and 30% after 10 years [1, 2]. In a study by Wluka, 50% of 460 patients continued on MTX for 12 years [3]. Thanks to the good effectiveness/toxicity ratio of MTX, patients are treated with MTX longer than with other DMARDs. In the current study the occurrence of adverse effects in patients seen in everyday clinical practice was analyzed. In most studies on DMARD−related adverse effects the data include some selected groups of patients due to requirements of compliance with the criteria of the study protocol. The analysis of adverse effects is very important in clinical practice for it may be useful to both physicians and patients.

effects during MTX therapy vary from 37 to 96%, while serious adverse effects occur in 8–30% of patients [4, 5].

The most frequent adverse effects accompany− ing MTX usage are GI related. They occur in 20–70% of patients within the first two years of therapy. As in the study by Hoekstra, the GI−asso− ciated adverse effects in the present study were more frequent in obese patients and in those with a prior history of GI adverse effects [6]. Such a high rate of GI adverse effects is explained by MTX’s effect on quickly dividing mucosal cells. It was determined that various plasma levels of MTX are required to inhibit DNA synthesis in var− ious cells (10 nM for bone marrow cells and 5 nM for gastrointestinal mucosal cells). This fact is an explanation for the higher prevalence of adverse effects related to GI mucosa damage than myelo− suppressive effects during low−dose MTX therapy [7]. All the patients of the present study had been receiving folic acid supplementation, the role of which in reducing the rate of GI−related adverse effects was confirmed in several studies [8, 9]. It should be pointed out that gastrointestinal ailments occur in many patients regardless of the adminis− tered therapy and may be associated with the use of other drugs, especially NSAIDs. Dyspepsia, nausea, and abdominal pain have been found even in 25% of patients receiving placebo [10]. In most of the patients of the present study who developed GI adverse effects, these could be relieved by dividing the dose into two parts administered at 12−hour intervals and, in six patients, by switching from the oral to a parenteral route. In addition to the intramuscular form, subcutaneous injections are available. There are fewer GI−related adverse effects after administration by subcutaneous injec− tion than by the oral route.

The elevation of liver enzyme levels demand− ing therapy discontinuation occurred more fre− quently in patients over 65 years old who had been taking at least four other drugs, including steroids and NSAIDs. Two of them had been concomitant− ly receiving leflunomide. The mechanism behind hepatic fibrosis during MTX therapy is not fully understood. It is thought to be related more to a toxic than to an immunoallergic effect. However, not all authors have confirmed the effect in their studies. In a 3.5−year follow−up of 40 patients, Fathi found no correlation of the adverse effects of MTX with its plasma and hepatic levels, which were stable after 1 and 3.5 years of therapy [11]. In three patients in whom enzyme elevation occurred after at least 18 months of therapy, the toxic effect might have dominated, whereas in one patient who presented elevated enzymes as soon as after 2 months, the immunoallergic effect might have

lar volume (MCV), but also periodic checking of creatinine levels, especially in the elderly. Bone marrow function usually gradually returns to nor− mal within two weeks after MTX discontinuation,

which in fact occurred in three out of four of the patients of the present study. The most important prognostic factor in patients with pancytopenia is the rate of leukopenia resolution [18]. A frequent

Table 1.Adverse events during methotrexate therapy

Tabela 1.Działania niepożądane w czasie terapii metotreksatem

Kind of adverse events Total (Łącznie) Causing withdrawal of therapy

(Rodzaj działania niepożądanego) (N = 59) (Powodujące zaprzestanie terapii) n (% of all 105 patients)* (N = 20)

n (% of all 105 patients)

Gastrointestinal (żołądkowo−jelitowe) 33 (31) 9 (8.6)

nausea and vomiting (nudności i wymioty) 12 (11.4) 2 (1.9)

abdominal pain, (bóle brzucha) 12 (11.4) 2 (1.9)

diarrhea (biegunka) 1 (0.9) 1 (0.9)

LFT abnormalities (wzrost aktywności aminotransferaz) 8 (7.6) 4 (3.8)

Hematological (hematologiczne) 4 (3.8) 4 (3.8)

low neutrophil count (leukopenia) 2 (1.9) 2 (1.9)

pancytopenia (pancytopenia) 2 (1.9) 2 (1.9)

Pulmonary: pneumonitis, pulmonary fibrosis 6 (5.7) 4 (3.8) (pulmonologiczne: zapalenie płuc, zwłóknienie płuc)

Headache (bóle głowy) 5 (4.7) 0

Alopecia (łysienie) 4 (3.8) 0

Post−dosing reaction: fatigue and myalgia 4 (3.8) 0

(reakcje po podaniu leku: zmęczenie, bóle mięśni)

Malignancy (choroby nowotworowe) 2 (1.9) 2 (1.9)

MTX−associated nodulosis (guzki pometotreksatowe) 1 (0.9) 0

LFT – liver function test.

* In 6 patients (5.7%) at least two adverse effects occurred simultaneously, most often dyspepsia and headaches or dyspep− sia and increased hair loss.

* U 6 chorych (5,7%) wystąpiły co najmniej dwa działania niepożądane, najczęściej dolegliwości dyspeptyczne były skoja− rzone z bólami głowy lub zwiększoną utratą włosów.

Table 2.Major comorbidity in patients receiving low−dose methotrexate

Tabela 2.Najczęstsze choroby towarzyszące u chorych leczonych małymi dawkami metotreksatu

Major comorbidity Patients with Patients without adverse

(Najczęstsze choroby towarzyszące) adverse events events

(Pacjenci z działaniami (Pacjenci bez działań niepożądanymi) niepożądanych)

N = 54 N = 51

Hypertension (nadciśnienie) 21 22

Hyperlipidemia (hiperlipidemia) 16 19

Anemia (niedokrwistość) 10 8

Chronic gastritis (przewlekłe zapalenie błony śluzowej żołądka) 12 10

Coronary arterial disease (choroba niedokrwienna serca) 9 3

Obesity (otyłość) 5 5

Diabetes (cukrzyca) 4 5

Vasculitis (zapalenie naczyń) 5 0

Renal insufficiency (niewydolność nerek) 2 2

sign which may speak for the presence or danger of leukopenia is oral mucositis; however, this sign was absent in the patients of the present study.

The danger of infection is difficult to assess due to the fact that infections are more frequent in the course of RA itself, and steroid therapy, which favors infections, is also commonly used.

MTX is not yet considered a carcinogen. There were reports of lymphomas and cancers of the skin, lung, larynx, throat, esophagus, pancreas, prostate, and urinary bladder in patients on MTX; however, the coexistence of two diseases cannot be ruled out. The assessment of lymphoprolifera− tive disease morbidity is difficult due to their enhanced rate in the course of RA. Some cases of EBV−related lymphomas which resolved after dis− continuation of MTX have been reported [20]. In the present study there was one case of breast can− cer and one case of acute leukemia.

Disorders of the CNS may cause headaches and dizziness, memory deterioration, generalized weak− ness, drowsiness, chills, and depression. This may be related to an increase in the adenosine level in the cerebrospinal fluid. Different authors report incidences of CNS adverse events from 1 to 30% when using low doses of MTX [21]. It is very diffi− cult to prove that MTX is responsible for such non− specific and common adverse effects as headaches, depression, or memory gaps. These symptoms are commonly found among healthy people, and even more commonly among patients with RA. In the group of the present study they were present in five patients, but the headaches were mild and did not require therapy discontinuation.

In 1–10% of patients, a post−dosing reaction may develop after MTX administration. This is a reaction which begins within 24 hours after drug intake and often occurs after increasing the MTX

Table 3.Effects of significant concomitant drugs on patients receiving MTX

Tabela 3.Wpływ ważniejszych innych stosowanych leków na częstość działań niepożądanych u chorych leczonych MTX

Significant Patients with adverse events (AEs) Patients without

concomitant drugs (Pacjenci z działaniami niepożądanymi) adverse events

(Ważniejsze inne (Pacjenci bez dzia−

stosowane leki) łań niepożądanych)

(N = 51) n (%) withdrawal of no withdrawal total (łącznie)

MTX due to AEs of MTX due to AEs (N = 54) (n%) (odstawili MTX) (nie odstawili MTX)

(N = 18) n (%) (N = 36) n (%) Low−dose prednisolone

(Niskie dawki prednizolonu) 16 (88) 20 (55) 36 (66) 28 (54)

Salazosulfapyridine

(Sulfasalazyna) 0 1 (2.7) 1 (1.8) 8 (15)

Cyclosporin A

(Cyklosporyna A) 1 (5.5) 1 (2.7) 2 (3.7) 6 (11)

Leflunomide

(Leflunomid) 1 (5.5) 2 (5.5) 3 (5.5) 3 (5.8)

Chloroquine

(Chlorochina) 1 (5.5) 2 (5.5) 3 (5.5) 0

Infliximab

(Infliksimab) 1 (5.5) 1 (2.7) 2 (3.7) 2 (3.9)

Non−steroidal anti− 15 (83) 16 (44.4) 31 (57) 28 (54)

inflammatory drugs (Niesteroidowe leki przeciwzapalne)

Paracetamol 4 (22) 2 (5.5) 6 (11) 5 (9.8)

Tramadol 5 (27.7) 5 (5.5) 10 (18) 10 (19)

Diuretics

(Leki moczopędne) 2 (11) 5 (13.8) 7 (13) 8 (15)

ACE blockers

(Inhibitory ACE) 6 (33) 6 (16.6) 12 (22) 11 (21)

Sulfonylocarbamide derivations

dose [21]. The present authors managed to allevi− ate these reactions by dividing the dose into two parts taken at 12−hour intervals, and two patients started taking MTX on weekends.

Hair loss occurs in 2–6% of patients, but in long−term follow−up as many as one−third may complain of a decrease in hair density. However, in a study on a large group, less than 0.5% patients treated with low doses of MTX experienced signif− icant balding [22]. In the present study this prob− lem involved four patients, two of whom had their dosage reduced from 17.5 mg to 12.5 mg due do extensive hair loss, with good result. There is no effective therapy for hair loss so far. Hair condi− tioners which increase hair strength should be used along with folic acid supplementation; in some cases, lowering the MTX dose may be considered. During MTX therapy, so−called “methotrexate− induced nodules” may emerge or grow. These nod− ules affect as many as 8–11% of patients. They are localized mainly on the hands and feet, but also on the concha of the ear and sometimes even on the penis. They may decrease in size after MTX with− drawal and reemerge after reintroduction. They do not require therapy cessation. The histopathological picture is the same as classic rheumatoid nodules. The etiology of these nodules is not clearly estab− lished. An increased level of adenosine during MTX therapy may be responsible, since it stimulates the formation of giant multinucleate cells. Unfortu− nately, there is no effective treatment. In therapy, colchicine is sometimes used (which inhibits the for− mation of giant multinucleate cells in vitro) or hydroxychlorochine [23, 24]. In the present study

they affected one patient after 12 months of therapy, but MTX was continued due to very good clinical response, the dose being decreased instead.

In the current study, attempts were made to identify risk factors for the occurrence of adverse effects. Among the observed patients, adverse events were more common in persons over 65 years old. This is consistent with other authors who also reported more adverse effects in the elderly on MTX in their studies [1, 25]. Among other causes, impaired renal function in this group, which is associated with increased drug toxicity, may play a role. Adverse effects after MTX usage occurred significantly more often in those with more active disease.

Conclusions

Summarizing the observations of this study, it is concluded that MTX is quite well tolerated. The study by Kinder drew similar conclusions; he also estimated the likelihood of continued five−year MTX therapy to be 0.74 [1]. Similarly, Wluka, who had been observing 460 RA patients treated with MTX, demonstrated that 50% of them had contin− ued MTX therapy for at least 12 years [3]. To avoid potential adverse events one should avoid polypragmasia, and patients above 65 years old who take at least four other drugs concomitantly should be monitored closely. In case of GI adverse effects the dose should be divided into two parts, administered at 12−hour intervals, or the drug route should be switched from oral to parenteral.

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Address for correspondence:

Jerzy Świerkot Wrocławska 36A

55−012 Żerniki Wrocławskie Poland

Tel.: +48 71 734 33 00, +48 601 41 83 85 E−mail: [email protected]

Conflict of interest: None declared