Browse the corpus

Principles of Therapeutics Acetaminophen Disease-Modifying The efficacy of acetaminophen for osteoarthritis and lower back pain has been questioned. Controlled trials and meta Antirheumatic Drugs analyses have shown no benefit from the drug, even at high Nonbiologic Disease-Modifying doses. Hor.never, because of its favorable safety profile, it may Antirheumatic Drugs be empirically tried fbr short-term or add on therapy. The Table 9 summarizes the mechanisms of action, indications, and

Acetaminophen Disease-Modifying The efficacy of acetaminophen for osteoarthritis and lower back pain has been questioned. Controlled trials and meta Antirheumatic Drugs analyses have shown no benefit from the drug, even at high Nonbiologic Disease-Modifying doses. Hor.never, because of its favorable safety profile, it may Antirheumatic Drugs be empirically tried fbr short-term or add on therapy. The Table 9 summarizes the mechanisms of action, indications, and daily dosage should not exceed 3000 mg/d. ACR guidelines common monitoring parameters of various nonbiologic disease conditionally recommend acetaminophen for patients with modi$zing antirheumatic drugs (DMARDs). See Medications and knee, hip, or hand osteoarthritis and limited pharmacologic Pregnancy tbr infbrmation on these drugs in pregnancy. options. Methotrexate Methotrexate is a first-line medication for RA and other auto Tramadol immune diseases. Once weekly dosing is generally 10 to Tramadol is a mixed opioid analgesic and weak serotonin 25 mg; the drug can be given orally or subcutaneously. At doses norepinephrine reuptake inhibitor (SNRI) with a lower poten- above 15 mg, parenteral administration is more reliable but tial lor addiction than traditional opioids. It may be considered much more expensive. in a limited number of patients for whom other methods of Potential adverse effects include headaches, latigue, and analgesia were ineffective or not tolerated. Adverse efI'ects may nausea (particularly around the time of weekly dosing). include nausea, vomiting, constipation. lightheadedness, and Hepatotoxicity and cytopenia can occur (especially macro sedation. Traditional opioids should generally be avoided in cytic anemia), and dose adjustment is required with kidney rheumatologic treatment because of limited efficacy, high disease. Methotrexate should be avoided in patients lvith sig toxicity, and high potential lbr dependence. See MKSAP 19 nificant hepatic or kidney disease and is absolutely contrain- General Internal Medicine 1 fbr discussion of risk assessment dicated around pregnanc),. Folic acid supplements minimize and monitoring of long term opioid therapy. toxicity while preserving efficacy. Limiting alcohol intake is recommended. Serotonin-Norepineph rine Reu pta ke I n hi bitors Duloxetine is an SNRI approved by the FDA fbr the manage Hydroxychloroquine ment of chronic musculoskeletat pain and fibromyalgia. Hydroxychloroquine is an immunomodulator widely used in Duloxetine provides modest pain relief for knee osteoarthritis, systemic lupus erythematosus, in which it decreases mortality chronic lower back pain. and fibromyalgia. Milnacipran is and the likelihood olnephritis. It is rarely sufficient as single another SNRI approved for fibromyalgia. 'tb avoid withdrawal drug therapy fbr RA but is useful as an adjunctive therapy. symptoms, patients must be slowly weaned off SNRIs when the drug is discontinued. Sulfasalazine Sulfasalazine is used to treat RA and nonaxial psoriatic arthri

daily dosage should not exceed 3000 mg/d. ACR guidelines common monitoring parameters of various nonbiologic disease conditionally recommend acetaminophen for patients with modi$zing antirheumatic drugs (DMARDs). See Medications and knee, hip, or hand osteoarthritis and limited pharmacologic Pregnancy tbr infbrmation on these drugs in pregnancy. options. Methotrexate Methotrexate is a first-line medication for RA and other auto Tramadol immune diseases. Once weekly dosing is generally 10 to Tramadol is a mixed opioid analgesic and weak serotonin 25 mg; the drug can be given orally or subcutaneously. At doses norepinephrine reuptake inhibitor (SNRI) with a lower poten- above 15 mg, parenteral administration is more reliable but tial lor addiction than traditional opioids. It may be considered much more expensive. in a limited number of patients for whom other methods of Potential adverse effects include headaches, latigue, and analgesia were ineffective or not tolerated. Adverse efI'ects may nausea (particularly around the time of weekly dosing). include nausea, vomiting, constipation. lightheadedness, and Hepatotoxicity and cytopenia can occur (especially macro sedation. Traditional opioids should generally be avoided in cytic anemia), and dose adjustment is required with kidney rheumatologic treatment because of limited efficacy, high disease. Methotrexate should be avoided in patients lvith sig toxicity, and high potential lbr dependence. See MKSAP 19 nificant hepatic or kidney disease and is absolutely contrain- General Internal Medicine 1 fbr discussion of risk assessment dicated around pregnanc),. Folic acid supplements minimize and monitoring of long term opioid therapy. toxicity while preserving efficacy. Limiting alcohol intake is recommended. Serotonin-Norepineph rine Reu pta ke I n hi bitors Duloxetine is an SNRI approved by the FDA fbr the manage Hydroxychloroquine ment of chronic musculoskeletat pain and fibromyalgia. Hydroxychloroquine is an immunomodulator widely used in Duloxetine provides modest pain relief for knee osteoarthritis, systemic lupus erythematosus, in which it decreases mortality chronic lower back pain. and fibromyalgia. Milnacipran is and the likelihood olnephritis. It is rarely sufficient as single another SNRI approved for fibromyalgia. 'tb avoid withdrawal drug therapy fbr RA but is useful as an adjunctive therapy. symptoms, patients must be slowly weaned off SNRIs when the drug is discontinued. Sulfasalazine Sulfasalazine is used to treat RA and nonaxial psoriatic arthri Gabapentinoids tis. It is now most frequently used as part of combination DMARD therapy fbr RA. Serious adverse effects include blood Gabapentinoids (gabapentin and pregabalin) inhibit voltage dyscrasias, hepatitis, and hypersensitivity reactions. Because gated calcium channels. thereby reducing pain signaling from ol the benefit of its salicylate moiety for inflammatory bowel the periphery to the central nervous system. Pregabalin is FDA disease, it may be a useful strategr lbr patients with inflamma approved for fibromyalgia. Common adverse effects (dizziness, tory bowel disease-associated arthritis. disequilibrium, somnolence, weight gain. peripheral edema. and cognitive difficulties) may limit its utility. The FDA has Leflunomide issued a safety alert stating that serious breathing difficulties Leflunomide is FDA approved for RA and psoriatic arthritis, may occur in patients using gabapentin or pregabalin who with eflicacy similar to that ol methotrexate. Patients must be have respiratory risk factors (e.g., older persons, patients with monitored for hepatotoxicity and myelosuppression. Other COPD, and patients receiving opioids and other drugs that common adverse effects include nausea, headaches, rash. diar depress the central nervous system). rhea, and elevation o1'serum aminotransferase levels. Peripheral I(EY POIilI5 neuropathy is an uncommon adverse effect that is usually self' . The American College of Rheumatologr conditionally limited if the drug is discontinued. Leflunomide is highly tera recommends acetaminophen for knee, hip, and hand togenic and absolutely cclntraindicated around pregnancy. osteoarthritis. o Traditional opioids should generally be avoided in rheu- Azathioprine matologic treatment because of limited efficacy, high Azathioprine is an immunosuppressant used in various inflam toxicity, and high potential for dependence. matory diseases. Its primary toxicity is myelosuppression, especially in individuals with a decreased or absent thiopurine

Gabapentinoids tis. It is now most frequently used as part of combination DMARD therapy fbr RA. Serious adverse effects include blood Gabapentinoids (gabapentin and pregabalin) inhibit voltage dyscrasias, hepatitis, and hypersensitivity reactions. Because gated calcium channels. thereby reducing pain signaling from ol the benefit of its salicylate moiety for inflammatory bowel the periphery to the central nervous system. Pregabalin is FDA disease, it may be a useful strategr lbr patients with inflamma approved for fibromyalgia. Common adverse effects (dizziness, tory bowel disease-associated arthritis. disequilibrium, somnolence, weight gain. peripheral edema. and cognitive difficulties) may limit its utility. The FDA has Leflunomide issued a safety alert stating that serious breathing difficulties Leflunomide is FDA approved for RA and psoriatic arthritis, may occur in patients using gabapentin or pregabalin who with eflicacy similar to that ol methotrexate. Patients must be have respiratory risk factors (e.g., older persons, patients with monitored for hepatotoxicity and myelosuppression. Other COPD, and patients receiving opioids and other drugs that common adverse effects include nausea, headaches, rash. diar depress the central nervous system). rhea, and elevation o1'serum aminotransferase levels. Peripheral I(EY POIilI5 neuropathy is an uncommon adverse effect that is usually self' . The American College of Rheumatologr conditionally limited if the drug is discontinued. Leflunomide is highly tera recommends acetaminophen for knee, hip, and hand togenic and absolutely cclntraindicated around pregnancy. osteoarthritis. o Traditional opioids should generally be avoided in rheu- Azathioprine matologic treatment because of limited efficacy, high Azathioprine is an immunosuppressant used in various inflam toxicity, and high potential for dependence. matory diseases. Its primary toxicity is myelosuppression, especially in individuals with a decreased or absent thiopurine 10

Principles of Therapeutics TABLE 9. Nonbiologic Disease-ModifyingAntirheumatic Drugs Agent Mechanisms of Action lndications Common Monitoring Parameters Methotrexate Low dose: anti-inflammatory agent via RA; psoriasis; psoriatic Baseline: chest radiography, hepatitis up-regulation of adenosine A2a signaling arthritis; IBD; SLE screening, CBC, LCTs, serum creatinine (arthritis only); reactive High dose: antimetabolite/{olate Thereafter: CBC, LCTs, serum creatinine arthritis; DM; PM; antagonist used in neoplastic disease after first month, then approximately vasculitis every 2-3 months" Hydroxych loroquine Uncertain; appears to involve SLE; RA Baseline: CBC, LCTs, serum creatinine stabilization of lysosomal vacuoles, leading to inhibition of antigen Retinal examinations at baseline and processing and/or inhibition of Toll-like annual examination after 5 years of receptor activation therapy to evaluate for retinopathy

TABLE 9. Nonbiologic Disease-ModifyingAntirheumatic Drugs Agent Mechanisms of Action lndications Common Monitoring Parameters Methotrexate Low dose: anti-inflammatory agent via RA; psoriasis; psoriatic Baseline: chest radiography, hepatitis up-regulation of adenosine A2a signaling arthritis; IBD; SLE screening, CBC, LCTs, serum creatinine (arthritis only); reactive High dose: antimetabolite/{olate Thereafter: CBC, LCTs, serum creatinine arthritis; DM; PM; antagonist used in neoplastic disease after first month, then approximately vasculitis every 2-3 months" Hydroxych loroquine Uncertain; appears to involve SLE; RA Baseline: CBC, LCTs, serum creatinine stabilization of lysosomal vacuoles, leading to inhibition of antigen Retinal examinations at baseline and processing and/or inhibition of Toll-like annual examination after 5 years of receptor activation therapy to evaluate for retinopathy Sulfasalazine Unknown; the prodrug is broken down RA; SpA; IBD Baseline: CBC, LCTs, serum creatinine into 5-amino salicylic acid (active metabolite in gastrointestinal tract) and Thereafter: CBC, LCTs, serum creatinine every 3-6 months sulfapyridine (exerts systemic action) Leflunomide lnhibits mitochondrial enzyme RA; psoriatic arth ritis Baseline: hepatitis screening, CBC, LCTs, dihydroorotate dehyd rogenase to block serum creatinine pyrimidine synthesis (decreasing Thereafter: CBC, LCTs, serum creatinine lymphocyte prod uction); antiproliferative after 4 weeks, then every 3 months Azathioprine Prodrug of 6-mercaptopurine; purine SLE; DM; PM; Baseline: CBC, LCTs, serum creatinine analogue; inhibits DNA synthesis vasculitis; IBD Thereafter: CBC, LCTs, serum creatinine essential for proliferating T and B every 3 monthsu lymphocytes Cyclophosphamide Alkylating agent; blocks DNA synthesis Severe and life- Close monitoring clinically and and causes cell death, especially of threatening measuring CBC, chemistries, LCTs, T cells complications in SLE, urinalysis every 4-8 weeks DM, PM, and vasculitis; may be used when other agents fail Mycophenolate Active metabolite (mycophenolic acid) SLE (especially lupus Baseline: CBC, LCTs, serum creatinine mofetil inhibits purine synthesis; preferentially nephritis); vasculitis (maintenance Thereafter: CBC, LCTs, serum creatinine inhibits T and B lymphocytes after 4 weeks and then every 3 monthsa therapy); DM; PM; SSc Cyclosporine, lnhibit calcineurin (transcription SLE; psoriasis; RA Baseline: CBC, LCTs, serum creatinine voclosporin activating factor); preferentially target (cyclosporine) Thereafter: CBC, LCTs, serum creatinine T cells Lupus nephritis every 2-3 months" (voclosporin) Tofacitinib, Janus kinase inhibitors RA (tofacitinib, Baseline: CBC, LCTs, serum creatinine, baricitinib, baricitinib, lipid panel upadacitinib upadacitinib) Thereafter: CBC, LCTs, serum creatinine Psoriatic arthritis every 8 weeks, lipids after 8 weeks and (tofacitinib) then every 6 months Apremilast Phosphodiesterase-4 in hibitor Psoriasis; psoriatic Baseline: weight arthritis; oral ulcers Thereafter: weight, neuropsychiatric associated with effects Behget syndrome

Sulfasalazine Unknown; the prodrug is broken down RA; SpA; IBD Baseline: CBC, LCTs, serum creatinine into 5-amino salicylic acid (active metabolite in gastrointestinal tract) and Thereafter: CBC, LCTs, serum creatinine every 3-6 months sulfapyridine (exerts systemic action) Leflunomide lnhibits mitochondrial enzyme RA; psoriatic arth ritis Baseline: hepatitis screening, CBC, LCTs, dihydroorotate dehyd rogenase to block serum creatinine pyrimidine synthesis (decreasing Thereafter: CBC, LCTs, serum creatinine lymphocyte prod uction); antiproliferative after 4 weeks, then every 3 months Azathioprine Prodrug of 6-mercaptopurine; purine SLE; DM; PM; Baseline: CBC, LCTs, serum creatinine analogue; inhibits DNA synthesis vasculitis; IBD Thereafter: CBC, LCTs, serum creatinine essential for proliferating T and B every 3 monthsu lymphocytes Cyclophosphamide Alkylating agent; blocks DNA synthesis Severe and life- Close monitoring clinically and and causes cell death, especially of threatening measuring CBC, chemistries, LCTs, T cells complications in SLE, urinalysis every 4-8 weeks DM, PM, and vasculitis; may be used when other agents fail Mycophenolate Active metabolite (mycophenolic acid) SLE (especially lupus Baseline: CBC, LCTs, serum creatinine mofetil inhibits purine synthesis; preferentially nephritis); vasculitis (maintenance Thereafter: CBC, LCTs, serum creatinine inhibits T and B lymphocytes after 4 weeks and then every 3 monthsa therapy); DM; PM; SSc Cyclosporine, lnhibit calcineurin (transcription SLE; psoriasis; RA Baseline: CBC, LCTs, serum creatinine voclosporin activating factor); preferentially target (cyclosporine) Thereafter: CBC, LCTs, serum creatinine T cells Lupus nephritis every 2-3 months" (voclosporin) Tofacitinib, Janus kinase inhibitors RA (tofacitinib, Baseline: CBC, LCTs, serum creatinine, baricitinib, baricitinib, lipid panel upadacitinib upadacitinib) Thereafter: CBC, LCTs, serum creatinine Psoriatic arthritis every 8 weeks, lipids after 8 weeks and (tofacitinib) then every 6 months Apremilast Phosphodiesterase-4 in hibitor Psoriasis; psoriatic Baseline: weight arthritis; oral ulcers Thereafter: weight, neuropsychiatric associated with effects Behget syndrome CBC=complerebloodcount; DM=dermatomyositis; IBD=in{lammatorybowel disease; LCT=liverchemistrytest; PM=polymyositis; RA=rheumatoidarthritis; SLE=systemic lupus erythematosus; SpA = spondyloarthritis; SSc = systemic sclerosis.

Sulfasalazine Unknown; the prodrug is broken down RA; SpA; IBD Baseline: CBC, LCTs, serum creatinine into 5-amino salicylic acid (active metabolite in gastrointestinal tract) and Thereafter: CBC, LCTs, serum creatinine every 3-6 months sulfapyridine (exerts systemic action) Leflunomide lnhibits mitochondrial enzyme RA; psoriatic arth ritis Baseline: hepatitis screening, CBC, LCTs, dihydroorotate dehyd rogenase to block serum creatinine pyrimidine synthesis (decreasing Thereafter: CBC, LCTs, serum creatinine lymphocyte prod uction); antiproliferative after 4 weeks, then every 3 months Azathioprine Prodrug of 6-mercaptopurine; purine SLE; DM; PM; Baseline: CBC, LCTs, serum creatinine analogue; inhibits DNA synthesis vasculitis; IBD Thereafter: CBC, LCTs, serum creatinine essential for proliferating T and B every 3 monthsu lymphocytes Cyclophosphamide Alkylating agent; blocks DNA synthesis Severe and life- Close monitoring clinically and and causes cell death, especially of threatening measuring CBC, chemistries, LCTs, T cells complications in SLE, urinalysis every 4-8 weeks DM, PM, and vasculitis; may be used when other agents fail Mycophenolate Active metabolite (mycophenolic acid) SLE (especially lupus Baseline: CBC, LCTs, serum creatinine mofetil inhibits purine synthesis; preferentially nephritis); vasculitis (maintenance Thereafter: CBC, LCTs, serum creatinine inhibits T and B lymphocytes after 4 weeks and then every 3 monthsa therapy); DM; PM; SSc Cyclosporine, lnhibit calcineurin (transcription SLE; psoriasis; RA Baseline: CBC, LCTs, serum creatinine voclosporin activating factor); preferentially target (cyclosporine) Thereafter: CBC, LCTs, serum creatinine T cells Lupus nephritis every 2-3 months" (voclosporin) Tofacitinib, Janus kinase inhibitors RA (tofacitinib, Baseline: CBC, LCTs, serum creatinine, baricitinib, baricitinib, lipid panel upadacitinib upadacitinib) Thereafter: CBC, LCTs, serum creatinine Psoriatic arthritis every 8 weeks, lipids after 8 weeks and (tofacitinib) then every 6 months Apremilast Phosphodiesterase-4 in hibitor Psoriasis; psoriatic Baseline: weight arthritis; oral ulcers Thereafter: weight, neuropsychiatric associated with effects Behget syndrome CBC=complerebloodcount; DM=dermatomyositis; IBD=in{lammatorybowel disease; LCT=liverchemistrytest; PM=polymyositis; RA=rheumatoidarthritis; SLE=systemic lupus erythematosus; SpA = spondyloarthritis; SSc = systemic sclerosis. methyltransferase enzyme. Because azathioprine is metabo- Cyclophosphamide has largely been displaced by safer drugs lized by xanthine oxidase, concomitant use with xanthine for first line treatment of ANCA-associated vasculitis and oxidase inhibitors (allopurinol, febuxostat) is contraindicated. lupus nephritis (rituximab and mycophenolate mofetil, respectively) but is still used in severe cases or when these Cyclophosphamide agents fail. Serious potential adverse effects include severe Cyclophosphamide has a rapid onset of action (days to weeks). immunosuppression, leukopenia, hemorrhagic cystitis, and It is used to treat vasculitis, life threatening complications of ovarian failure, as well as long-term risk for bladder cancer, systemic lupus erythematosus, and interstitial lung disease. leukemia, and lymphoma.

methyltransferase enzyme. Because azathioprine is metabo- Cyclophosphamide has largely been displaced by safer drugs lized by xanthine oxidase, concomitant use with xanthine for first line treatment of ANCA-associated vasculitis and oxidase inhibitors (allopurinol, febuxostat) is contraindicated. lupus nephritis (rituximab and mycophenolate mofetil, respectively) but is still used in severe cases or when these Cyclophosphamide agents fail. Serious potential adverse effects include severe Cyclophosphamide has a rapid onset of action (days to weeks). immunosuppression, leukopenia, hemorrhagic cystitis, and It is used to treat vasculitis, life threatening complications of ovarian failure, as well as long-term risk for bladder cancer, systemic lupus erythematosus, and interstitial lung disease. leukemia, and lymphoma. 11