CASE 44-5, QUESTION 6: When being counseled regarding HCQ, T.Z. was told that the drug can cause
What monitoring parameters are appropriate?
HCQ is usually well tolerated. The most serious toxicity, retinal damage and
subsequent visual impairment, is rare.
28,128 Risk of retinopathy is increased with high
cumulative doses (>800 g), increased age (>60 years), liver disease, and retinal
disease. The increased risk of retinopathy in the elderly seems to be related to the
increased prevalence of macular disease in this age group. Daily HCQ doses <5
mg/kg for the first 5 years are very rarely associated with increased risk of retinal
damage, particularly in patients without renal or hepatic dysfunction. HCQ should not
be used for patients with significant renal impairment.
Patients should be instructed to stop therapy immediately and undergo an
poor night vision, and loss of peripheral vision).
129 The fully developed lesion of
antimalarial retinopathy is seen on ophthalmoscopy as a pigmentary disturbance with
a characteristic bull’s-eye appearance in the macular region. The 4-amino-quinolines
bind to melanin, and as a result,
concentrate in the uveal tract and retinal pigment epithelium. The retinopathy can
be progressive even after discontinuation of the drug.
A baseline eye examination is recommended prior to starting HCQ therapy, then
annually after 5 years of treatment.
130 More frequent testing is recommended for
Taking more than 6.5 mg/kg daily
Who have received a cumulative dose of >200 mg
With existing poor visual acuity
become apparent, and what adverse effects might be anticipated?
The onset of SSZ effect is generally more rapid than that of HCQ, usually
providing benefits within 2 to 3 months.
130 Overall, SSZ adverse effects are
relatively mild, although SSZ is considered to be slightly more toxic than HCQ.
Adverse effects include nausea, abdominal discomfort, heartburn, dizziness,
headaches, skin rashes, and, rarely, hematologic effects such as leukopenia (1%–3%)
or thrombocytopenia. A complete blood count (CBC) is recommended every 2 to 4
weeks for the first 3 months of therapy, then every 3 months thereafter. Leukopenia,
agranulocytosis, or hepatitis are rare, but serious side effects of SSZ usually manifest
within the first 2 to 3 months of therapy. To minimize GI-related adverse effects, SSZ
is initiated at 500 mg/day or 1 g/day, and the dosage is increased at weekly intervals
by 500 mg until 1,000 mg 2 or 3 times daily is reached.
QUESTION 1: S.S., a 41-year-old Asian woman diagnosed with RA, presents with inflammation in both
left. A decision is made to treat S.S. with MTX. Why is MTX a good selection for her?
MTX is recommended as initial DMARD therapy for all patients with RA.
has many indicators of severe disease (e.g., an SDAI score indicating high disease
activity [see Table 44-7], multiple joint involvement, extra-articular manifestations
[i.e., subcutaneous nodules], radiographic evidence of erosions, elevated ESR,
positive anti-CCP, positive RF with a high titer of 1:1,280 [high titers correlate with
greater disease severity]). MTX is ideal because it has a rapid onset (usually 1–2
months before a plateau of effectiveness), a high efficacy rate at managing symptoms
and slowing disease progression, low toxicity, and a long history of successful use.
CASE 44-6, QUESTION 2: How should MTX be dosed and administered to S.S.?
In general, MTX is administered orally at an initial dose of 7.5 mg once a week,
usually in a single weekly dose. The dose can also be divided into three equal parts
(e.g., starting dose of 2.5 mg every 12 hours for a total of three doses) for patients
who are unable to tolerate adverse effects, particularly hepatotoxicity.
shows no objective response in 1 to 2 months, the dose is increased to 15 mg/week
(or 5 mg every 12 hours for three doses) for at least 12 additional weeks. If no
response is seen at this time, then (a) the dose can be increased to the maximum of 25
mg/week, (b) the dose can be administered as a subcutaneous or IM injection to
address bioavailability concerns, (c) the same dose can be continued for a longer
time, or (d) another DMARD can be added to MTX or MTX can be substituted.
When subcutaneous MTX was compared with oral MTX in a 6-month randomized,
controlled trial of 384 MTX-naïve patients with active RA,
treated with subcutaneous MTX achieved an ACR-20 response, and only 70% of
those treated with oral MTX achieved a similar response. At week 16 of this study,
patients treated with oral MTX, who failed to attain an ACR-20 response, were
switched to subcutaneous MTX; patients treated with subcutaneous MTX who failed
to attain an ACR-20 response were given a larger MTX dose (20 mg)
subcutaneously. The patients who were converted from oral dosing to subcutaneous
dosing and the patients who were given a larger subcutaneous dose had a 30% and
23% ACR response rate at week 24, respectively. As a result, subcutaneous MTX
seems to be more effective than oral MTX and not associated with a higher incidence
CASE 44-6, QUESTION 3: What subjective and objective data should be evaluated for evidence of MTX
S.S. should be monitored for nausea and other GI distress, malaise, dizziness,
mucositis, and mild alopecia, which are commonly encountered adverse effects
associated with low-dose MTX therapy.
128 More serious, but less common, adverse
effects include myelosuppression, pneumonitis, and hepatic fibrosis and cirrhosis. A
CBC, LFTs, and a serum creatinine concentration should be obtained for her at
baseline, monthly for the first 6 months of therapy, and then every 4 to 8 weeks during
MTX therapy. Renal dysfunction can result in accumulation of MTX and higher risk
of myelosuppression. Interstitial pneumonitis, occurring in <1% of patients, has no
known risk factors for development, although it may be more common in patients
with a history of lung disease.
In addition, interstitial pneumonitis can occur at any
time during therapy and at any MTX dosage. A baseline chest radiograph is
recommended within the year before MTX initiation. If the patient is found to have
preexisting lung disease, MTX treatment should be reconsidered because further
pulmonary damage could be devastating to the patient. S.S. also should be monitored
carefully for cough, dyspnea on exertion, and shortness of breath at each clinic visit.
MTX-induced liver disease is rare, but increased age, long duration of therapy,
obesity, diabetes mellitus, ethanol consumption, and a history of hepatitis B or C
increase the risk of hepatotoxicity.
131 MTX should be prescribed with great caution,
if at all, in patients with preexisting liver disease. The serum concentrations of liver
enzymes commonly are modestly increased
after administration for 1 to 2 days. However, MTX should be withheld if liver
enzymes increase to 3 times the baseline value or if the liver enzyme serum
concentrations remain elevated for sustained periods during therapy. Patients taking
MTX should avoid alcohol and be instructed to report symptoms of jaundice or dark
CASE 44-6, QUESTION 4: The following laboratory test results were obtained for S.S. before starting
Aspartate aminotransferase (AST), 30 IU/L
Alkaline phosphatase, 100 IU/L
Should a baseline liver biopsy be performed before S.S. starts MTX?
Liver biopsy is only recommended at baseline for MTX patients who have a
history of heavy alcohol consumption, persistently elevated liver function tests
(defined as elevations above the upper limit of normal [ULN] in AST for 5 of 9 tests
within a 12-month period [or 6 of 12 if tests are performed every month] or a
reduction in serum albumin below normal range), or chronic hepatitis B or C. During
therapy, patients with persistently elevated liver functions tests or serum albumin
below normal range should have a repeat liver biopsy. Otherwise, routine liver
biopsy is unnecessary and not cost-effective.
131 Diligent liver function testing has
proven to be highly effective at preventing liver injury.
escalating methotrexate dosing, ALT with or without AST, creatinine and CBC
should be checked every 4 to 6 weeks until stable dosing is achieved, then testing
should be repeated every 1 to 3 months thereafter along with screening for adverse
effects and hepatotoxicity risk factors at every visit.
Because S.S.’s LFTs are normal and there is not a history of liver disease noted,
there is no reason to consider a baseline liver biopsy.
Methotrexate and Folate or Folinic Acid
Folate supplementation appears to reduce the incidence of several MTX-related
adverse effects including GI disturbances, mucositis (mouth or GI ulcerations), and
133 The current consensus and evidence-based recommendation is >5
mg folic acid daily. Although daily doses of folic acid as low as 1 mg are associated
with protection against liver toxicity, GI disturbances are best prevented at doses
above 5 mg daily. Although folinic acid has also proven to be effective at lowering
GI and hepatotoxicity, doses above 5 mg/week are associated with worsening of
arthritis symptoms, consistent with the fact that MTX is a folate antagonist, and folic
acid supplementation could adversely impact efficacy.
Methotrexate-Related Pulmonary Disorders
CASE 44-6, QUESTION 6: S.S. is treated with MTX 7.5 mg and with folic acid 7 mg orally once a week.
dyspnea in the past week. Why might these symptoms be related to MTX?
Pneumonitis, a rare complication of MTX therapy, is characterized by a
nonproductive cough, malaise, and fever, progressing to severe dyspnea.
factors include older age (over 60 years), previous use of DMARDs, low albumin,
and diabetes. Recognition of this unusual reaction is important to ensure that MTX is
discontinued before the pneumonitis progresses to respiratory failure. After
discontinuation of MTX, pulmonary function improves. Corticosteroids can
accelerate improvement in pulmonary symptoms associated with pneumonitis. S.S.’s
dyspnea and shortness of breath might be related to MTX. If appropriate tests rule out
other causes for her pulmonary complaints, MTX-induced pulmonary toxicity should
be considered and MTX treatment discontinued.
CASE 44-6, QUESTION 7: What major MTX food and drug interactions need to be discussed with S.S. by
NSAIDs increase MTX serum concentrations and increase the risk of toxicity.
MTX doses should be adjusted cautiously if S.S. is taking NSAIDs concurrently to
manage her RA pain. Trimethoprim, frequently used as part of the treatment for
urinary tract infections, can increase the risk of MTX-induced bone marrow
suppression. The concurrent use of MTX and LEF has been associated with major
liver damage, including fatalities; as a result, this combination should be avoided.
The inorganic acids in cola drinks appear to delay MTX elimination and can increase
risk of toxicity, including renal toxicity; as a result, cola drinks should be avoided
135 Because MTX is protein bound and renally excreted, other
drugs (e.g., salicylates, probenecid, penicillin, and ciprofloxacin) also might interact
MTX therapy. Would LEF be a reasonable consideration for her?
LEF, an oral csDMARD, seems to be similar in efficacy to MTX with regard to
ACR-20, radiographic response, and work productivity.
early as 4 weeks) and the percentage of patients who discontinue LEF therapy
because of either lack of efficacy or toxicity are similar for LEF, MTX, and SSZ. The
preferred initial csDMARD is MTX because of a long history of safety and efficacy,
but LEF is a reasonable consideration as a replacement for MTX-intolerant patients,
CASE 44-7, QUESTION 2: How should therapy with LEF be initiated in B.W. and how would you monitor
The active metabolite of LEF, A77 1726 or M1, is responsible for virtually all the
pharmacologic activity of LEF.
131 The serum half-life of the M1 metabolite is
approximately 2 weeks. As a result, LEF should be initiated with a loading dose of
100 mg orally once daily for 3 days to reduce time to steady state, followed by 20 mg
once daily. If this dose is not tolerated, the dose should be reduced to 10 mg once
Monitoring for Adverse Effects
Diarrhea (20%–30%), rash (10%), alopecia (10%–17%), and reversible liver
enzyme elevations more than 3 times the ULN (2%–4%) are common adverse effects
131 Routine laboratory testing includes a baseline ALT followed by monthly
ALT testing for several months. When it is evident that ALT results
are stable and within normal limits, testing can be performed less often according to
the clinician’s judgment. Because of the risk of liver toxicity and the need for
activation by the liver to the M1 active metabolite, LEF is not recommended in
patients with preexisting liver disease, including hepatitis B or C.
Potential hepatotoxicity is the greatest concern with LEF; however, the rate of
LEF-induced liver enzyme elevation is not significantly different than MTX.
Guidelines for managing potential hepatotoxicity include dosage reduction from 20 to
10 mg/day if ALT increases more than 2 times the ULN.
steady between 2 and 3 times the ULN and treatment continuation is desired, a liver
biopsy is recommended. If ALT elevations are persistently more than 3 times the
ULN despite dosage reduction and cholestyramine administration to enhance
elimination (see Case 44-7, Question 3), then the drug should be discontinued and
another course of cholestyramine elimination therapy should be given.
Enhancement of Elimination with Cholestyramine
CASE 44-7, QUESTION 3: After 2 months of therapy, B.W. does not respond to LEF and the treatment
LEF (pregnancy category X) has not been tested in pregnant women, but it greatly
increases the risk of fetal death or teratogenicity in animals receiving as little as 1%
131 After discontinuation of therapy, however, up to 2
years may be needed to elapse before plasma M1 metabolite levels of LEF are
undetectable. As a result, cholestyramine is recommended for all women who
discontinue LEF and who are hoping to become pregnant. After stopping the
medication, cholestyramine 8 g 3 times daily is administered for 11 days (which need
not be consecutive). Plasma levels of the M1 metabolite are reduced by 40% to 65%
in 24 to 48 hours and should become undetectable (<0.02 mg/L) at the end of therapy.
B.W.’s blood should be tested at least 14 days apart to verify the absence of the
metabolite. If plasma M1 levels remain greater than 0.02 mg/L, more cholestyramine
should be administered. Cholestyramine also can be used to enhance elimination of
LEF in patients who experience hepatotoxicity or who overdose with this drug.
Activated charcoal also can reduce plasma M1 levels by 50% after 48 hours and can
be an effective alternative to cholestyramine when LEF overdosages need to be
Hydroxychloroquine and Sulfasalazine
CASE 44-7, QUESTION 4: Would it be reasonable to switch B.W. from MTX to either HCQ or SSZ?
Although both HCQ and SSZ are recommended first-line DMARDs for patients
with mild-to-moderate RA, it is more common to add either or both of these to the
regimen of patients who are not achieving adequate RA control from MTX.
usually dosed at 200 to 400 mg daily, is a very well-tolerated DMARD. The greatest
adverse effect of concern, retinal damage, is rare and easily prevented with diligent
monitoring and dose limitations. SSZ, dosed at 2 to 3 g/day divided into two or three
doses, is also well tolerated, although toxicity in general is greater than that with
HCQ. GI distress (nausea, anorexia) and rash are common. Although leukopenia,
agranulocytosis, and hepatitis are serious side effects, they are rare and, if they do
occur, normally manifest in the first 2 to 3 months of therapy. As a result, CBC,
LFTs, and renal function testing is recommended more frequently early in the course
of therapy. Both HCQ and SSZ appear to be safe in pregnancy.
Although B.W. has failed to respond to MTX and LEF, combinations of
csDMARDs and bDMARDs offer greater efficacy with lower toxicity and are
Traditional Disease-Modifying Antirheumatic Drug Combination Therapy
CASE 44-7, QUESTION 5: Is there evidence to support the early and safe use of DMARDs in combination
Because most RA patients develop joint erosions within the first 2 years of
disease, the initiation of disease-modifying agents early in the course of therapy, and
using them in combination, has been associated with improved patient outcomes. The
rationale for combination therapy is based on the premise that a combination of drugs
might improve outcomes because of different pharmacologic mechanisms of action or
different sites of actions. A combination of drugs also may allow the use of lower
doses of individual drugs, thereby reducing the risk of toxicity while maintaining or
Current ACR guidelines support csDMARD combinations as an alternative for
patients who fail to reach treatment goals on a single csDMARD but give equal
weight to considering other treatment options such as bDMARDs with or without
28 Few studies have compared csDMARD combinations with
bDMARD therapy. However, one study that randomized patients who failed MTX to
receive either MTX + SSZ + HCQ or MTX + infliximab found no difference in
clinical measures and serious adverse effects between the two groups after 24
months, although radiographic evidence of disease progression was slightly but not
significantly greater in patients receiving MTX + SSZ + HCQ.
In summary, every RA patient, including B.W., should receive csDMARD therapy
at or shortly after diagnosis, with MTX monotherapy as preferred initial treatment.
Patients who experience loss of efficacy or intolerable adverse effects from MTX
can add one or two csDMARDs, or add or substitute a bDMARD or tofacitinib
which will be discussed in ensuing sections.
CASE 44-7, QUESTION 6: After 6 months of treatment with csDMARDs (MTX with LEF, then MTX with
According to the EULAR guidelines, biologic DMARDs should be considered for
patients with moderate-to-high disease activity with poor prognostic factors, who do
not reach treatment targets with the first csDMARD strategy (MTX alone or in
combination with another csDMARD) within 6 months or without poor prognostic
factors, who fail a second csDMARD strategy.
28 The ACR guidelines recommend the
use of bDMARDs for patients with moderate or high disease activity despite trial
28 There are five TNF-α inhibitors available for the
treatment of RA including etanercept, adalimumab, infliximab, certolizumab pegol,
and golimumab. Given that B.W. has tried two different csDMARD combinations and
continues to have highly active RA with poor prognostic factors, it is time to
consider a bDMARD. In fact, patients who fail to respond to csDMARD or
bDMARD therapy within 3 months should receive consideration for an alternative
treatment. A TNF-α inhibitor, adalimumab, or tocilizumab would all be appropriate
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