Antimalarials
The first report of efficacy in RA with antimalarial therapy was in 1951. In the late 1970 s, the popularity of antimalari- als decreased due to concern for ocular toxicity. This senti- ment has reversed with the recognition of the rarity of this adverse event when appropriate doses of antimalarials are
given and vigilance is exercised. Two antimalarial medica- tions are usually used for the treatment of RA: hydroxychlo- roquine and chloroquine; hydroxychloroquine is used more often in North America and chloroquine is used more fre- quently in Central and South America.
Currently, the mechanism(s) of action for hydroxychloro- quine and chloroquine are not well understood. However, several theories have emerged to explain their action in RA patients. These agents may block the activation of toll-like receptors (TLR) TLR9, TLR3, and TLR7 and act as anti- inflammatory agents [42, 43]. In addition, the literature sug- gests that antimalarial therapies may interfere with lysosomal action within cells, thereby decreasing the production of cytokines and other inflammatory mediators [44]. In general, the mechanism of action of hydroxychloroquine and chloro- quine are very similar [45, 46].
However, one study specifically evaluating chloroquine found an overall decrease in TNF-messenger RNA and secre- tion of TNF [47]. In addition, Oerlemans et al. demonstrated chloroquine resistance was associated with the overexpres- sion of multidrug resistance-associated protein 1, thus it may theoretically increase drug resistance [48].
Clinical Pharmacology
Approximately 75% of hydroxychloroquine and chloroquine are rapidly absorbed. Hydroxychloroquine has an elimina- tion half-life of 7–40 days and its metabolites are 50% bound to albumin [49]. Hydroxychloroquine is metabolized by the liver (30–60%) and eliminated through the kidneys (45%), intestine (5%), skin (7.3%), and feces (24%).
For antimalarials, the onset of action is slow and it may take 6–9 months to fully assess efficacy [50]. It is felt that it is important that the dose of hydroxychloroquine be less than or equal to 6.5 mg/kg per day [51]. Hydroxychloroquine can be given once daily and is usually given at doses between 200 and 400 mg and chloroquine can be given at a dose of 250 mg per day.
Efficacy
Hydroxychloroquine is efficacious in treating RA, although it is less efficacious than sulfasalazine or methotrexate. In a double-blind, randomized trial of hydroxychloroquine (400 mg per day) or placebo in 126 RA patients, hydroxy- chloroquine demonstrated a clinically and statistically sig- nificant improvement over placebo in joint score, pain, grip strength, and patient and physician global assessments [52].
To date, there is no data supporting a decrease in radiographic progression of RA [53]. However, when used in combination
155 17 Disease-Modifying Antirheumatic Drug Use in Older Rheumatoid Arthritis Patients
with methotrexate and sulfasalazine, hydroxychloroquine is shown to have a synergistic effect.
Interestingly, antimalarials decrease dyslipidemia, can be used as an anti-coagulant in high doses, and reduce the risk of developing diabetes in patients with RA [54–56].
Safety
Antimalarials are generally well tolerated and have minimal serious side effects. In a study of 1,042 patients with various rheumatologic diseases, among which 558 patients had RA, 57% of the patients received chloroquine and 43% received hydroxychloroquine. The hazard ratio (HR) for discontinua- tions due to toxicity was lower for hydroxychloroquine (HR = 0.6, 95% CI 0.4, 0.9), while hydroxychloroquine was associated with a higher HR for discontinuations due to inef- ficacy (HR = 1.4, 95% CI 1.1, 1.9) compared with the chloro- quine group. Thus, use of hydroxychloroquine is associated with less toxicity, but at the same time, is less effective than chloroquine [57].
Although the most common side effects include head- ache, nausea, and skin rash, the rare (0.5%) but most con- cerning adverse reaction is hydroxychloroquine or chloroquine-related retinopathy [51]. There is a relation- ship between total dose and toxicity, with cumulative doses of 500 g hydroxychloroquine being associated with more retinopathy [58]. However, in a study of 270 RA patients who received chloroquine treatment, the frequency of maculopathy increased with increased total dose only in the older age group (age >63) [59]. Risk factors for hydroxychloroquine retinopathy include daily dosage of hydroxychloroquine (exceeding 6.5 mg/kg), cumulative dosage (above 500 g), duration of treatment, coexisting renal or liver disease, patient age, and concomitant retinal disease [60]. In a retrospective study of 139 patients (54, 49, and 36 cases of RA, systemic lupus erythematosus, and scleroderma, respectively) who received chloroquine treat- ment, ocular toxicities (retinopathy and corneal deposi- tion) were seen more frequently in those with lower creatinine clearance (66.9 ± 26.9 vs. 72.3 ± 20.0 ml/min, p-value: 0.046); age did not play a role in this analysis [61].
It must be noted, however, that there is a high prevalence of macular degeneration in the older population, and hydroxy- chloroquine and chloroquine may make appropriate screen- ing difficult.
Decreased hepatic toxicity is seen with concomitant use of hydroxychloroquine with methotrexate. In fact, efficacy is increased with the combination of these two drugs when compared with single therapy. There is evidence that the effi- cacy of hydroxychloroquine and methotrexate is maintained for an additional 3 months after methotrexate is discontinued [62]. These effects may be due to increased gastric emptying of
methotrexate when used in combination with antimalarials and changes in the pharmacokinetics of methotrexate in methotrexate–hydroxychloroquine combination [63]. In a small randomized, crossover study in 10 healthy subjects, the mean area under the concentration–time curve for metho- trexate was increased (p-value : 0.005) when methotrexate was coadministered with hydroxychloroquine, compared with methotrexate alone [64].
Although antimalarials are generally well tolerated, gas- trointestinal toxicities (such as dyspepsia, nausea, etc.) and rarely myopathy and cardiotoxicity can occur. Older age may be a risk factor for developing ocular toxicity in RA patients receiving antimalarials, since it is seen to occur more com- monly in patients with renal impairment and older patients are more prone to this condition. In addition, the relatively high frequency of cataracts and macular degeneration in the older person might make it difficult for appropriate hydroxy- chloroquine toxicity screening.
Leflunomide
Leflunomide or N-(4-trifluoromethylphenyl)-5-methylisoxazole- 4-carboxamide is an isoxazole immunomodulatory agent that inhibits pyrimidine synthesis and results in cell cycle arrest, especially in rapidly dividing cell such as activated lymphocytes [65]. Leflunomide was originally developed specifically for RA by Bartlett and Schleyerbach in 1985 [66]. It was approved by the Food and Drug Administration (FDA) for RA treatment in 1998 and is indicated in early or late disease with moderate-to- severe RA.
Clinical Pharmacology
Approximately 50% of leflunomide is absorbed in the gas- trointestinal tract and is converted into its active metabolite A77 1726 (referred as M1). A77 1726 is responsible for most of the drug’s biologic effects in vivo. It is highly protein bound with a low volume of distribution and has a rather long half-life of 15–18 days. Approximately two-thirds of M1 is excreted in the feces and one-third in the urine.
A77 1726 prevents lymphocytic proliferation by inhibit- ing dihydroorotate dehydrogenase, a mitochondrial enzyme vital to the de novo synthesis of pyrimidine. Leflunomide also inhibits the activity of tyrosine kinases, nuclear factor kappa-B [NFk(kappa)B], and chemotaxis via intracellular adhesion molecules and vascular cell adhesion molecules [67–69]. Since the mechanism of action of leflunomide is different from methotrexate, these drugs can be used in the combination to treat RA [70].
Efficacy
Leflunomide is used (about 10% of prescriptions) to treat RA, with good evidence that it decreases the rate of radio- graphic progression. Four multicenter double-blind RA clinical trials demonstrated that leflunomide monotherapy is efficacious [65, 71–73]. Leflunomide is superior to pla- cebo and is as efficacious as sulfasalazine and methotrexate in RA. Leflunomide improves functional scores (Health Assessment Questionnaire–Disability Index [HAQ–DI]) by 0.37 at 12 months [74] and demonstrates an improved American College of Rheumatology (ACR) response (spe- cifically, ACR20) vs. placebo at 24 weeks.
There are no specific studies in the literature evaluating the efficacy of leflunomide in older RA patients. A lefluno- mide consensus report stated that there was no need for dose reduction when using leflunomide in older RA patients, although the prescriber should be cautious about comorbidi- ties (specifically renal insufficiency) and drug interactions.
These recommendations were based on expert opinion and meta-analyses of available data, though no subanalysis of older RA patients was presented.
Safety
When RA patients are treated with leflunomide, the most common side effects include gastrointestinal symptoms:
diarrhea (17%), nausea (9%), abdominal pain (5%), and increased hepatic enzymes (5–10%) [75]. Many adverse events are transient and require no change in dosing regi- mens, while others can be managed by dose reduction and symptomatic treatment. However, due to the long half-life of leflunomide and its M1 metabolite (usually between 15 and 18 days, although highly variable), a dose reduction from 20 to 10 mg will not cause a rapid improvement of adverse events. Cholestyramine (8 g three times daily for 11 days) may be required to diminish adverse effects rapidly; shorten- ing the clearance time to 3 months [74].
Although there are no studies specifically directed to eval- uating adverse events in older RA patients treated with leflunomide, two small studies have reported associated side effects. Chan et al. reported 18 cases of pancytopenia associ- ated with leflunomide in Australia since 2000. Median age of these patients was 65.5 years (range 18–79 years), 16 of 18 patients were above the age of 60; 14 patients used concomi- tant methotrexate. Five of the eighteen patients died second- ary to pancytopenia and three of those five patients were above the age of 60. The authors felt that older age (>60 years) and concomitant use of methotrexate may increase the risk for pancytopenia [76].
One study evaluated the incidence and predictors of peripheral neuropathy in leflunomide-treated patients [77].
Of 113 consecutive patients started on leflunomide, eight patients were newly diagnosed with peripheral neuropathy, while two patients had worsening of their existing peripheral neuropathy (9%). Patients with neuropathy were more likely to be older, diabetic, and taking concomitant neurotoxic medications. No multivariate analysis was not done to evalu- ate whether age was an independent risk factor for lefluno- mide-induced peripheral neuropathy.
In summary, there are no adequate data to examine the comparative efficacy and toxicity of leflunomide in older ver- sus younger RA patients. Treatment guidelines for older RA patients are similar to those for the general population, while being cognizant of commonly associated comorbidities (e.g., renal insufficiency and nonalcoholic steatohepatitis) in the older patients that may change treatment regimens.
Methotrexate
The results of several randomized clinical trials in the 1980s led to the FDA’s approval of methotrexate for use in RA patients [78–81]. Since that approval (and even before), methotrexate has been accepted as a first-line agent for RA treatment in the USA for patients of all ages. The results of one study showed that older-onset RA patients (>60 years) used methotrexate more often when compared with younger-onset RA patients having the same disease duration (N: 2,101; 63.9 vs. 59.6%; p-value < 0.01). However, the methotrexate dose used in older RA patients was lower than that used in younger RA patients (median 11 vs. 16 mg) [6].
Clinical Pharmacology
Several mechanisms for the action of methotrexate have been proposed. Methotrexate competitively inhibits dihydrofolate reductase (DHFR) and also inhibits aminoimidazole carbox- amide ribonucleotide (AICAR) [82]. DHFR reduces dihy- drofolic acid to tetrahydrofolic acid, a cofactor necessary for DNA synthesis [83]. Through AICAR, methotrexate also decreases monocyte and neutrophil chemotaxis. Secondary effects through these mechanisms include decreased mono- cyte proliferation and increased apoptosis. Other downstream effects include the inhibition of cyclo-oxygenase/lipoxyge- nases and synovial metalloproteinases [84].
Methotrexate is administered weekly and it may be given orally, subcutaneously, or intramuscularly. Oral methotrex- ate has an absolute bioavailability of 70–75%, although there is great variability. Methotrexate is 50% protein bound, and a small fraction (up to about 10%) is monohydroxylated to 7-OH-methotrexate in the liver. Once in the cells, it is poly- glutamated to methotrexate glutamates of varying lengths
157 17 Disease-Modifying Antirheumatic Drug Use in Older Rheumatoid Arthritis Patients
[85]. These remain in cells for prolonged periods and are responsible for prolonged enzyme inhibition [86, 87].
Methotrexate has an elimination half-life of 8–24 h. It is principally eliminated renally, with about 50–80% removed through glomerular filtration [86, 87], while 9–26% is elimi- nated through the bile [86, 88]. Since renal function decreases with age, the methotrexate dosage regimen may need to be adjusted in older RA patients, although it is also possible that there is a compensatory increase in biliary clearance so that the decreased renal clearance is partially compensated [89].
The results of a study comparing methotrexate pharmacoki- netics of older RA patients (65–83 years) with younger patients (21–45 years) revealed a longer elimination half-life of methotrexate in the older RA group [90]. The free and total clearances of methotrexate were 169 and 95.9 ml/min in the older patients versus 225 and 126 in the younger RA patients, respectively (p-values <0.001). Overall, methotrex- ate clearance had a stronger correlation with creatinine clear- ance than with age. Therefore, dosing regimen should be adjusted in patients with renal insufficiency, without a pri- mary focus on age per se.
NSAIDs sometimes increase serum methotrexate concen- trations by inhibiting renal clearance of methotrexate [85, 86], although this has not necessarily resulted in increased toxicity at the low doses of methotrexate used in rheumatology [91].
Given the relative decrease in renal function with aging, older RA patients should be monitored more closely when using methotrexate and NSAIDs together [92]. No specific pharma- cokinetic/pharmacodynamic interactions were reported with concomitant use of the cyclo-oxygenase-2 inhibitor celecoxib and methotrexate [93]. Pharmacodynamic interactions can occur when methotrexate and folate antagonists are used together [92]. For example, cotrimoxazole and other folate antagonists can interact with methotrexate to produce life- threatening pancytopenia [85, 94, 95].
Efficacy
Methotrexate is one of the most effective medications for the treatment of RA [96, 97]. Patients receiving methotrexate remain on it longer than any other nonbiologic DMARD (NBD) and studies have shown that >50% of RA patients continue its use for at least 5 years [98]. Also, among NBDs, methotrexate has a relatively rapid onset of action and slows the rate of radiographic progression compared with some other NBDs [31, 99, 100].
In a cohort study of 235 RA patients investigating the effect of age on methotrexate efficacy and toxicity, Wolf et al. reported no difference in methotrexate efficacy in older (> 65 years) versus younger groups [101]. In addition, a review of 11 methotrexate clinical trials, comprising 496 RA patients (69% below the age of 60), showed that age did not
affect methotrexate efficacy. There were similar reported tender/swollen joint counts, erythrocyte sedimentation rates, and pain levels for the patients in the older and younger groups [102].
Interestingly, one study showed that a lower weekly methotrexate dose was used in a group of older-onset RA patients when compared with younger-onset RA patients (median = 11 mg vs. 16 mg), with equal efficacy in the two groups [6]. As renal function decreases in the older patients, resulting in the potential for lower methotrexate renal clear- ance and higher methotrexate concentrations, this difference may actually be due to a differential pharmacokinetic effect.
Safety
Methotrexate is tolerated well by most patients, with 10–30%
of patients discontinuing the drug due to toxicity [85, 97, 99, 103]. Some adverse effects (AEs) mimic the symptoms of folate deficiency (e.g., nausea, diarrhea, and abdominal pain); possibly due to the antifolate activity of methotrexate [99], thus folic acid supplementation helps to reduce these symptoms. Unfortunately, it does so at the expense of an approximately 10% loss in efficacy [104].
Both mild and moderate infections have been associated with methotrexate usage, though there are no apparent differ- ences in the incidence of infections between older and younger RA patients [105]. In a recent study, Shunsuke et al.
speculate that methotrexate-associated pneumocystis jiroveci pneumonia (PCP) is more commonly seen in older RA patients based on case reports and anecdotal literature review.
Of the 15 cases in their review, 13 patients were above the age of 60; in most cases, PCP occurred within 1 year of ini- tiating methotrexate [106].
Hepatotoxicity, including elevated liver enzymes, liver fibrosis, and cirrhosis, is another side effect of methotrexate.
In a review by Nyfors in 1980 of psoriatic arthritis patients, hepatic toxicity was more common in the older patients;
however, age-related renal function changes were not accounted for in this study [107].
Pulmonary side effects secondary to methotrexate can be worrisome. However, these are rare complications when methotrexate is used in RA. Acute hypersensitivity pneu- monitis, the most common of the methotrexate-induced lung diseases, occurs in less than 1% of patients. Patients can pres- ent with dyspnea, hypoxia, fevers, nonproductive cough, and infiltrates on chest X-ray [108]. Although some reports show that age is not related to an increase risk of methotrexate pul- monary toxicity in RA patients [109, 110], a multicenter study by Alarcon et al. showed a sixfold increase in metho- trexate-induced pulmonary toxicity in RA patients above the age of 60 compared with younger RA patients [111].
In addition, Engelbrecht et al. described six older RA patients
with acute methotrexate pneumonitis (ages ranged between 58 and 75 years) [112]. Thus, it is our view that rheuma- tologists should keep these uncommon-to-rare pulmonary complications of methotrexate in mind when prescribing it in the older RA patients.
There is much debate regarding a possible increased risk of cancer in RA patients receiving methotrexate treatment.
RA patients on methotrexate have developed Hodgkin’s and non-Hodgkin’s lymphomas and leukemia [86, 103, 113];
however, it is not clear whether these are related to the dis- ease itself, whether it occurs secondary to methotrexate treat- ment, or whether this is due to a combination of an underlying Epstein–Barr virus infection plus methotrexate [114–116].
In summary, the results of most studies suggest that meth- otrexate is just as effective in older RA patients as in younger RA patients. When evaluating safety, older RA patients being treated with methotrexate do not seem to be at a higher risk for AEs [105]. However, particularly in frail older individu- als who have potentially occult, compromised renal function, careful monitoring with complete blood count, liver, and renal function testing is advisable.
Sulfasalazine
In 1938, Professor Nana Svartz created sulfasalazine by com- bining an antibiotic (sulfapyridine) with an anti-inflammatory agent (salicylic acid) [117, 118]. The drug was rarely used until 1980 when McConkey et al. published findings showing sulfasalazine’s superior efficacy when compared with intra- muscular gold and penicillamine in RA patients [119].
Clinical Pharmacology
Sulfasalazine is a combination of sulfapyridine and 5-amino- salicylic acid (ASA). It is felt that sulfapyridine and sul- fasalazine are the active agents in RA, while 5-ASA is the principle active agent in inflammatory bowel disease [120].
Approximately 20–30% of sulfasalazine is absorbed (mainly in the small intestine), while 5-ASA is not [121]. Sulfasalazine undergoes enterohepatic circulation, resulting in a sulfasala- zine parent compound bioavailability of 10%. The other 70%
of sulfasalazine reaches the colon intact and is metabolized by bacteria to sulfapyridine and 5-ASA. Sulfapyridine is metabolized in the liver (acetylated and hydroxylated) and its metabolites are excreted in the urine.
The half-life of sulfasalazine per se for fast acetylators is 6 h, whereas in slow acetylators the half-life is 14 h [122].
Some studies demonstrated more toxicity in slow acetylators compared with fast acetylators, principally an increase in gastrointestinal side effects [123–125]. The clinical pharma- cokinetics of enteric-coated sulphasalazine (Salazopyrin-EN)
were evaluated in 12 older and 8 young ‘active’ RA patients (mean age 74.4 vs. 40.5; range 71–83 years vs. 35–46 years).
This study revealed that the time to reach maximum concen- tration of drug, elimination half-life, and volume of distribu- tion of sulfapyridine were increased in the older patient after a single dose of Salazopyrin-EN at 2 g was given. These dif- ferences compared with younger patients disappeared with continued sulfasalazine use. The acetylator status, rather than age, determined maximum concentration of the drug, elimination half-life, “steady-state” serum concentration, apparent volume of distribution, and total clearance of sul- fapyridine. It was concluded that acetylator phenotype rather than age plays a significant role in the pharmacokinetics of sulfasalazine [124].
Efficacy
With the increased use of methotrexate and the advent of mul- tiple DMARDs used in combination and the appearance of biologics over the last 10–15 years, sulfasalazine is no longer a first-line agent. Sulfasalazine is usually used in combination with other DMARDs, rather than as monotherapy.
Sulfasalazine is an effective medication which improves both clinical and laboratory measure of RA disease activity and slows radiographic progression [126, 127]. It has a more rapid onset of action (4–6 weeks) and greater efficacy than hydroxychloroquine [128–130]. Sulfasalazine is as effica- cious as intramuscular gold, penicillamine, and leflunomide, with less toxicity [128].
Wilkieson et al. retrospectively evaluated 352 RA patients in five clinical trials to examine the medium- to long-term efficacy of sulfasalazine in the older patients [131]. The patients were categorized into three groups: <45 years, between 45 and 65 years, and >65 years. The >65-year-old RA patients’ baseline values for erythrocyte sedimentation rate, C-reactive protein (CRP), morning stiffness, and pain were increased compared with the two other groups.
However, each group improved significantly compared with baseline values with sulfasalazine treatment.
Safety
Seventeen to thirty percent of sulfasalazine treated patients discontinue therapy due to AEs during the first year. AEs most frequently occur within the first few months of therapy;
this incidence can be decreased by starting at a low dose with gradual dose escalation – increasing by 500 mg every week to a maximum dose of 2–3 g [128]. Common AEs include gastrointestinal disturbances (nausea, vomiting, and gastric distress), dizziness, skin rash, decreased sperm count, and anorexia. In a small study of 50 sulfasalazine naïve patients who were randomized to receive uncoated and enteric-coated