Benefit and risk of treatment in

R. Rau, G. Herborn

Rheumaklinik, Ratingen, Germany. ABSTRACT This article presents an overview of our Rolf Rau, MD; Gertraud Herborn, MD. This is a literature review on the effica- present knowledge of the benefits and Please address correspondence to: cy and toxicity of low dose weekly me- risks of low dose MTX treatment. Rolf Rau, MD, Rheumaklinik, thotrexate treatment in rheumatoid ar- Rosenstrasse no. 2, 40882 Ratingen, thritis. Personal recommendations on Beneficial pharmacologic properties Germany. dosing and monitoring (of) the drug and mechanisms of action Clin Exp Rheumatol 2004; 22 (Suppl. 35): are given. MTX is generally taken weekly by the S83-S94. oral or parenteral (iv,im,sc) route. Oral © Copyright CLINICAL AND EXPERIMENTAL Introduction absorption of doses between 10 and 25 RHEUMATOLOGY 2004. The last two decades have seen impor- mg may be as low as 25% and as high Key words: Rheumatoid arthritis, tant achievements in the treatment of as 100% (mean 70%) (3-6). With the MTX treatment, MTX efficacy, rheumatoid arthritis. higher doses of 25-40 mg (median 30 MTX toxicity, review article. 1. There is general agreement now that mg) weekly, the bio-availability in RA disease modifying anti-rheumatic drug patients ranged from 21% - 96% (mean (DMARD) treatment should be intro- 64%) when compared to subcutaneous duced as early as possible in the course application (7). If efficacy is insuffici- of the disease, to suppress disease acti- ent, parenteral dosing may be tried. The vity and thereby provide the possibility absorption rate remains constant over of avoiding joint damage and disability. time in the same individual at the low 2. An improved understanding of the dose of 7.5 mg/week (8), but decreases pathophysiology of rheumatoid arthri- by 13.5% at a maintenance dose of 17 tis has facilitated the development of mg (9). Renal function is critical for new drugs specifically targeted at cyto- drug elimination and thereby to prevent kines, which play a well defined role in toxicity, as 50-80% of the drug is elim- the inflammatory process. These "bio- inated unchanged through glomerular logic agents" have been proven to be filtration with a half-life of 2-4 hours, effective and well tolerated, but are the mean renal clearance being 110 ml/ very expensive. min/m2 (3). Impaired renal function (10) 3. The broad introduction of metho- or advanced age (11) may decrease trexate (MTX) for the treatment of clearance and increase toxicity. rheumatoid arthritis (RA) some 20 The short total half-life of 6-7 hours years ago had even larger consequen- (12) has practical advantages in the ces from a practical and economic clinical "handling" of MTX when com- point of view. This drug proved to be pared with other DMARDs such as very effective, had a relatively rapid on- parenteral and . Nor- set of action, was well tolerated in most mally, after 24 hours no MTX can be cases, and could be prescribed in a detected in the serum. However, MTX wide dose range taking into account the (and its oxidation product 7-hydroxy- needs of each individual patient. These MTX) can be found in the polygluta- features led to MTX becoming the mated form after more than one week most widely used DMARD worldwide. within the cells of RA patients being Moreover, MTX adds to the efficacy of treated with low dose weekly MTX (13), tumor necrosis factor alpha (TNF-α) allowing for a once-weekly dosage. biologic agents, which appear to be MTX may have different mechanisms indicated in only a minority of patients of action. The classical mechanism in suffering from severe RA despite con- the treatment of neoplasia involves the ventional DMARDs (1). MTX remains inhibition of dihydrofolate reductase the "anchor drug" in the treatment of (DHFR) and other folate dependent en- the majority of patients with RA (2). zymes, thereby interfering with the syn-

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Benefit and risk of methotrexate treatment in RA / R. Rau & G. Herborn thesis of pyrimidine and purines (14). lite, 7-OH-MTX, thus potentiating MTX effect usually appeared to be sustained The inhibitory effect of MTX on cyto- efficacy (and toxicity) (25). These drug during the entire follow-up period. kine production can be reversed by the interactions may have few practical Marked improvement (>50% decrease) addition of folinic acid or thymidine implications, since the MTX dose can in the number of swollen joints occur- and hypoxanthine (15). easily be adapted according to tolera- red in > 50% (51), and 69% (45) of pa- The rapid onset of the clinical effect of bility. tients. Clinical remissions, according to MTX in RA Ð the CRP decreases sig- the definition of Pinals (53), however, nificantly within days after a single in- Beneficial effects of MTX on clinical were infrequent and are difficult to jection (16) Ð indicates strong anti-in- outcome parameters achieve in patients with severe destruc- flammatory properties (14). The occur- The first observation of the successful tive disease. rence of opportunistic infections may treatment of 7 RA patients with amino- A long adherence to a treatment can point to additional immunosuppressive pterin in 1951 (26) was forgotten be- serve as a surrogate for both good toler- effects. cause of the dramatically positive ef- ability and effectiveness. In long-term fects of corticosteroids in the treatment studies, drug survival rates of more than Interactions of MTX with other of RA and the fear of MTX toxicity. 5 years occur in more than 50% of pa- drugs have to be considered Between 1951 and 1980 only a few re- tients. In routine clinical care, MTX Some NSAIDs, including ibuprofen, ports on the treatment of RA with MTX treatment was continued substantially naproxen, ketoprofen or salicylates, with weekly i.v. doses of 15 mg (27) longer than treatment with other may significantly reduce the clearance and oral weekly doses of 10-15 mg (28) DMARDs (54-58) Ð e.g. a treatment of creatinine and MTX, while other appeared. In 1979, the authors ap- continuation rate of 57% for MTX was nonsteroidal anti-inflammatory drugs proached the manufacturers of MTX to seen after 5 years compared to 20% and (NSAIDs), including etodolac, piroxi- study its use in patients with RA, and 25% for other DMARDs (p<0.01) (58). cam and meloxicam, do not interact were told that MTX was designed for In 460 patients from 7 private practices with MTX. In general, these interac- the treatment of malignancies and was in Melbourne, Australia 75.4% of pa- tions are not clinically important, al- far too toxic for treating RA patients. tients were still taking MTX after 6 though substantial individual variation In the early 1980s, open pilot studies years (56) and 53% of patients were con- regarding drug interactions may be seen, indicated effectiveness of 7.5Ð15 mg tinuing at 12 years (59). However, in and single cases with severe side ef- MTX weekly in RA patients not re- two other studies the continuation rate fects have been reported (17-19). sponsive to conventional DMARDs after 4 years was not different between NSAIDs did not affect the pharmacoki- (29-32). Between 1984 and 1989, sev- MTX and other DMARDs (60, 61). netic variables of MTX at weekly MTX eral randomized placebo-controlled tri- One reason for the long continuation doses of 7.5 mg, but reduced the renal als over 6-26 weeks with weekly MTX rate of MTX may be the possibility to clearance by 20% at a mean mainte- doses of 7.5Ð25 mg demonstrated a sig- adapt the dose in a wide range to the nance dose of 17 mg (20). There was nificant improvement in the patients' needs of the individual patient, which also a 20% reduction in MTX clearance clinical status (33-36). A significant is more difficult with other DMARDs. in patients receiving long-term corti- dose-response relationship of MTX The patient must be observed carefully costeroid treatment (21). Probenecid was documented (37), in terms of a ra- and the dose may be increased in cases increases the 24 hour MTX plasma lev- pid and excellent response to weekly of increasing disease activity. In a fol- els up to 400% (22). was i.v. doses of 25 mg (38) and 50 mg (39). low-up of 437 patients starting MTX found to reduce the bio-availability of between 1988 and 1996, health assess- MTX by approximately 50% (23). How- Long-term observational studies ment questionnaire (HAQ) disability ever, significantly demonstrate superior effectiveness index values improved up to month 30, increased the mean area under the and tolerability but after 42 months re-progressed again, curve for MTX by approximately 65% Multiple, carefully monitored, long- reaching baseline values after approx- (p = 0.005) and at the same time the term observational studies have docu- imately 8 years (62). There is the need peak MTX concentration was reached mented lasting clinical effectiveness for a more rapid upward dosage titra- later and was lower (24). Cyclosporine and good tolerability of MTX with low tion and the longer maintenance of an A (CSA) may reduce creatinine as well discontinuation rates (40-52). These optimal or highest tolerated dosage (62). as MTX clearance, thereby increasing studies had follow-up periods of up to Although MTX was equally or even the effective MTX dose. Furthermore, 11 years and included between 26 and more effective in patients older than 65 the co-administration of CSA led to a 453 patients, most of them suffering years (63, 64), withdrawal occurred significant increase in the MTX plasma from long-lasting disease unresponsive more frequently in these patients (52, concentration and an 80% decrease in to previous DMARD treatment. MTX 56). the plasma-7-OH-MTX concentration resulted in a significant improvement in the area under the curve, indicating of all clinical measures, including acute MTX is a potent inhibitor of that CSA may block the oxidation of phase reactants, with a peak effect radiographic progression MTX to its relatively inactive metabo- reached after 6 months. The beneficial The primary consequences of RA are

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Benefit and risk of methotrexate treatment in RA / R. Rau & G. Herborn functional disability and joint destruc- Three clinical trials found no signifi- were withdrawn due to liver enzyme tion, which are correlated significantly cant differences in clinical improve- elevations (88). in the later stages of the disease (65). ment between parenteral gold and MTX, The new biologic agents have been cel- Therefore, the most important goals of while MTX appeared to be slightly less ebrated as a "breakthrough" in the treat- treatment are to prevent the progres- toxic (78-80). In a two-center, double- ment of RA and have already changed sion of joint damage and functional blind comparison between parenteral treatment habits, more in the United disability by early aggressive treatment gold (50 mg per week) and parenteral States than in Europe. Only one study aimed at remission. MTX (15 mg per week) in 174 patients compared MTX with one of the TNF- The capacity to retard radiographic signs with early erosive RA (median disease inhibitors, etanercept, in patients with of disease progression is regarded as duration 11 months), all of the clinical early RA. In that study a clinical re- the most important criterion for disease parameters and acute phase reactants sponse was seen earlier with etanercept modification. In long-term studies doc- were improved significantly by > 50% than with MTX. This difference may umenting radiographic outcomes, most after 1 and 3 years without significant have resulted in part from the low ini- patients usually demonstrated ongoing inter-group differences. Marked improve- tial dose adopted of 7.5 mg MTX per progression under MTX treatment (41, ment (>50%) occurred in 68% of MTX- week (with folate supplementation), 43,51,66,67). In contrast, patients who treated patients and 76% of patients which was increased to 15 mg after 4 had remission of disease activity dis- treated with gold. Tolerability was sig- weeks and to 20 mg after 8 weeks in played an arrest of damage progression nificantly better with MTX (81, 82). In many patients. The difference in ACR (41,43,51,67). Two studies found a sig- a randomized, but open study in 141 20 response after one year was small: nificant inhibition of progression dur- patients, all efficacy parameters were 72% responders with etanercept, 65% ing MTX treatment, compared to radio- improved significantly with parenteral with MTX (p=0.16) (89). At 24 months, logical progression during prior treat- gold or MTX treatment by 24 weeks (p the difference was great, 72% with etan- ment with DMARDs which were clini- < 0.001); inter-group differences were ercept, 59% with MTX, and statistical- cally insufficient (68, 69), while no sig- not seen for efficacy, but gold caused ly significant; fewer patients completed nificant difference was seen in one stu- significantly more withdrawals for tox- the study with MTX (59% versus 74%) dy (70). In patients with early erosive icity (p = 0.0026) (83). (90). Radiographic progression was 1.59 RA, radiographic progression was clear- In 42 patients treated over 24 weeks, no Sharp units with MTX and 1.0 with eta- ly inhibited in patients treated with significant difference was seen be- nercept, corresponding to 0.25% and either parenteral gold or intramuscular tween 100 mg (AZA)/day 0.385% of the maximum total Sharp MTX, with no significant difference and 10 mg MTX/week, with a trend to- score. After 2 years, the progression in between the groups (71,72). Other stu- wards earlier and more marked im- the total Sharp score was 3.2 units with dies comparing MTX with other provement with MTX (84). In another MTX and 1.3 with etanercept. DMARDs also demonstrated a flatten- study, 7.5 Ð 15 mg MTX/week (n = 33) Direct comparisons of results with bio- ing of the progression curve over time was significantly better than 100-150 logic agents and conventional DMARDs (73). A meta-analysis stated that dis- mg AZA/day (n = 31) over a period of in different studies are difficult, since ease progression with MTX treatment 48 weeks (73); after 48 weeks, only there are differences in patient selec- was comparable to that seen with par- 36% of patients remained on AZA, tion, methodology, dosing, concomitant enteral gold (74), but it was less than while 91% continued on MTX. A meta- steroid treatment, outcome parameters, under treatment with other DMARDs analysis of clinical trials in 3957 pa- etc. However, such comparisons have (73-75). Based on these results, it is rea- tients found MTX to be more effective been made for the step-up combination sonable to conclude that MTX delays than and comparable to D- of MTX with different TNF-alpha block- radiological progression in patients and parenteral gold (85). ing agents (91). In a similar compari- who also respond favorably in terms of In a large American study the ACR20/ son, conventional DMARDs performed clinical effectiveness. 50/70 response rates were 72/56/26% very well when compared with the bio- for leflunomide and 67/43/20% for logic agents based on outcome in com- MTX compares favorably with MTX, with supplementation of 1-2 mg/ posite scores (ACR, EULAR), ESR, other DMARDs day folic acid. The CRP improved sig- CRP, swollen joint count and radio- The relative efficacy and toxicity of nificantly in both groups, while the graphic progression (92). MTX has been investigated in several ESR declined only marginally (86). The studies. In one study, a dose of 7.5Ð15 ACR response rates were maintained MTX is an ideal combination mg MTX weekly was superior to 6-9 over 24 months (87). In a European stu- partner mg Auranofin per day in terms of im- dy comparing leflunomide with MTX, Combinations of different DMARDs proving disease activity as well as with- in which only 10% of patients had fo- provide additional, or even potentiat- drawal rates (76), while another study late supplementation, improvement of ing, effects, and therefore have become indicated non-significant differences in all efficacy parameters was significant- widely used (92a, 93). Early meta-anal- the efficacy of 7.5 mg MTX weekly ly greater with MTX than with lefluno- yses did not find evidence for a superi- versus 6 mg auranofin per day (77). mide. However, more patients on MTX ority of combination treatment over

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Benefit and risk of methotrexate treatment in RA / R. Rau & G. Herborn monotherapy in parallel comparisons leflunomide was significantly more ef- cates a favorable tolerability with pre- (94, 95). The various designs of combi- fective than placebo (ACR20 46.2% sumptive effectiveness and limited tox- nation studies Ð parallel design, step- and 19.5%; p < 0.001), while discontin- icity of MTX in RA patients. However, down design, add-on step-up design Ð uation rates were similar in both treat- a drug with desirable effects on multi- have to be considered when judging the ment groups (107). ple organ systems must have undesir- results. For example, the comparison of The combination of infliximab with able effects as well. Some adverse ev- placebo or infliximab added to ongoing MTX appeared to reduce antibody for- ents appear to be related to the antifo- MTX treatment in patients with insuffi- mation and improve the tolerability of late activity of MTX and mimic the cient response to MTX is more a com- infliximab. Infliximab serum concen- symptoms of folate deficiency. Fortu- parison between placebo and infliximab trations tended to be higher when com- nately, clinically relevant side effects than combination versus monotherapy. bined with MTX than with infliximab are rare. In prospective long-term stud- MTX has emerged as the optimal an- monotherapy. At this time, all TNF in- ies in which patients were seen fre- chor drug to be used in combination hibitors are combined with MTX be- quently (41,43, 46-49, 51, 118), as well with other DMARDs, and has been so cause study results and general experi- as in studies with the i.v. application of studied in several trials (2). In one, a ence have demonstrated a better effica- higher MTX doses (39), 60Ð85% of pa- combination of MTX with auranofin cy of the combinations. In the case of tients reported adverse events and 10- was not more effective than the indi- adalimumab, this may be due to a pro- 30% discontinued MTX due to toxicity. vidual drugs (77). A combination with longation of the half-life and increased Elevated creatinine serum levels (119), azathioprine was not superior to MTX serum levels when combined with advanced age (56,120) and low folic alone regarding outcome parameters. MTX (108). To the best knowledge of acid levels (121) predisposed to ad- However, fewer patients in the combi- the authors, a formal interaction study verse events. The creatinine elevations nation group required a dose increase of etanercept + MTX has not been per- are generally reversible when MTX is than patients in the single drug arms formed. discontinued. (96,97). The combination of MTX with A post-dosing reaction characterized chloroquine was clearly more effective MTX may have favorable and by arthralgias/myalgias or fatigue/ma- than MTX alone (98), although in a unfavorable effects on the extra- laise or both is seen in approximately pharmacokinetic study chloroquine was articular manifestations of RA 10% of patients within hours after dos- found to reduce the bioavailibility of In two case reports (109, 110) and two ing (122). MTX by approximately 50% (23). case series of 4 (111) and 7 patients The combination of MTX with sulfa- (112) with Felty's syndrome, an in- Gastrointestinal side effects salazine (SAS) was only marginally su- crease in the number of neutrophils, Nausea, malaise and vomiting were perior to the individual drugs (99, 100). and an improvement in the ESR and observed in prospective studies in 10- Triple combination treatment including number of swollen joints was observed, 50% of patients, starting 1-8 hours after MTX+SAS+hydroxychloroquine dem- accompanied by a reduction in the cor- medication and continuing for a few onstrated high effectiveness in one stu- ticosteroid dose when treated with hours up to one week. Some patients dy (101). In a parallel design the triple MTX. are unable to work after dosing and combination MTX + HCQ + SAS was Rheumatic vasculitis may respond fa- take MTX only on weekends. MTX more effective than the combination vorably to MTX, resulting in the heal- polyglutamate is accumulated in cells MTX+SAS and the combination MTX ing of vasculitic ulcerations and digital of the intestinal mucosa (123), which +HCQ after 2 years (ACR20 78%, 60% infarctions (113, 114). On the other may explain in part the gastrointestinal and 49%, respectively). Similar trends hand, MTX therapy can also induce side effects in some patients. Healing were seen for the ACR50 response vasculitic lesions, which may disappear of peptic ulcers caused by concomitant (102). when treatment is continued (115). NSAID medication may be delayed The addition of 2.5 Ð 5.0 mg of cyclo- An accelerated nodulosis has been esti- (124). Hence, an active peptic ulcer sporine/day to ongoing MTX treatment mated to occur in approximately 8% of should be regarded as a relative con- in patients with only a partial response RA patients treated with MTX (116). traindication for MTX. to MTX improved efficacy significant- Multiple small nodules, histologically ly over 1 and 2 years, while creatinine indistinguishable from the "usual" rheu- Skin and mucous membranes levels increased only marginally (103, matoid nodules, may develop in the has been observed in long- 104). Also, in two studies with a paral- hands and feet. The nodules may heal term studies in 12-37% of patients (42, lel design the combination MTX+ CSA with the discontinuation of MTX and 48, 120, 125) and was the reason for was more effective than MTX mono- reappear with its reintroduction. Nod- discontinuation in 6% (51). Mild alope- therapy in improving clinical measures ules may also develop in the heart or cia occurs in up to 27% of patients (40, and radiographic progression (105, the lungs (117). 48, 120, 125), but prompted discontin- 106). When leflunomide was added to uation in only 4% (51). Urticaria (126), an ongoing MTX treatment in patients Risks of MTX treatment in RA small vessel vasculitis, and granuloma- with an incomplete response to MTX, A superior "drug survival rate" indi- tous vasculitis are rare.

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Benefit and risk of methotrexate treatment in RA / R. Rau & G. Herborn

Hematopoetic system monary function changes (134). Rales mentation or even the unchanged con- Hematologic complications of weekly may be present on physical examina- tinuation of treatment (41,51,148). Fre- MTX treatment for RA are seen infre- tion, and interstitial infiltrates may be quent elevations of aminotransferases quently. In short term studies, even seen on chest radiographs. Lung biopsy indicate structural liver abnormalities with higher doses, they occurred in 2- may reveal hypersensitivity pneumoni- (149-152) and were correlated signifi- 3% in some reports (38,39,124), and in tis characterized by massive interstitial cantly with liver biopsy grades (153, 11% in another report (127). In long- and alveolar infiltration with inflam- 154). Galactose elimination capacity term studies, bone marrow side effects matory cells, predominantly lympho- and the aminopyrine breath test declin- occurred in up to 24% of patients (42, cytes, and granuloma formation with ed significantly during MTX treatment 48, 125). The most frequent abnormali- giant cells (135). Other causes of pul- over 3.8 years (155). ty is mild to moderate leucopenia (41). monary disease, e.g. nosocomial infec- A high prevalence of minor histologic In one long-term follow up, mild leu- tions (136-138), must be excluded be- changes in the liver of patients with RA copenia was observed in only 8 and fore a diagnosis of MTX-induced is seen (156, 157), which may be clas- mild thrombocytopenia in 7 out of 271 pneumonitis can be established. sified as mild reactive hepatitis in one- RA patients (51). Pancytopenia occur- Pulmonary complications occurred in third of patients (157). Some of these red in 7 of 511 patients (1.4%) included 2.1% to 6.8% of patients (140-142), but changes may be related to the underly- in prospective trials (128). The number some clinical studies did not encounter ing disease, as they can be observed of withdrawals due to cytopenia ranged any pulmonary complications (96, 143). before any drug treatment has taken from 0 to 5.9% (42, 48, 125). Impaired Between 1981 and 1993, 27 patients place. Comparative liver biopsy studies renal function (119,129), folic acid de- with MTX pneumonitis were identified did not show differences in a number of pletion (121), advanced age, current in- in 6 clinical centers, and reports on 68 histologic parameters, among them fection, multiple co-medication (128), patients were found in the medical lit- "necrosis", "inflammation" and "fibro- and treatment with trimetoprim-sul- erature (134). The mortality rate in these sis", between biopsies taken before and fametoxazol (128) have been identified patients was approximately 17.5% during MTX treatment (158,159), even as risk factors for bone marrow toxici- (134). Pre-existing lung disease does in cumulative doses of up to 8,400 mg ty. Usually, blood counts are normal- not seem to pre-dispose to MTX pul- (160). Minor fibrosis was present in ap- ized within 2 weeks after the withdraw- monary adverse events (139, 140). Fur- proximately 25% of patients before and al of MTX, but some patients may re- thermore, there is no evidence to sug- during MTX treatment (158). Only 5 of quire supplementation with folic acid gest that low-dose MTX is associated 25 liver biopsies demonstrated minor (121,130) or even treatment with colo- with chronic interstitial lung disease fibrosis in patients who received MTX ny stimulating factors (131). (144). for more than 10 years (161). However, Kremer observed a significant increase Central nervous system Liver toxicity of fibrosis in 29 patients with baseline Central nervous disturbances, includ- Among patients with psoriasis, liver and yearly follow-up biopsies over 4 ing headache, dizziness, vertigo, light- fibrosis and cirrhosis developed with years (162), and a significant increase headedness, and mood alterations were increasing cumulative doses in up to of the Roenigk score after 6 years reported in up to 36% of patients in 24% of patients treated with daily MTX. (163). long-term studies (41, 48, 118). Again, Risk factors for liver toxicity, in addi- Baseline electron microscopy showed advanced age and elevated serum crea- tion to daily dosing, included high al- collagen deposits in the space of Disse tinine are predisposing risk factors cohol consumption, obesity, and diabe- and lysosomal changes not seen in con- (132). In 2 patients with a history of ep- tes. Weekly dosing was found to be bet- trols (164), but these did not increase ilepsy, seizures reappeared within 6 ter tolerated than daily dosing. Aware- after a mean follow-up period of 8.2 weeks of starting MTX treatment and ness of potential liver side effects in the years (163). In several overviews, the disappeared when MTX was discontin- long-term treatment with MTX is nec- frequency of fibrosis among MTX- ued. essary, although hepatotoxicity has not treated RA patients was estimated to be been a substantial problem with weekly between 3% and 11%. Among RA pa- Respiratory system low-dose MTX in patients with RA. tients treated with MTX for more than MTX-induced lung disease is a rare, There are proposals to change the guide- 5 years, the incidence of cirrhosis was but potentially life-threatening compli- lines for monitoring liver function tests estimated to be 1:1000 (165). At these cation, and the rapid evaluation of pul- (145). levels, the risk of complications of liver monary symptoms in patients receiving Transient slight elevations in liver en- biopsy are greater than the risk of cir- MTX is crucial (133). The predominant zymes were observed in up to 48% of rhosis, and liver biopsy is rarely indi- symptoms of MTX pulmonitis are the patients in one study (146), and in 53% cated. subacute development of dyspnea and in a more recent study (147). These ele- dry non-productive cough and fever, vated levels returned to normal after Infections accompanied by headache, malaise, cy- dose reduction, a change in the concur- Infections occur more often in patients anosis, hypoxemia and restrictive pul- rent NSAID therapy, folic acid supple- treated with MTX than with other

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DMARDs (166,167), especially in pa- Oncogenicity prednisone without MTX (p = 0.004) tients with severe RA (168) and during Large studies of cancer and psoriasis (196). the first years of treatment. In prospec- did not establish an association be- tive studies, they were observed in up tween MTX and malignancy. RA pa- Folate supplementation does to 25% of patients (42). This pheno- tients have a disease-related increased reduce MTX toxicity menon may be confounded by a higher risk of developing certain lymphoid The mode of action of MTX may be rate of infections in patients with RA, malignancies. Cases of Hodgkin's dis- related in part to its activity particularly severe RA, and the fact ease (182, 183) and leukemia (184) (198), and several MTX adverse events that patients treated with MTX have have been reported in RA patients treat- mimic the clinical manifestations of more severe RA. Opportunistic infec- ed with MTX. The majorityÐmore than folate deficiency. Folate supplementa- tions (136,137,169), serious fungal in- 50 (185) Ð of cases with malignancy tion has been shown to reduce MTX fections (61, 170), increased frequency were non-Hodgkin-lymphomas (185), toxicity in several studies (199-203), of herpes zoster (167, 171), as well as most of which were associated with although in two studies toxicity was re-activation of hepatitis B (172) and Epstein-Barr-virus (EBV) infection unchanged (204, 205). In a large 48- tuberculosis (173,174) have been re- (186, 187). week randomised study, 434 RA pa- ported. Some patients must discontinue Whether MTX plays a role in the dev- tients beginning MTX treatment were MTX permanently because of recurrent elopment of lymphoma in RA patients supplemented with folic acid (1 mg/ infections, mostly affecting the small remains unclear (186). RA patients are day), folinic acid (2.5 mg/week), or pla- airways or the urinary tract. known to have a defect in HBV-direct- cebo. Side effect-related withdrawals Perioperative complications, i.e. wound ed suppressor T-cell-function (187). It occurred in 38% in the placebo group, infections or wound healing distur- is not established that MTX augments 17% in the folic acid group, and 12% in bances, were increased after orthopedic (or may correct) this T-cell-suppressor the folinic acid group. The difference surgery in some studies, but in others defect, although opportunistic infec- was almost entirely accounted for by an they were not. Some authors withhold tions are clearly associated with MTX elevation of hepatic transaminases (in- MTX for 2 weeks prior to surgery use (perhaps in patients with severe creased in 53% of all patients !). No (133), but others continue treatment RA) (188). The risk for RA patients to differences were seen between the through a surgical intervention (175). develop lymphoma while taking MTX groups with respect to all the other ad- is increased in those with severe dis- verse events (147). In one study, side Kidneys and the reproductive system ease activity, intense immunosuppres- effects were inversely related to red The excretion of MTX and its metabo- sion, genetic predisposition, and latent cell folate levels and occurred at levels lites is delayed in patients with impair- infections with EBV virus (185, 189). < 800 nmol/L (206). Unfortunately, in ed renal function, leading to potentially Some lymphomas associated with EBV all the other studies noted above the increased toxicity (10). MTX treatment infection remit after the discontinua- folate status was not documented. may also impair renal function, at least tion of MTX (185, 189, 191) or with in elderly patients; in one study the glo- treatment with rituximab (192). How- Folate supplementation may merular filtration rate and tubular ex- ever, in 16,263 patients with RA, no reduce MTX efficacy cretion was reduced by 10% during or- increase in lymphoma was observed in Although the mode of action of MTX is al MTX treatment with 15 mg weekly patients taking MTX (190). related in part to its antifolate activity without any co-medication (176). MTX (198), and the addition of folinic acid clearance and creatinine clearance also Bone reverses the inhibitory effect of MTX decreased with a stable MTX dose of Active RA is associated with osteopor- on cytokine production (15), there is 7.5 mg/week (177). These observations osis, especially in patients taking corti- still much controversy about whether emphasize the need to monitor creati- costeroids (193). In rats treated with or not folate supplementation diminish- nine levels during MTX treatment. MTX, the osteoid volume decreased sig- es the efficacy of MTX. With the ex- Oligospermia, impotence, and gyneco- nificantly, bone formation was reduced ception of one study (207), folate sup- mastia have been reported with MTX markedly (194), and significant osteo- plementation did not appear to interfere use in 11 cases. No malformations were penia developed through the suppres- with MTX efficacy (208). However, detected among 10 pregnancies during sion of osteoblast activity (195). How- the number of patients in these studies low-dose MTX treatment in RA pa- ever, in RA patients there was no dif- was small, and the outcome parameters tients (179). However, a case with mul- ference in bone mineral density be- were too insensitive to reliably recog- tiple congenital abnormalities has been tween those treated with and those not nize any effect on efficacy. In a Dutch described, after the mother had been treated with MTX (196,197). However, study (147), the final MTX dose was treated with weekly low-dose MTX when patients who were taking predni- higher in patients taking folic acid, during the first trimester of pregnancy sone in doses ≥ 5 mg/day were addi- compared with those receiving placebo (180). Furthermore, malformations have tionally treated with MTX, they show- (mean 18 and 14.5 mg/week, respec- been reported after MTX was used to ed significantly greater bone loss than tively), indicating an indirect reduction induce abortion (178). patients treated with a similar dose of in the MTX dose with folate supple-

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Benefit and risk of methotrexate treatment in RA / R. Rau & G. Herborn mentation. The MTX dose was adapted Personal recommendations for Table I. Contraindications to MTX thera- to achieve a sufficient response. In a administration and drug monitoring py. large phase III trial in the United States, MTX can be administered orally or by MTX with folate supplementation was intra-muscular, intravenous, or subcu- 1. Renal insufficiency (serum creatinine > upper limit) less effective than leflunomide, com- taneous injection with doses ranging 2. Inadequate contraception pared to a corresponding European stu- from 7.5Ð30 mg once a week. The dose 3. Active liver disease dy in which MTX without folate sup- depends on body weight, gender, renal 4. Regular alcohol intake plementation was significantly more function, concomitant disease, general 5. Acute or chronic infection effective than leflunomide (86, 88). health status, and disease activity. 6. Leucopenia or thrombocytopenia It has been suggested that homocys- We usually start treatment with a rela- (exception: Felty's syndrome) teine is an independent risk factor for tively high dose of 15Ð25 mg given 7. Serious underlying systemic disease cardiovascular disease and mortality. parenterally to exclude the individual 8. Non-compliance Folic acid supplementation can prevent differences in bioavailability of oral me- the increase in homocysteine concen- dication and to achieve a rapid re- tration caused by MTX treatment (209, sponse. After 6-12 weeks, most pa- full blood counts, including the differ- 210). However, there are no reports tients are converted to oral medication ential white blood count and platelets, about increased cardiovascular mortali- and the dose is adjusted according to serum creatinine, and aminotransferas- ty in RA patients treated with MTX. On efficacy and tolerability. Most rheuma- es, weekly during the first month, ev- the contrary, MTX treatment reduced tologists prefer to begin with lower oral ery two weeks during months 2 and 3, the risk of all-cause mortality by 60% doses, and then increase the dosage. and monthly thereafter. and reduced even more the risk of car- Tolerability can often be improved by MTX should be discontinued tempor- diovascular mortality (211). As inflam- administering the drug in the evening arily under the following conditions: matory mechanisms seem to be impor- or in two equal doses in the morning serum creatinine exceeding normal val- tant for the development of atheroscle- and evening of the same day, by chang- ues; aminotransferases exceeding 3- rosis, the reduction in cardiovascular ing the route of administration (paren- fold the normal values; leucopenia or mortality may be explained by the sup- teral versus oral), reducing the dose, or thrombocytopenia; stomatitis; acute in- pression of inflammation (212). An in- by supplementation with folic acid. fections; severe concurrent illness; crease in life expectancy was clearly Nausea and vomiting frequently may concomitant treatment with sulfonam- related to a good response to MTX (213). indicate the presence of a peptic ulcer. ides; or acute pulmonary symptoms. However, in RA patients with estab- Possible interactions with NSAIDs Whether MTX should be discontinued lished cardiovascular disease and/or should taken into consideration. We before and after surgery should be de- hypertension, MTX was associated with consider folate supplementation when cided in co-operation with the operat- an increased risk of death by a factor of side effects occur in the presence of ing surgeon. Pre-treatment liver biop- 3.4 (214). An intriguing observation in- concomitant folate deficiency. With 5 sies are recommended only in patients dicated that homocysteine levels were mg of folic acid 2 days after MTX ap- with significant alcohol consumption correlated significantly with disease plication, folate levels usually normal- or a history of liver disease. Biopsies activity (p < 0.001) and with creatinine ize after several weeks and supplemen- during MTX treatment are recommen- levels (p < 0.001). These data suggest tation can be stopped. Most authors re- ded only if over 50% of the ALT (ala- that MTX may increase homocysteine commend folic supplementation with 1 nine aminotransferase) level readings levels in some patients by inducing mg per day. within 1 year Ð measured every 4-8 mild renal insufficiency (215). Relative or absolute contraindications weeks Ð are elevated to more than twice The improvement in MTX tolerability to MTX treatment are listed in Table I. the normal level, or if the serum albu- by folate supplementation may, at least If there is no alternative to MTX in a min concentration falls below normal. in part, be due to a relative dose reduc- patient with renal impairment, we start Treatment can be continued if liver tion of MTX, which in turn results in with lower doses (i.e. 5 mg/week) and biopsies reveal a Roenigk-class I, II or the need to increase the dose of MTX. check the MTX serum level after 24 IIIa. In patients with moderate to sev- Over the last 10-15 years the mean hours to ensure that it is below 0.05 ere fibrosis or cirrhosis (class IIIb or MTX dose in American long-term ob- mM/l. Regular monitoring of serum IV), MTX should be permanently dis- servational studies has been steadily creatinine is necessary to avoid toxici- continued (152, 216). increasing. Therefore, we have supple- ty. Women with childbearing potential Parameters of disease activity, radio- mented folic only temporarily in those should practice adequate contracep- graphic progression, the development patients who experienced side effects tion. The safe amount of alcohol con- of deformities, and functional capacity in the presence of folate deficiency, and sumption while taking MTX is not should be monitored regularly. In the had good experience with this strategy. known and may differ from patient to case of unsatisfactory response we in- However, most authors recommend patient. Usually, we allow only one or crease the dose or, if this is impossible, folic acid supplementation in all pa- two glasses of wine or beer per week. combine MTX with another conven- tients. During MTX treatment, we monitor tional DMARD or a biologic agent.

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