Joint Bone Spine 73 (2006) 388–395
`
`Original article
`
`http://france.elsevier.com/direct/BONSOI/
`
`Methotrexate therapy for rheumatoid arthritis:
`clinical practice guidelines based on published evidence and expert opinion ☆
`
`Stephan Pavy a, Arnaud Constantin b, Thao Pham c, Laure Gossec d, Jean-Francis Maillefert e,
`Alain Cantagrel b, Bernard Combe f, René-Marc Flipo g, Philippe Goupille h, Xavier Le Loët i,
`Xavier Mariette j, Xavier Puéchal k, Thierry Schaeverbeke l, Jean Sibilia m, Jacques Tebib n,
`Daniel Wendling o, Maxime Dougados d,*
`
`a Service de rhumatologie A, CHU Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France
`b Service de rhumatologie, CHU Rangueil, Toulouse, France
`c Service de rhumatologie, CHU de la Conception, Marseille, France
`d Service de rhumatologie B, CHU Cochin, 27, rue du Faubourg, Saint-Jacques, 75014 Paris, France
`e Service de rhumatologie, CHU de Dijon, Dijon, France
`f Service d’immunorhumatologie, CHU Lapeyronie, Montpellier, France
`g Service de rhumatologie, CHRU Roger-Salengro, Lille, France
`h Service de rhumatologie, CHU de Trousseau, Tours, France
`i Service de rhumatologie, CHU de Bois-Guillaume, Rouen, France
`j Service de rhumatologie, CHU de Bicêtre, Le Kremlin Bicêtre, France
`k Service de rhumatologie, centre hospitalier, Le Mans, France
`l Service de rhumatologie, CHU Pellegrin–Tripode, Bordeaux, France
`m Service de rhumatologie, CHU Hautepierre, Strasbourg, France
`n Service de rhumatologie, CHU Lyon-Sud, Pierre-Bénite, France
`o Service de rhumatologie, CHU Jean-Minjoz, Besançon, France
`
`Received 5 January 2006; accepted 25 January 2006
`Available online 23 March 2006
`
`Abstract
`
`Objectives: To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based ap-
`proach and expert opinion.
`Methods: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations.
`Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French
`Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of
`rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement
`among experts were specified.
`Results: The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/
`week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to
`methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3:
`When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or
`subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present,
`there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investiga-
`tions that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels,
`serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C
`
`☆ This project was supported by a grant from Abbott France.
`* Corresponding author.
`E-mail address: maxime.dougados@cch.ap-hop-paris.fr (M. Dougados).
`
`1297-319X/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
`doi:10.1016/j.jbspin.2006.01.007
`
`Medac Exhibit 2029
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
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`389
`
`and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests
`with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring metho-
`trexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained
`at least once a month for the first 3 months then every 4–12 weeks; 7: Folate supplementation can be given routinely to patients treated with
`methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8:
`In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should
`evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immedi-
`ately.
`Conclusion: Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice
`uniformity and, ultimately, to improve the management of RA.
`© 2006 Elsevier SAS. All rights reserved.
`
`Keywords: Rheumatoid arthritis; Methotrexate; Recommendations
`
`1. Introduction
`
`2.2. Selection of questions
`
`Methotrexate is used by most rheumatologists as the first-
`line disease-modifying antirheumatic drug for patients with
`rheumatoid arthritis (RA). This choice rests on the good effec-
`tiveness and safety profile of the drug, its low cost, and the
`availability of long-term follow-up data on RA patients given
`methotrexate [1,2]. In addition, recent data indicate that meth-
`otrexate can produce substantial survival benefits by reducing
`cardiovascular mortality in patients with RA [3].
`However, 20 years after the first randomized controlled
`trials (RCTs) demonstrated that methotrexate as monotherapy
`was effective in decreasing disease activity in RA [4,5],
`15 years after the first RCTs established its ability to slow
`the progression of structural joint damage [6,7], and nearly
`10 years after the first RCTs of the efficacy and safety of meth-
`otrexate combined with other conventional disease-modifying
`antirheumatic drugs [8,9] or biotherapies [10–12], considerable
`variability continues to exist in the modalities of methotrexate
`use in RA, most notably regarding starting and maximal do-
`sages, dosage adjustment, criteria used to monitor patients in
`daily practice, and the use of folate supplementation.
`The objective of this work was to develop clinical practice
`guidelines for the use of methotrexate in patients with RA,
`using evidence from the international literature and expert opi-
`nion, with the goal of optimizing everyday clinical practice
`[13].
`
`2. Methods
`
`The procedure for developing the recommendations in-
`volved several steps, as detailed in the article by Pham et al.
`[14,15].
`
`2.1. Selection of topics by the scientific committee members
`
`The scientific committee selected three topics: cardiovascu-
`lar risk and RA [15], use of methotrexate in RA, and nonphar-
`macological management of patients with recent-onset RA
`[16]. The use of methotrexate in RA is discussed in this article.
`
`Five questions were selected using a Delphi prioritization
`procedure:
`
`1. What dosages and routes of administration should be used:
`more specifically, what is the optimal starting dose, how
`and when should the dosage be adjusted, what is the max-
`imal dosage, and which routes of administration should be
`used and when?
`2. Does the methotrexate dosage deserve special consideration
`in patients who are also receiving TNFα antagonist therapy?
`3. What
`investigations (including pulmonary investigations)
`should be performed before starting, and during, low-dose
`methotrexate treatment in patients with RA?
`4. Should folate supplementation be given routinely (product,
`dosage, frequency, expected benefit).
`5. What is the optimal management strategy when respiratory
`symptoms develop in an RA patient taking methotrexate?
`
`2.3. Literature review
`
`We searched the Cochrane databases, PubMed, and the da-
`tabases of the meetings of the French Society for Rheumatol-
`ogy (2003 and 2004), European League Against Rheumatism
`(2003, 2004, and 2005), and American College of Rheumatol-
`ogy (2003 and 2004). Articles published in French or in Eng-
`lish before June 2005 were considered. The keywords rheuma-
`toid arthritis and methotrexate were used in combination with
`other keywords: dosage,
`intramuscular, subcutaneous, and
`parenteral for question 1; adalimumab, etanercept, and inflix-
`imab for question 2; monitoring, hepatitis B virus, hepatitis C
`virus, hematologic diseases, renal function, respiratory tract
`diseases, and pneumonitis for questions 3 and 5; and folic acid
`and folinic acid for question 4.
`Of the 1859 publications retrieved by the literature search,
`764 were selected based on the titles, and of those 285 based
`on the abstracts. The full texts of relevant publications were
`reviewed. The level of evidence in each publication was deter-
`mined as recommended by Shekelle et al. [17].
`
`Page 00002
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`390
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`S. Pavy et al. / Joint Bone Spine 73 (2006) 388–395
`
`The procedure used to select the experts, to present the lit-
`erature review results to them and to develop and evaluate the
`recommendations are detailed in the article by Pham et al. [15].
`
`3. Results and discussion
`
`Eight recommendations about using methotrexate in patients
`with RA were developed during the 2005 Meeting of Rheuma-
`tology Experts. The wording and strength of the recommenda-
`tions are shown in Table 1, as well as the extent of agreement
`of the experts with each recommendation.
`
`3.1. The starting dosage for methotrexate in patients with RA
`should not be less than 10 mg/week and should be determined
`based on disease severity and patient-related factors
`
`The therapeutic effectiveness of methotrexate is dose-depen-
`dent, and effects have been reported with a dosage as low as
`5 mg/week [18]. Nevertheless, the first RCTs of methotrexate
`versus placebo showed that a starting dosage of 7.5 mg/week
`was often inadequately effective, requiring a dosage increase
`after 6 weeks in 66–97% of cases [4,5]. In addition, a starting
`dosage of 10 mg/m2 per week (12.5–20 mg/week) was more
`effective than 5 mg/m2 per week (5–7.5 mg/week), with no
`
`statistically significant safety differences between the two
`groups [19]. Based on these data and on their experience with
`methotrexate used to treat RA, the experts recommended a
`starting dosage of at least 10 mg/week.
`The experts agreed that the starting dosage should be ad-
`justed according to the patient’s body weight and co-morbid-
`ities. Moderate to severe renal failure usually requires a starting
`dosage below 10 mg/week. Two pharmacokinetic studies
`showed that methotrexate clearance was correlated with creati-
`nine clearance [20,21]. In patients whose creatinine clearance
`was lower than 45 ml/min, serum methotrexate levels were 30–
`60% higher than in patients with normal renal function. A
`meta-analysis of 11 controlled trials showed that moderate re-
`nal failure (creatinine clearance < 60 ml/min) significantly in-
`creased the risk of serious methotrexate toxicity, most notably
`for the lung and liver [22]. Other co-morbidities may require a
`starting dosage of less than 10 mg/week; a history of drug-in-
`duced hepatitis is an example.
`Several experts underlined the need to consider body weight
`when selecting the starting dosage. We are not aware of any
`clinical studies in which methotrexate dosages are reported in
`mg/kg body weight. The article by Furst et al. [19] is the only
`study that used a relative methotrexate dosage, in mg/m2 per
`week, which can be difficult to compute in everyday rheuma-
`tological practice. Given this lack of scientific data, the recom-
`
`Table 1
`The eight recommendations about methotrexate used to treat rheumatoid arthritis, with the strength of each recommendation and the degree of agreement among
`experts at the 2005 Rheumatology Expert Panel meetings [17]
`
`1
`
`2
`
`3
`
`4
`
`5
`
`The starting dosage for methotrexate in patients with RA should not be less than
`10 mg/week and should be determined based on disease severity and patient-related
`factors.
`When a patient with RA shows an inadequate response to methotrexate, the dosage
`should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance
`and patient-related factors.
`When starting methotrexate treatment in a patient with RA, preference should be given
`to the oral route. A switch to the intramuscular or subcutaneous route should be con-
`sidered in patients with poor compliance, inadequate effectiveness, or gastrointestinal
`side effects.
`At present, there is no evidence indicating that a change in methotrexate dosage is in
`order when a TNF antagonist is given concomitantly.
`The investigations that are mandatory before starting methotrexate therapy in a patient
`with RA consist of a full blood cell count, serum transaminase levels, serum creatinine
`with computation of creatinine clearance, and a chest radiograph. In addition, serolo-
`gical tests for the hepatitis viruses B and C and a serum albumin assay are recom-
`mended. In patients with a history of respiratory disease or current respiratory symp-
`toms, lung function tests with determination of the diffusing capacity for carbon
`monoxide are recommended.
`Investigations that are mandatory for monitoring methotrexate therapy in patients with
`RA consist of full blood cell counts and serum transaminase and creatinine assays.
`These tests should be obtained at least once a month for the first 3 months then every
`4–12 weeks.
`Folate supplementation can be given routinely to patients treated with methotrexate for
`RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance
`from the methotrexate dose, is appropriate.
`In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug
`must be stopped and symptom severity evaluated. Should evidence of serious disease
`be found, the patient should be admitted immediately or advice from a pulmonologist
`should be obtained immediately.
`* percentage of “agrees completely” and “agrees with reservation” votes.
`
`6
`
`7
`
`8
`
`Level of
`evidence
`1b/2
`
`Strength of the
`recommendation
`C
`
`Agreement among
`experts (%)*
`82.5
`
`1b/2
`
`2/3
`
`–
`
`1b/3
`
`3
`
`1a/1b
`
`2/3
`
`C
`
`D
`
`–
`
`D
`
`D
`
`A
`
`D
`
`88.8
`
`91.7
`
`–
`
`73.4
`
`88.1
`
`88.5
`
`80.4
`
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`
`391
`
`mendation states the methotrexate starting dosage as a minimal
`total dosage. However, in overweight patients, a starting do-
`sage close to the maximum recommended dosage can be used.
`The presence of characteristics suggesting particularly severe
`disease [14] may warrant the use of a starting dosage greater
`than 10 mg/week in order to rapidly induce the maximum treat-
`ment response, despite the risk of minor side effects [1].
`
`3.2. When a patient with RA shows an inadequate response
`to methotrexate, the dosage should be increased at intervals
`of 6 weeks, up to 20 mg/week, according to tolerance
`and patient-related factors
`
`A single RCT investigated the additional efficacy obtained
`by increasing the methotrexate dosage above 15 mg/week in
`patients with RA [23]. Fifty-four patients with an inadequate
`response to oral methotrexate in a dosage of 15–20 mg/week
`were divided into two groups: the controls received 15 mg/
`week of methotrexate intramuscularly and the intensive treat-
`ment group had their intramuscular methotrexate dosage in-
`creased every 4 weeks as long as the DAS28 was greater than
`3.2, up to 45 mg/week. At the end of the trial, no significant
`differences were found between the two groups regarding dis-
`ease activity or the number of patients whose DAS28 was less
`than 3.2. One of the RCTs vs. placebo was started with three
`methotrexate dosages, 5, 10, and 20 mg/m2 per week [19].
`With the highest dosage, which resulted in administration of
`25–35 mg of methotrexate per week, one third of patients dis-
`continued methotrexate therapy prematurely because of serious
`adverse events, and recruitment to this group was stopped.
`The mean relative bioavailability of oral methotrexate com-
`pared to intramuscular methotrexate varies from 0.64 to 0.85
`according to the dosage [24,25]. Based on this fact and on their
`own experience, the experts decided to recommend 20 mg/
`week as the maximal dosage. Good tolerance of methotrexate
`in its current dosage is a prerequisite to a dosage increase.
`For the reasons listed in the previous recommendation, in-
`creasing the methotrexate dosage above 20 mg/week may be
`appropriate in severely overweight or obese patients. The ex-
`perts recommended a 6-week interval between dosage incre-
`ments for inadequate effectiveness. This interval is warranted
`by the active nature of the disease. It is consistent with the
`recommendation about clinical and laboratory test monitoring
`developed at the 2004 Meeting of Rheumatology Experts [14].
`
`3.3. When starting methotrexate treatment in a patient with
`RA, preference should be given to the oral route
`
`A switch to the intramuscular or subcutaneous route should
`be considered in patients with poor compliance, inadequate ef-
`fectiveness, or gastrointestinal side effects
`Bioavailability data for methotrexate in dosages of less than
`20 mg/week, together with the ease of use and low cost of oral
`methotrexate, warrant first-line use of the oral route. Pharma-
`cokinetic studies have shown that the relative bioavailability of
`
`the oral route compared to the intramuscular route is good with
`low dosages but decreases as the methotrexate dosage in-
`creases. With 7.5 mg/week, the absolute oral bioavailability
`of methotrexate is close to 1 [26]. In a group of patients given
`10–17.5 mg/week of methotrexate, the mean relative bioavail-
`ability of the oral route compared to the intramuscular route
`was 0.85 (95% CI, 0.77–0.93) [24]. The lower value of 0.64
`(95% CI, 0.21–0.94) was found with dosages greater than
`20 mg/week [25]. In these studies, no statistically significant
`differences in bioavailability were detected between the intra-
`muscular and the subcutaneous routes. The clinical efficacy
`and/or safety of methotrexate, according to the route of admin-
`istration has been evaluated only in open-label trials and retro-
`spective studies. In the above-mentioned study investigating
`the potential benefits of methotrexate dosages greater than
`15 mg/week [23], 64 patients with inadequate responses to oral
`methotrexate in dosages of 15–20 mg/week were given 15 mg/
`week intramuscularly during the 6 weeks preceding the rando-
`mization phase. The switch from oral to intramuscular admin-
`istration resulted in a 0.42 (95% CI, 0.15–0.69) point decrease
`in the DAS28; this reduced the DAS28 to less than 3.2 in 4
`(6.25%) patients. A similar open-label prospective study
`showed a significant reduction in the DAS28, by a mean of
`0.6, in 33 patients switched from oral to intramuscular metho-
`trexate [27]. Three retrospective studies showed that gastroin-
`testinal symptoms related to methotrexate administration de-
`creased after switching from the oral to the parenteral route
`[28–30].
`
`3.4. At present, there is no evidence indicating that a change
`in methotrexate dosage is in order when a TNF antagonist is
`given concomitantly
`
`In RCTs of the efficacy and/or safety of methotrexate com-
`bined with TNF antagonist therapy, the mean methotrexate do-
`sage ranged from 7.5 to 16 mg with infliximab [10,31], 14.5–
`18.5 mg with etanercept [11,32], and 17–20 mg with adalimu-
`mab [12,33]. The influence of the methotrexate dosage on ef-
`ficacy and safety was not investigated in these studies. In a
`single uncontrolled study of 22 RA patients with an inadequate
`response to infliximab (3 mg/kg) and methotrexate in combina-
`tion, increasing the methotrexate dosage from a mean of 9.9
`± 3.9 mg/week to a mean of 15 ± 4.3 mg/week improved the
`therapeutic response to infliximab in 36.4% of cases (8/22 pa-
`tients), within 16 weeks. However, this study was not con-
`trolled, and in seven of the eight patients the improvement
`was moderate according to EULAR criteria [34].
`
`3.5. The investigations that are mandatory before starting
`methotrexate therapy in a patient with RA consist of a full
`blood cell count, serum transaminase levels, serum creatinine
`with computation of creatinine clearance, and a chest
`radiograph
`
`In addition, serological tests for the hepatitis viruses B and
`C and a serum albumin assay are recommended. In patients
`
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`
`with a history of respiratory disease or current respiratory
`symptoms, lung function tests with determination of the diffus-
`ing capacity for carbon monoxide are recommended.
`Determination of serum transaminase levels before starting
`methotrexate therapy is mandated by the risk of methotrexate-
`induced liver toxicity. A meta-analysis of 17 prospective or
`retrospective studies reporting the results of liver biopsies in
`719 patients taking methotrexate for RA showed 103 (14%)
`cases of mild fibrosis (Roenigk class IIIA), 6 (0.8%) cases of
`moderate fibrosis (Roenigk class IIIB), and 2 (2.8‰) cases of
`cirrhosis (including one patient who had known cirrhosis be-
`fore the initiation of methotrexate therapy) [35]. The frequency
`of clinically serious liver disease in patients taking methotrex-
`ate for RA can be estimated at 1% to 1‰ and the cumulative
`risk of developing clinically serious liver disease at about 1‰
`after 5 years [35]. A meta-analysis of six RCTs reporting the
`results of serial liver tests done over a 3-month period in 657
`RA patients taking methotrexate or a placebo showed that pa-
`tients taking methotrexate had higher rates of ALAT elevation
`(x 1-2 N, 6.7% vs. 0.4%), ASAT elevation (x 1-2 N, 4.9% vs.
`0.4%), and serum alkaline phosphatase (x 1-2 N, 16% vs. 3%)
`[35]. The far higher rate of alkaline phosphatase elevation
`(16% with methotrexate and 3% with a placebo) compared to
`ALAT and ASAT elevation suggested to the authors of this
`meta-analysis that alkaline phosphatase may be too sensitive
`to serve as a marker for liver injury [35]. Finally, in a prospec-
`tive study of three cohorts including a total of 94 patients trea-
`ted with methotrexate for RA, serial testing showed a correla-
`tion between serum transaminase levels and liver biopsy
`results: elevation of the mean pre-biopsy serum transaminase
`level was correlated with an increased risk of finding an abnor-
`mal histological grade, whereas normal values for over 50% of
`pre-biopsy serum transaminase levels had 97% specificity for a
`normal histological grade [36].
`The recommendation that serological tests for the hepatitis
`viruses B and C be performed before the initiation of metho-
`trexate therapy rests on the theoretical risk of potentiated meth-
`otrexate-induced liver toxicity in patients who have hepatitis B
`or C. Reactivation of the hepatitis B virus has been reported in
`five patients given methotrexate to treat RA, including four
`patients who experienced fulminating hepatitis at methotrexate
`discontinuation [37–41]. A single case of hepatitis C reactiva-
`tion, with a good response to ribavirin, was reported among six
`patients given methotrexate (12.5 ± 3 mg/week for 15.2
`± 9.9 months) to treat joint manifestations related to chronic
`hepatitis C [42]. Two patients with RA and hepatitis C infec-
`tion were treated with methotrexate for 6 months without ex-
`periencing transaminase elevation [43]. Based on these data,
`and considering that no conclusions can be drawn from the
`few anecdotal cases available to date, the experts recommend
`obtaining serological tests for the hepatitis viruses B and C
`before initiating methotrexate therapy in patients with RA.
`The hematological toxicity of methotrexate requires that a
`full blood cell count be obtained before treatment initiation.
`Cytopenia (pancytopenia, neutropenia, or thrombocytopenia)
`occurred in about 1% of patients in long-term prospective stu-
`
`dies of RA patients given low-dose methotrexate therapy. Cy-
`topenia can occur at any time during treatment, even after the
`first dose, and may be fatal in as many as 15%–25% of cases.
`Risk factors for cytopenia may include renal dysfunction, hy-
`poalbuminemia, infection, interactions with specific medica-
`tions
`(e.g.
`trimethoprim-sulfamethoxazole), and accidental
`overdosage [44–46].
`Renal dysfunction may potentiate the toxicity of methotrex-
`ate in patients with RA. Consequently, a serum creatinine as-
`say with creatinine clearance estimation should be performed
`before methotrexate initiation. As specified in the recommen-
`dation on the starting dosage of methotrexate, moderate to se-
`vere renal failure is associated with elevated serum methotrex-
`ate levels that result in a significant increase in the risk of
`serious adverse effects, most notably hepatic and pulmonary
`toxicity [20–22].
`Because hypoalbuminemia is associated with increased
`methotrexate toxicity, serum albumin should be assayed before
`treatment initiation. Hypoalbuminemia has been reported as a
`potential risk factor for methotrexate-induced hematological
`and pulmonary toxicity [45,47].
`The well-established pulmonary toxicity of methotrexate re-
`quires that a chest radiograph be obtained before treatment in-
`itiation. In patients with a history of respiratory disease or cur-
`rent
`respiratory
`symptoms,
`lung
`function
`tests with
`determination of the diffusing capacity for carbon monoxide
`(DLCO) should be performed also. Methotrexate-induced pul-
`monary toxicity manifests chiefly as infectious or immunoaller-
`gic pneumonia. Immunoallergic pneumonia, which causes in-
`terstitial pneumonitis, occurs in nearly 2% of patients given
`methotrexate to treat RA and carries a mortality rate of about
`10–20%. Methotrexate pneumonitis can develop at any time
`during methotrexate therapy but may be more common during
`the first year. Potential risk factors may include pre-existing
`lung disease, most notably with interstitial involvement; older
`age; renal dysfunction; and diabetes mellitus. The symptoms of
`methotrexate pneumonitis set in gradually, over several days to
`weeks. They are nonspecific, consisting chiefly of a fever, a
`nonproductive cough, and dyspnea. Among tests that can assist
`in the diagnosis of methotrexate pneumonitis, chest radiogra-
`phy has low sensitivity and low specificity but may disclose
`interstitial and/or alveolar densities predominating in the lung
`bases. Lung function testing with determination of blood gas
`values and DLCO is sensitive but lacks specificity; the results
`may show hypoxia, a DLCO reduction (≤ 70% of the predicted
`age-specific value), and/or a restrictive ventilatory pattern.
`High-resolution computed tomography is sensitive and more
`specific than lung function testing. Findings may include inter-
`stitial infiltrates and/or ground-glass densities predominating in
`the lung bases. The appropriateness of bronchoscopy with
`bronchoalveolar
`lavage and transbronchial
`lung biopsies
`should be discussed on a case-by-case basis with a pulmonol-
`ogist. Based on these facts, the experts concluded that a chest
`radiograph, and lung function testing with DLCO determina-
`tion in patients having a history of respiratory disease or cur-
`rent respiratory symptoms, should be performed routinely be-
`
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`393
`
`fore methotrexate initiation, both to provide baseline data and
`to ensure identification of potential risk factors for methotrex-
`ate pneumonitis, such as preexisting interstitial involvement or
`a low respiratory reserve [47–54].
`
`3.6. Investigations that are mandatory for monitoring
`methotrexate therapy in patients with RA consist of full blood
`cell counts and serum transaminase and creatinine assays
`
`These tests should be obtained at least once a month for the
`first 3 months then every 4–12 weeks.
`Blood cell counts and serum levels of transaminases and
`creatinine should be monitored to detect evidence of metho-
`trexate-induced hepatic and hematological toxicity and to look
`for renal dysfunction, which may potentiate methotrexate toxi-
`city, as stated regarding recommendation 5. The only evidence
`about the frequency of investigations comes from a meta-ana-
`lysis of two uncontrolled studies that report the results of liver
`function tests done every 2–6 weeks in RA patients given
`methotrexate for 30 months (N = 45) or 102 months (N = 18)
`[35]. The optimal frequency of transaminase monitoring was
`30–60 days [35]. Based on these data,
`the experts recom-
`mended a monitoring schedule that is widely used in their clin-
`ical practice, namely, tests at least once a month during the first
`3 months and every 4–12 weeks thereafter.
`
`3.7. Folate supplementation can be given routinely to patients
`treated with methotrexate for RA
`
`In practice, a minimal dosage of 5 mg of folic acid once a
`week, at a distance from the methotrexate dose, is appropriate.
`A meta-analysis showed that routine supplementation with
`folic acid or folinic acid had no major effects on variables re-
`flecting the activity of RA [55]. Data from a RCT, however,
`suggested that folic acid or folinic acid supplementation might
`require a slight methotrexate dosage increase to maintain effi-
`cacy [63]. Compared to a placebo, routine folic acid supple-
`mentation resulted in a 79% decrease in methotrexate-related
`gastrointestinal symptoms (stomatitis, abdominal pain, anorex-
`ia, nausea, vomiting, diarrhea, and constipation) (odds ratio,
`0.21; 95% CI, 0.10–0.44; P < 0.0001) [55,58,62]. Compared
`to continued folic acid supplementation, stopping supplementa-
`tion was associated with an increased risk of methotrexate dis-
`continuation due to gastrointestinal side effects (45% vs. 7%,
`P = 0.001) [64]. Routine folic acid or folinic acid supplementa-
`tion decreased the 1-year rate of methotrexate discontinuation
`because of transaminase elevation, compared to a placebo (4%
`with folic acid and 6% with folinic acid vs. 26% with the pla-
`cebo, P < 0.001) [63]. Stopping routine folic acid supplementa-
`tion (compared to continuing supplementation) was associated
`with an increase in the 1-year rate of methotrexate discontinua-
`tion for neutropenia (< 2000 neutrophils/mm3), although the
`difference was not statistically significant, probably because
`of the small number of neutropenia cases [64].
`
`Regarding the overall safety profile of methotrexate, routine
`folic acid or folinic acid supplementation decreased the 1-year
`rate of methotrexate discontinuation for adverse events (12%
`with folinic acid, 17% with folic acid, and 38% with the pla-
`cebo; P < 0.001) [60]. Stopping routine folic acid supplemen-
`tation increased the 1-year rate of methotrexate discontinuation
`for adverse events (46% vs. 21% when supplementation was
`continued, P = 0.02) [64].
`The influence of the product used for supplementation (folic
`acid vs. folinic acid), the dosage, and the dosing schedule
`(once a day vs. once a week) on the efficacy or safety of meth-
`otrexate in patients with RA is unclear. Various folate supple-
`mentation regimens were used in RCTs [55–64]. The results do
`not suggest major differences between low and high dosages of
`folic acid (ranges used: 1–5 mg/day and 5–27.5 mg/week) or
`folinic acid (ranges used: 1–5 mg/day and 2.5–20 mg/week)
`[55–64]. Therefore, the experts recommended a simple supple-
`mentation schedule consistent with existing clinical practice,
`namely, 5 mg of folic acid or folinic acid once a week, at a
`distance from the methotrexate dose.
`
`3.8. In the event of respiratory symptoms possibly related
`to methotrexate toxicity, the drug must be stopped
`and symptom severity evaluated
`
`Should evidence of serious disease be found, the patient
`should be admitted immediately or advice from a pulmonolo-
`gist should be obtained immediately.
`Methotrexate-induced lung toxicity was discussed about the
`recommendation on investigations required before methotrex-
`ate initiation in patients with RA. Lower respiratory tract infec-
`tions and immunoallergic pneumonitis are the main manifesta-
`tions. These potentially life-threatening complications may
`occur at any time during treatment. The symptoms are nonspe-
`cific and consist of a fever, a nonproductive cough, and dys-
`pnea. Respiratory symptoms that develop in an RA patient re-
`ceiving methotrexate
`therapy may
`indicate
`infection,
`methotrexate pneumonitis, or another cause of respiratory dis-
`ease related or unrelated to RA. The first step in differentiating
`among these possibilities is a thorough physical examination.
`The results are used to choose diagnostic investigations among
`the following: chest radiograph, cytological and microbiologi-
`cal stu