Medications in Rheumatology
DMARDs and similar
To be designated as a DMARD, a drug must change the course of the disease for at least 1 year as evidenced
by sustained improvement in physical function, decreased inflammatory synovitis, slowing/prevention of
structural joint damage.
Methotrexate
Mechanism of action: folic acid analog. DHFR is essential for converting dihydrofolate (DHF) into
tetrahydrofolate (THF), which is a necessary cofactor for the synthesis of nucleotides (thymidylate, purines).
i) DHFR inhibition→ blocking of THF formation and purine synthesis (in cancer-doses). When purine
synthesis is inhibited by MTX, cells rely more heavily on the purine salvage pathway, however, immune cells
have limited activity of this pathway, so they fail to survive/reproduce.
ii) AICAR transformylase inhibition → increases extracellular adenosine, which exerts its
antiinflammatory effects via adenosine receptors (A2A receptors on macrophages) and by skewing
macrophage differentiation to M2 (tissue repairing, immunoregulation). AICAR is a precursor of IMP (and
therefore AMP) and it accumulates because it cannot be fully converted to AMP as part of the normal purine
biosynthesis process. AICAR accumulation inhibits AMP deamination, so AMP accumulates and leaks out of the
cell where it’s eventually converted to adenosine. This happens because accumulated AICAR is converted to
ZMP (an AMP analog) which competitively inhibits AMP deaminase (so AMP isn’t converted to IMP) causing
intracellular rise of AMP, which then exit the cell.
Bioavailability: at dosages of ≥15mg/wk, oral absorption may be decreased by as much as 30% compared with
parenteral dosing, that’s why a greater clinical response is seen with (sc) vs. oral MTX at these dosages. Oral
absorption is limited because MTX is absorbed from the GI tract primarily from a saturable active transport
system. Splitting the dose of oral MTX into two divided doses taken on the same day improves bioavailability.
The T1/2 of MTX ranges 6-8h and it is undetectable in the serum by 24 hours. MTX and its metabolite are
primarily excreted in the urine (and a small portion is excreted in the bile). Renal clearance is due to a
combination of filtration and secretion in the proximal tubule, with subsequent reabsorption in the distal
tubule. Initial response may be noted in 3-6 weeks, but a plateau is observed after 12-16wks.
Pharmacology: MTX enters the cell via two separate mechanisms, the reduced folate carrier and the folate
receptors and is transported inside the cell by endocytosis. Intracellular MTX undergoes polyglutamation. This
prevents intracellular MTX from being transported out of the cell. MTX in its ingested form is therefore
essentially a prodrug, with the polyglutamated form being the active compound. The time required for
intracellular accumulation and elimination of the active MTX polyglutamates explains why a drug with a serum
T1/2 of 8h is effective when administered weekly and why it takes 4-6 weeks for a clinical response to occur.
AE: teratogen, gastrointestinal, myelotoxicity, macrocytosis, transaminasemia, alopecia, oral ulcers, nodulosis
(skin, lung), pneumonitis, lymphoproliferative disease, nephrotoxicity [ i) mainly excreted by kidneys ii)
crystallization and precipitation of MTX in renal tubules], osteopathy.
MTX-associated LPD (<0.5%): mainly by diffuse large B-cells and extranodal. EBV genome is usually
found in B-cells and is believed that MTX immunosuppression allows EBV reactivation. It is treated firstly by
d/c MTX and then with R-CHOP and other regimens.
MTX-associated osteopathy: rare, usually in lower limbs, can be bilateral and presents with atypical
fractures ± bone marrow edema (MRI: band-like lines at growth plates). Low metabolic activity. Probably due
to osteoblast inhibition. Treatment: stop MTX and give anti-osteoporotic/anabolic agents .
MTX-pneumonitis: hypersensitivity reaction with fever, dyspnea, desaturation, eosinophilia, ↑ WBC
(but ≤15.000), GGOs, centrilobular nodules, reticulation and rarely pleural effusion, usually within the first 1-2
years. In a patient with preexisting lung disease, we recommend an assessment of respiratory reserve before
starting MTX, to determine whether a patient could cope with potential decompensation in the rare event of
pneumonitis, given that preexisting lung disease is a risk factor for the development of MTX-pneumonitis.
Contraindication in GFR <30mL/min. The drug is not cleared in routine dialysis.
Antidote: i) hydration (for urine excretion), ii) urine alkalization (prevent MTX precipitation), iii) leucovorin. AE
mitigation with folic or folinic (=leucovorin), the latter given 8-24h after MTX because otherwise it might block
,its efficacy. Leucovorin provides a direct source of THF by bypassing DHFR (which is blocked by MTX). Dose:
most administer 10mg/m2 IV (or 15mg/m2 of leucovorin calcium orally) every 6 hours until plasma MTX levels
are <0.05-0.1μmol → for an average person it’s 20mg x4 (IV). Anecdotally, use N-acetylcysteine for quicker
liver detox.
Pregnancy: medication should be discontinued 3 months before conception because of the high spontaneous
abortion rate. ACR recommends waiting one ovulatory cycle after stopping MTX before attempting
conception. In women treated with low-dose (<25 mg) MTX within 1 month prior to conception, folic acid
supplementation (5 mg/d) should be continued during the 1st trimester. For men there’s no danger, low
concentration in sperm.
Lactation: no
Interactions: TMP/SMX interferes with folic acid metabolism; therefore when combined with MTX, it may
increase the risk of bone marrow suppression. Excretion of MTX is inhibited by weak organic acids such as
aspirin, NSAIDs, penicillin G and probenecid, but this is generally only clinically relevant with higher doses of
MTX. Sulfonamides may also decrease renal tubular secretion MTX.
Leflunomide
Mechanism of action: is a prodrug that is metabolized in the liver to its active form, teriflunomide, which
inhibits DHODH (Dihydroorotate Dehydrogenase), a mitochondrial enzyme essential for the de novo
production of uridine monophosphate (UMP), a precursor for pyrimidine (C, T, U) nucleotides in T-cells.
Pharmacology: at a dosage of 20mg/d, steady state is reached in 7 weeks. Its metabolite undergoes
enterohepatic circulation and biliary recycling, which contributes to its long T1/2 of 2 weeks.
AE: teratogen, transaminitis, gastrointestinal, hypertension, alopecia, rash, peripheral polyneuropathy (after 6-
10 months), ILD, pancytopenia, pneumonitis (very rarely).
Wash-out: cholestyramine: 8gr x3 for 11 days, because LEF has a T1/2 of 14-18 days / charcoal 50gr x4
Contraindication: pregnancy, GFR<60mL/m.
Interactions: RIF induces cytochrome → enhanced metabolism to teriflunomide → toxicity
Pregnancy: women should discontinue at least 3 months or undergo washout and have their plasma
metabolite’s level checked to ensure that it is <0.02mg/L, on two occasions 14 days apart (which the original
manufacturer recommended as the threshold for best minimizing teratogenic risk).
Lactation: avoid (not much data).
Sulfasalazine
Mechanism of action: is made of sulfapyridine (an antibiotic) + 5-aminosalicylic acid (5-ASA) (an anti-
inflammatory). The drug is broken down in the colon by gut bacteria into these two components.
Dose: RA: 2-3gr/day (start from 500mg/day and uptitrate) + folic acid.
AE: myelotoxicity, agranulocytosis, liver toxicity, gastrointestinal, rash, hypersensitivity/Steven Johnson,
reversible oligospermia, urine coloring, hemolysis (in G6PD deficiency).
Contraindication: in G6PD deficiency.
Pregnancy: safe. Should be given with folic acid to prevent kernicterus, in pre-conception period and during 1st
trimester. Men with difficulty conceiving should discontinue this medication for 3 months (reversible
oligospermia).
Lactation: cautiously, cuz can be milk-transferred.
HCQ
5mg/kg: 200, 400mg (max).
Mechanism of action:
1) inhibition of lysosomal activity by ↑ their pH, interfering with antigen loading to MHC-II
2) inhibition of TLRs (mainly TLR3/7/9) in DCs (less nucleic acid binding)
3) inhibition of NADPH oxidase
4) inhibition of the secondary calcium signaling pathway.
Pharmacology: the response of HCQ is very slow and typically occurs after 6 weeks; its peak efficacy may not
be reached for 4 months. Excretion mostly by kidneys. T1/2 almost 40 days. It has a strong binding of HCQ to
melanin, resulting in the accumulation of HCQ in tissues containing large amounts of melanin, such as the skin
and the eye. The presence of the lipophilic ring makes it possible for HCQ to easily penetrate the cell
, membrane and accumulate inside the lysosomes and endosomes. As a result, ↑ pH of the lysosomal matrix
from 4→6, leading to inactivation of various enzymes, like lysosomal hydrolases. Alkalization is one of the
main factors responsible for disrupting several immune response processes.
AE: crampy abdominal pain, diarrhea (<10%), rash ± itchiness (<5%), retinopathy, cardiomyopathy (median
treatment >7yrs), myopathy, nephropathy, prolonged QT, skin and nail hyperpigmentation, hemolytic anemia
(in G6PD deficiency), AGEP, peripheral neuropathy.
Retinopathy: 1% after 5 years of treatment, 2% after 10 years and up to 20% after 20 years, but the
analysis did not consider serum drug concentrations – if dosage is kept <5mg/kg, then the risk is lower. HCQ
can accumulate in the eye, damaging photoreceptor cells in the retinal pigment epithelium. Initially presents
as bilateral pigmentary retinopathy and symptomatically as paracentral scotomas and loss of red light
perception. This can progress to bull’s eye maculopathy, characterized by a ring of retinal pigment epithelium
depigmentation in the macula. Irreversible. Risk factors: high dose, GFR<60mL/min, the use of tamoxifen
(retinotoxic) and the presence of a preexisting maculopathy. American Ophthalmology Association guidelines
say OCT at screening (BSR says within 1 year of initiation), after 5 years and then every year, but if risk factors
are present, more often. Damage detected at an early stage can stabilize, without serious visual loss, if HCQ is
stopped. Decrease dose by 50% if GFR<30mL/min.
*Notably, owing to a different chemical composition, quinacrine does not cause retinopathy.
Myopathy: proximal muscles and neck, cardiac muscle involvement and respiratory muscles, ↑ CPK,
ECG: automatic activity, 6 months – 4 years after drug initiation. Histology: vacuoles, mild inflammatory
infiltrate (same for cardiomyopathy).
Rash: photosensitive, similar to SCLE (same as the one by TNFis, antiepileptics, PPIs, NSAIDs). IIM
patients with anti-SRP have higher risk of rash.
Pregnancy: safe (while HCQ crosses the placenta, it doesn’t cause adverse effects, such as congenital
malformations). However, there’s a minor teratogenic risk during the 1st trimester, with urinary tract and oral
cleft malformations.
Colchicine
Mechanism of action: colchicine binds tightly to tubulin and disrupts microtubule polymerization; thereby
inhibits neutrophil chemotaxis, phagocytosis and cytokine secretion. Colchicine acts disproportionately on
highly proliferating cells (ex. bone marrow, GI tract lining). May also modulate pyrin expression (FMF).
Pharmacokinetic: metabolized by CYP3A4 and eliminated by biliary/ fecal excretion via P-gp.
Contraindications: most P-gp inhibitors also inhibit cytochrome CYP3A4 (which metabolizes colchicine)
Avoid colchicine use in patients who are on:
-CYP3A4 inhibitors (like CyA)
-P-gp inhibitors (CyA, clarithromycin)
-GFR <30mL/min
Important combinations to avoid:
i) macrolides (clarithromycin, erythromycin) promote serious colchicine toxicity, including death.
azithromycin, though, seems to be safe.
ii) CyA (neuromyopathy risk)
iii) statins (mostly simvastatin [=Lepur], lovastatin) have additive myotoxic effect (both compete for P-
gp and CYP).
iv) Paxlovid (contains Ritonavir, a protease inhibitor)
Dosage: reduce by 50% in GFR<50mL/min, contraindicated in GFR<30mL/min or give 0.5mg once or twice a
week.
AE: GI toxicity (diarrhea, nausea, vomiting [rare]). The overdose can cause: myelosuppression (the nadir
occurring 1wk after drug initiation), neuromyopathy, cardiac toxicity, hepatotoxicity, alopecia. Colchicine
toxicity can be lethal. No antidote.
neuromyopathy: affects proximal more than distal muscles and is accompanied by ↑ CPK in the
early phase and by varying neuropathy, can mimic IIM.
Pregnancy / Lactation: safe
Glucocorticoids
DMARDs and similar
To be designated as a DMARD, a drug must change the course of the disease for at least 1 year as evidenced
by sustained improvement in physical function, decreased inflammatory synovitis, slowing/prevention of
structural joint damage.
Methotrexate
Mechanism of action: folic acid analog. DHFR is essential for converting dihydrofolate (DHF) into
tetrahydrofolate (THF), which is a necessary cofactor for the synthesis of nucleotides (thymidylate, purines).
i) DHFR inhibition→ blocking of THF formation and purine synthesis (in cancer-doses). When purine
synthesis is inhibited by MTX, cells rely more heavily on the purine salvage pathway, however, immune cells
have limited activity of this pathway, so they fail to survive/reproduce.
ii) AICAR transformylase inhibition → increases extracellular adenosine, which exerts its
antiinflammatory effects via adenosine receptors (A2A receptors on macrophages) and by skewing
macrophage differentiation to M2 (tissue repairing, immunoregulation). AICAR is a precursor of IMP (and
therefore AMP) and it accumulates because it cannot be fully converted to AMP as part of the normal purine
biosynthesis process. AICAR accumulation inhibits AMP deamination, so AMP accumulates and leaks out of the
cell where it’s eventually converted to adenosine. This happens because accumulated AICAR is converted to
ZMP (an AMP analog) which competitively inhibits AMP deaminase (so AMP isn’t converted to IMP) causing
intracellular rise of AMP, which then exit the cell.
Bioavailability: at dosages of ≥15mg/wk, oral absorption may be decreased by as much as 30% compared with
parenteral dosing, that’s why a greater clinical response is seen with (sc) vs. oral MTX at these dosages. Oral
absorption is limited because MTX is absorbed from the GI tract primarily from a saturable active transport
system. Splitting the dose of oral MTX into two divided doses taken on the same day improves bioavailability.
The T1/2 of MTX ranges 6-8h and it is undetectable in the serum by 24 hours. MTX and its metabolite are
primarily excreted in the urine (and a small portion is excreted in the bile). Renal clearance is due to a
combination of filtration and secretion in the proximal tubule, with subsequent reabsorption in the distal
tubule. Initial response may be noted in 3-6 weeks, but a plateau is observed after 12-16wks.
Pharmacology: MTX enters the cell via two separate mechanisms, the reduced folate carrier and the folate
receptors and is transported inside the cell by endocytosis. Intracellular MTX undergoes polyglutamation. This
prevents intracellular MTX from being transported out of the cell. MTX in its ingested form is therefore
essentially a prodrug, with the polyglutamated form being the active compound. The time required for
intracellular accumulation and elimination of the active MTX polyglutamates explains why a drug with a serum
T1/2 of 8h is effective when administered weekly and why it takes 4-6 weeks for a clinical response to occur.
AE: teratogen, gastrointestinal, myelotoxicity, macrocytosis, transaminasemia, alopecia, oral ulcers, nodulosis
(skin, lung), pneumonitis, lymphoproliferative disease, nephrotoxicity [ i) mainly excreted by kidneys ii)
crystallization and precipitation of MTX in renal tubules], osteopathy.
MTX-associated LPD (<0.5%): mainly by diffuse large B-cells and extranodal. EBV genome is usually
found in B-cells and is believed that MTX immunosuppression allows EBV reactivation. It is treated firstly by
d/c MTX and then with R-CHOP and other regimens.
MTX-associated osteopathy: rare, usually in lower limbs, can be bilateral and presents with atypical
fractures ± bone marrow edema (MRI: band-like lines at growth plates). Low metabolic activity. Probably due
to osteoblast inhibition. Treatment: stop MTX and give anti-osteoporotic/anabolic agents .
MTX-pneumonitis: hypersensitivity reaction with fever, dyspnea, desaturation, eosinophilia, ↑ WBC
(but ≤15.000), GGOs, centrilobular nodules, reticulation and rarely pleural effusion, usually within the first 1-2
years. In a patient with preexisting lung disease, we recommend an assessment of respiratory reserve before
starting MTX, to determine whether a patient could cope with potential decompensation in the rare event of
pneumonitis, given that preexisting lung disease is a risk factor for the development of MTX-pneumonitis.
Contraindication in GFR <30mL/min. The drug is not cleared in routine dialysis.
Antidote: i) hydration (for urine excretion), ii) urine alkalization (prevent MTX precipitation), iii) leucovorin. AE
mitigation with folic or folinic (=leucovorin), the latter given 8-24h after MTX because otherwise it might block
,its efficacy. Leucovorin provides a direct source of THF by bypassing DHFR (which is blocked by MTX). Dose:
most administer 10mg/m2 IV (or 15mg/m2 of leucovorin calcium orally) every 6 hours until plasma MTX levels
are <0.05-0.1μmol → for an average person it’s 20mg x4 (IV). Anecdotally, use N-acetylcysteine for quicker
liver detox.
Pregnancy: medication should be discontinued 3 months before conception because of the high spontaneous
abortion rate. ACR recommends waiting one ovulatory cycle after stopping MTX before attempting
conception. In women treated with low-dose (<25 mg) MTX within 1 month prior to conception, folic acid
supplementation (5 mg/d) should be continued during the 1st trimester. For men there’s no danger, low
concentration in sperm.
Lactation: no
Interactions: TMP/SMX interferes with folic acid metabolism; therefore when combined with MTX, it may
increase the risk of bone marrow suppression. Excretion of MTX is inhibited by weak organic acids such as
aspirin, NSAIDs, penicillin G and probenecid, but this is generally only clinically relevant with higher doses of
MTX. Sulfonamides may also decrease renal tubular secretion MTX.
Leflunomide
Mechanism of action: is a prodrug that is metabolized in the liver to its active form, teriflunomide, which
inhibits DHODH (Dihydroorotate Dehydrogenase), a mitochondrial enzyme essential for the de novo
production of uridine monophosphate (UMP), a precursor for pyrimidine (C, T, U) nucleotides in T-cells.
Pharmacology: at a dosage of 20mg/d, steady state is reached in 7 weeks. Its metabolite undergoes
enterohepatic circulation and biliary recycling, which contributes to its long T1/2 of 2 weeks.
AE: teratogen, transaminitis, gastrointestinal, hypertension, alopecia, rash, peripheral polyneuropathy (after 6-
10 months), ILD, pancytopenia, pneumonitis (very rarely).
Wash-out: cholestyramine: 8gr x3 for 11 days, because LEF has a T1/2 of 14-18 days / charcoal 50gr x4
Contraindication: pregnancy, GFR<60mL/m.
Interactions: RIF induces cytochrome → enhanced metabolism to teriflunomide → toxicity
Pregnancy: women should discontinue at least 3 months or undergo washout and have their plasma
metabolite’s level checked to ensure that it is <0.02mg/L, on two occasions 14 days apart (which the original
manufacturer recommended as the threshold for best minimizing teratogenic risk).
Lactation: avoid (not much data).
Sulfasalazine
Mechanism of action: is made of sulfapyridine (an antibiotic) + 5-aminosalicylic acid (5-ASA) (an anti-
inflammatory). The drug is broken down in the colon by gut bacteria into these two components.
Dose: RA: 2-3gr/day (start from 500mg/day and uptitrate) + folic acid.
AE: myelotoxicity, agranulocytosis, liver toxicity, gastrointestinal, rash, hypersensitivity/Steven Johnson,
reversible oligospermia, urine coloring, hemolysis (in G6PD deficiency).
Contraindication: in G6PD deficiency.
Pregnancy: safe. Should be given with folic acid to prevent kernicterus, in pre-conception period and during 1st
trimester. Men with difficulty conceiving should discontinue this medication for 3 months (reversible
oligospermia).
Lactation: cautiously, cuz can be milk-transferred.
HCQ
5mg/kg: 200, 400mg (max).
Mechanism of action:
1) inhibition of lysosomal activity by ↑ their pH, interfering with antigen loading to MHC-II
2) inhibition of TLRs (mainly TLR3/7/9) in DCs (less nucleic acid binding)
3) inhibition of NADPH oxidase
4) inhibition of the secondary calcium signaling pathway.
Pharmacology: the response of HCQ is very slow and typically occurs after 6 weeks; its peak efficacy may not
be reached for 4 months. Excretion mostly by kidneys. T1/2 almost 40 days. It has a strong binding of HCQ to
melanin, resulting in the accumulation of HCQ in tissues containing large amounts of melanin, such as the skin
and the eye. The presence of the lipophilic ring makes it possible for HCQ to easily penetrate the cell
, membrane and accumulate inside the lysosomes and endosomes. As a result, ↑ pH of the lysosomal matrix
from 4→6, leading to inactivation of various enzymes, like lysosomal hydrolases. Alkalization is one of the
main factors responsible for disrupting several immune response processes.
AE: crampy abdominal pain, diarrhea (<10%), rash ± itchiness (<5%), retinopathy, cardiomyopathy (median
treatment >7yrs), myopathy, nephropathy, prolonged QT, skin and nail hyperpigmentation, hemolytic anemia
(in G6PD deficiency), AGEP, peripheral neuropathy.
Retinopathy: 1% after 5 years of treatment, 2% after 10 years and up to 20% after 20 years, but the
analysis did not consider serum drug concentrations – if dosage is kept <5mg/kg, then the risk is lower. HCQ
can accumulate in the eye, damaging photoreceptor cells in the retinal pigment epithelium. Initially presents
as bilateral pigmentary retinopathy and symptomatically as paracentral scotomas and loss of red light
perception. This can progress to bull’s eye maculopathy, characterized by a ring of retinal pigment epithelium
depigmentation in the macula. Irreversible. Risk factors: high dose, GFR<60mL/min, the use of tamoxifen
(retinotoxic) and the presence of a preexisting maculopathy. American Ophthalmology Association guidelines
say OCT at screening (BSR says within 1 year of initiation), after 5 years and then every year, but if risk factors
are present, more often. Damage detected at an early stage can stabilize, without serious visual loss, if HCQ is
stopped. Decrease dose by 50% if GFR<30mL/min.
*Notably, owing to a different chemical composition, quinacrine does not cause retinopathy.
Myopathy: proximal muscles and neck, cardiac muscle involvement and respiratory muscles, ↑ CPK,
ECG: automatic activity, 6 months – 4 years after drug initiation. Histology: vacuoles, mild inflammatory
infiltrate (same for cardiomyopathy).
Rash: photosensitive, similar to SCLE (same as the one by TNFis, antiepileptics, PPIs, NSAIDs). IIM
patients with anti-SRP have higher risk of rash.
Pregnancy: safe (while HCQ crosses the placenta, it doesn’t cause adverse effects, such as congenital
malformations). However, there’s a minor teratogenic risk during the 1st trimester, with urinary tract and oral
cleft malformations.
Colchicine
Mechanism of action: colchicine binds tightly to tubulin and disrupts microtubule polymerization; thereby
inhibits neutrophil chemotaxis, phagocytosis and cytokine secretion. Colchicine acts disproportionately on
highly proliferating cells (ex. bone marrow, GI tract lining). May also modulate pyrin expression (FMF).
Pharmacokinetic: metabolized by CYP3A4 and eliminated by biliary/ fecal excretion via P-gp.
Contraindications: most P-gp inhibitors also inhibit cytochrome CYP3A4 (which metabolizes colchicine)
Avoid colchicine use in patients who are on:
-CYP3A4 inhibitors (like CyA)
-P-gp inhibitors (CyA, clarithromycin)
-GFR <30mL/min
Important combinations to avoid:
i) macrolides (clarithromycin, erythromycin) promote serious colchicine toxicity, including death.
azithromycin, though, seems to be safe.
ii) CyA (neuromyopathy risk)
iii) statins (mostly simvastatin [=Lepur], lovastatin) have additive myotoxic effect (both compete for P-
gp and CYP).
iv) Paxlovid (contains Ritonavir, a protease inhibitor)
Dosage: reduce by 50% in GFR<50mL/min, contraindicated in GFR<30mL/min or give 0.5mg once or twice a
week.
AE: GI toxicity (diarrhea, nausea, vomiting [rare]). The overdose can cause: myelosuppression (the nadir
occurring 1wk after drug initiation), neuromyopathy, cardiac toxicity, hepatotoxicity, alopecia. Colchicine
toxicity can be lethal. No antidote.
neuromyopathy: affects proximal more than distal muscles and is accompanied by ↑ CPK in the
early phase and by varying neuropathy, can mimic IIM.
Pregnancy / Lactation: safe
Glucocorticoids
