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Principles of Therapeutics TABTE 7. Synovial Fluid Analysis Normal Noninflammatory lnflammatory Crystal-lnduced lnfectious Hemorrhagic Appearance Clear/yellow/ Clear/yellow/ Yellow/white/ Yellow/white/ Yellow/white/ Red/opaque transpa rent tra nspa rent translucenV tra nsl u ce nt/ opaq ue opaque opaque Leu kocyte <200/Stl(0.2x 200-2000/stL 2000-20,000/pL 1 0,000-50,000/pL >50,000/prL cou nt 10e/L) (0.2 2.0 x 10e /L) (2.0-20 x 10e/l) (1050x1Oe/L) (50 x 1 Oell) (may be higher) (may be higher) (may be lower) Other studies Negative Gram Negative Gram Negative Gram Negative Gram Positive Gram Negative stain; negative stain; negative stain; negative stain; positive stainb; positive Gram stain; cu ltu re culture culture crystals" culture' negative culture blue when paralle to the axis and ye low when perpendicular. stain sensitivity ior infection is approximately 30% to 50%. all cultures are positive except for infection caused 6y Ndsseria gonorrhoeae, which may be posrtive in 507o or fewer cases.

TABTE 7. Synovial Fluid Analysis Normal Noninflammatory lnflammatory Crystal-lnduced lnfectious Hemorrhagic Appearance Clear/yellow/ Clear/yellow/ Yellow/white/ Yellow/white/ Yellow/white/ Red/opaque transpa rent tra nspa rent translucenV tra nsl u ce nt/ opaq ue opaque opaque Leu kocyte <200/Stl(0.2x 200-2000/stL 2000-20,000/pL 1 0,000-50,000/pL >50,000/prL cou nt 10e/L) (0.2 2.0 x 10e /L) (2.0-20 x 10e/l) (1050x1Oe/L) (50 x 1 Oell) (may be higher) (may be higher) (may be lower) Other studies Negative Gram Negative Gram Negative Gram Negative Gram Positive Gram Negative stain; negative stain; negative stain; negative stain; positive stainb; positive Gram stain; cu ltu re culture culture crystals" culture' negative culture blue when paralle to the axis and ye low when perpendicular. stain sensitivity ior infection is approximately 30% to 50%. all cultures are positive except for infection caused 6y Ndsseria gonorrhoeae, which may be posrtive in 507o or fewer cases. aspiration should be performed to diagnose the underlying XEY POIl{TS cause. Aspirated synovial fluid should be sent for leukocyte . Synovial fluid leukocy.te counts greater than 50,000/pL count. Gram stain, and cultures, as well as evaluation fbr crys- (50 x 10e/L) with polymorphonuclear cell predomi tals under polarized light. See Table 7 for more infbrmation. nance have a high likelihood of infection; counts less l'here is no absolute cutoff of synovial fluid leukocyte than 2000/trrL (2.0 x 10'q/L) are usually associated with counts for ruling out infectious arthritis; however. counts noninflammatory causes. greater than 50.000/gL (SO x 10e/L) with polymorphonuclear cell predominance have a high tikelihood of inf'ection. Counts . Tissue biopsy of involved organs can be helpful in diag- less than 200019L (2.0 x 10e/t.) are usually associated with nosing numerous rheumatologic conditions and in assessing disease activity in some conditions. noninflammatory causes. Notably, crystals can coexist with inf'ection. and their presence does not rule out infection if suspicion is high.

aspiration should be performed to diagnose the underlying XEY POIl{TS cause. Aspirated synovial fluid should be sent for leukocyte . Synovial fluid leukocy.te counts greater than 50,000/pL count. Gram stain, and cultures, as well as evaluation fbr crys- (50 x 10e/L) with polymorphonuclear cell predomi tals under polarized light. See Table 7 for more infbrmation. nance have a high likelihood of infection; counts less l'here is no absolute cutoff of synovial fluid leukocyte than 2000/trrL (2.0 x 10'q/L) are usually associated with counts for ruling out infectious arthritis; however. counts noninflammatory causes. greater than 50.000/gL (SO x 10e/L) with polymorphonuclear cell predominance have a high tikelihood of inf'ection. Counts . Tissue biopsy of involved organs can be helpful in diag- less than 200019L (2.0 x 10e/t.) are usually associated with nosing numerous rheumatologic conditions and in assessing disease activity in some conditions. noninflammatory causes. Notably, crystals can coexist with inf'ection. and their presence does not rule out infection if suspicion is high. Pri nci ples of Therapeutics Tissue Biopsy When appropriate, tissue biopsy of involved organs can be Overuiew helpful in diagnosing numerous rheumatologic conditions. This section reviews the indications for use. mechanisms ot' such as vasculitis (lung, kidney, or temporal artery biopsy) and action, major toxicities, and monitoring requirements of nredica SLE or dermatomyositis (skin biopsy). Tissue biopsy may also tions used in rheumatologic disease. Dmg applications in specific help assess disease activity (e.g., kidney biopsy in SLE). The disease states are elaboruted on in their respective sections.

Pri nci ples of Therapeutics Tissue Biopsy When appropriate, tissue biopsy of involved organs can be Overuiew helpful in diagnosing numerous rheumatologic conditions. This section reviews the indications for use. mechanisms ot' such as vasculitis (lung, kidney, or temporal artery biopsy) and action, major toxicities, and monitoring requirements of nredica SLE or dermatomyositis (skin biopsy). Tissue biopsy may also tions used in rheumatologic disease. Dmg applications in specific help assess disease activity (e.g., kidney biopsy in SLE). The disease states are elaboruted on in their respective sections. benefits should be appropriately balanced with possible risks of the procedure. Anti-l nfla m matory Agents Glucocorticoids Mental Health Screening Clucocorticoids are eff'ective in many rheumatologic dise:rses, Practitioners should be aware that patients with arthritis including rheumatoid arthritis (RA), acute crystal arthropathy, experience mental distress and have :r history of depression at systemic vasculitis, polymyalgia rheumatica. systemic lupus higher rates than the general population. Concurrent depres erythematosus, inflammatory myopathies, and autoinflam sion in chronic conditions, such as arthritis, is associated with matory diseases. Advantages include rapid onset, ease of use, reduced adherence to medical treatment recommendations. low cost, and universal availability; they are often disease Among patients with rheumatoid arthritis, anxiety and modifzing and sometimes lifesaving. depression are associated with reduced response to treatment Adverse eflects include osteoporosis, immunosuppression. and poorer quality of life. Active screening for depression, skin fragility, glaucoma, cataracts, weight gain. diabetes melli recommended lbr all adults, is therefore of still greater impor tus. hypertension, psychomotor agitation, osteonecrosis. and tance in individuals with arthritis and may improve outcomes. suppression of the hypothalamic pituitary adrenal axis. These Actively engaging adults with arthritis in evidence based self- effects are more likely with higher doses and longer treatment. management programs is helpful not only tbr arthritis but also The immunosuppressive adverse etfects of glucocorticoids for reducing depression and improving self efficacy. are apparent at moderate (prednisone at >20 mg/d) and high

benefits should be appropriately balanced with possible risks of the procedure. Anti-l nfla m matory Agents Glucocorticoids Mental Health Screening Clucocorticoids are eff'ective in many rheumatologic dise:rses, Practitioners should be aware that patients with arthritis including rheumatoid arthritis (RA), acute crystal arthropathy, experience mental distress and have :r history of depression at systemic vasculitis, polymyalgia rheumatica. systemic lupus higher rates than the general population. Concurrent depres erythematosus, inflammatory myopathies, and autoinflam sion in chronic conditions, such as arthritis, is associated with matory diseases. Advantages include rapid onset, ease of use, reduced adherence to medical treatment recommendations. low cost, and universal availability; they are often disease Among patients with rheumatoid arthritis, anxiety and modifzing and sometimes lifesaving. depression are associated with reduced response to treatment Adverse eflects include osteoporosis, immunosuppression. and poorer quality of life. Active screening for depression, skin fragility, glaucoma, cataracts, weight gain. diabetes melli recommended lbr all adults, is therefore of still greater impor tus. hypertension, psychomotor agitation, osteonecrosis. and tance in individuals with arthritis and may improve outcomes. suppression of the hypothalamic pituitary adrenal axis. These Actively engaging adults with arthritis in evidence based self- effects are more likely with higher doses and longer treatment. management programs is helpful not only tbr arthritis but also The immunosuppressive adverse etfects of glucocorticoids for reducing depression and improving self efficacy. are apparent at moderate (prednisone at >20 mg/d) and high 8

Principles of Therapeutics doses but can also occur at lower doses (e.g., z.s mg/d for more diclofenac may also be prelerred fbr patients at high risk for than a few weeks). The American College of Rheumatologr toxicity from oral NSAIDs or those 75 years of age or older. (ACR) recommends that patients who are anticipated to be receiving long term glucocorticoid treatment (prednisone at Colchicine >2.5 mg/d fbr >3 months) should have a baseline clinical risk Colchicine inhibits microtubules, impairs neutrophil func assessment for osteoporosis within 3 to 6 months of initiation tion. and inhibits inflammasome-mediated interleukin 1 of therapy. Those with risk factors and those older than age activation. Inflammasome is a central signaling system that 40 years should also undergo periodic bone mineral density regulates the inf'lammatory response. It is most commonly testing. Furthermore, those at moderate or high risk for osteo- used for gout and acute calcium pyrophosphate crystal arthri porotic fractures who are prescribed long-term glucocorticoid tis (pseudogout). It is also a treatment for hypersensitivity therapy should be treated prophylactically with an antiresorp- vasculitis and familial Mediterranean f'ever. tive agent, preferably an oral bisphosphonate. Gastrointestinal adverse eff'ects (particularly diarrhea) are common but reversible with dose adjustment or discontinua NSAIDS tion. With overdose, severe (even fatal) myelosuppression can NSAIDS prevent prostaglandin production by inhibiting the occur. Dosing must be adjusted fbr kidney disease. When two isofbrms of cyclooxygenase (COX): COX-1 and COX-2. given over the long term, colchicine can rarely cause neuro COX-2 is an inducible enzyme typically expressed in inflam muscular toxicity, particularly if coadministered with strong matory milieus, whereas COX 1 is constitutively expressed and CYP3A4 inhibitors (e.9., clarithromycin) that reduce the helps maintain organismal homeostasis. Nearly all available hepatic catabolism of colchicine. Such coadministration COX inhibitors are nonselective (i.e., they inhibit both COX should be avoided. isoforms), down regulating prostaglandin production in rtY P0rilTs inflammatory states, and interfering with functions of pros tanoids (e.g., renal blood flow and gut mucosal integrity main r Patients anticipated to be receiving long-term glucocorli coid treatment (prednisone at >2.5 mg/d for >3 months) tenance) (Table 8). Nonselective COX inhibitors also inhibit should have a baseline clinical risk assessment for thromboxane Ar, thereby inhibiting platelet function. osteoporosis within 3 to 6 months of initiation of Although they alleviate symptoms, COX inhibitors are not therapy. disease modiffing, with the possible exception of ankylosing spondylitis. Major concerns surrounding all COX inhibitors . Because of the increased risk for gastrointestinal bleed include increased risk lbr gastrointestinal bleeding and adverse ing and adverse cardiovascular and renal events. cardiovascular events; therefore, they should be prescribed at cyclooxygenase inhibitors should be prescribed at the the lowest dose fbr the shortest time possible. COX inhibitors lowest dose for the shortest time possible. should generally be avoided in patients receiving concomitant anticoagulation. NSAIDs vary with regard to kinetics, COX-112 selectivity, Analgesics and Pain and other features, and they carry somewhat different degrees oi cardiovascular and other risks; having experience with sev Pathway Modulators eral different NSAIDs is beneficial in clinical practice. Pain is a central symptom for patients with inflammatory A topical preparation of the NSAID diclofenac is available arthritis and osteoarthritis. It is important to use a patient both by prescription and over the counter fbr arthritis. It poses centered approach while managing pain in these patients. ln a lower risk for systemic adverse effects compared with oral addition to pharmacologic interventions, treatment should NSAlDs. Topical NSAIDs are strongly recommended fbr include patient education, guidance on physical activity and patients with knee osteoarthritis and conditionally recom exercise, orthotics, psychological and social interventions, mended for patients with hand osteoarthritis. Topical sleep hygiene education, and, il'indicated, sleep interventions.

doses but can also occur at lower doses (e.g., z.s mg/d for more diclofenac may also be prelerred fbr patients at high risk for than a few weeks). The American College of Rheumatologr toxicity from oral NSAIDs or those 75 years of age or older. (ACR) recommends that patients who are anticipated to be receiving long term glucocorticoid treatment (prednisone at Colchicine >2.5 mg/d fbr >3 months) should have a baseline clinical risk Colchicine inhibits microtubules, impairs neutrophil func assessment for osteoporosis within 3 to 6 months of initiation tion. and inhibits inflammasome-mediated interleukin 1 of therapy. Those with risk factors and those older than age activation. Inflammasome is a central signaling system that 40 years should also undergo periodic bone mineral density regulates the inf'lammatory response. It is most commonly testing. Furthermore, those at moderate or high risk for osteo- used for gout and acute calcium pyrophosphate crystal arthri porotic fractures who are prescribed long-term glucocorticoid tis (pseudogout). It is also a treatment for hypersensitivity therapy should be treated prophylactically with an antiresorp- vasculitis and familial Mediterranean f'ever. tive agent, preferably an oral bisphosphonate. Gastrointestinal adverse eff'ects (particularly diarrhea) are common but reversible with dose adjustment or discontinua NSAIDS tion. With overdose, severe (even fatal) myelosuppression can NSAIDS prevent prostaglandin production by inhibiting the occur. Dosing must be adjusted fbr kidney disease. When two isofbrms of cyclooxygenase (COX): COX-1 and COX-2. given over the long term, colchicine can rarely cause neuro COX-2 is an inducible enzyme typically expressed in inflam muscular toxicity, particularly if coadministered with strong matory milieus, whereas COX 1 is constitutively expressed and CYP3A4 inhibitors (e.9., clarithromycin) that reduce the helps maintain organismal homeostasis. Nearly all available hepatic catabolism of colchicine. Such coadministration COX inhibitors are nonselective (i.e., they inhibit both COX should be avoided. isoforms), down regulating prostaglandin production in rtY P0rilTs inflammatory states, and interfering with functions of pros tanoids (e.g., renal blood flow and gut mucosal integrity main r Patients anticipated to be receiving long-term glucocorli coid treatment (prednisone at >2.5 mg/d for >3 months) tenance) (Table 8). Nonselective COX inhibitors also inhibit should have a baseline clinical risk assessment for thromboxane Ar, thereby inhibiting platelet function. osteoporosis within 3 to 6 months of initiation of Although they alleviate symptoms, COX inhibitors are not therapy. disease modiffing, with the possible exception of ankylosing spondylitis. Major concerns surrounding all COX inhibitors . Because of the increased risk for gastrointestinal bleed include increased risk lbr gastrointestinal bleeding and adverse ing and adverse cardiovascular and renal events. cardiovascular events; therefore, they should be prescribed at cyclooxygenase inhibitors should be prescribed at the the lowest dose fbr the shortest time possible. COX inhibitors lowest dose for the shortest time possible. should generally be avoided in patients receiving concomitant anticoagulation. NSAIDs vary with regard to kinetics, COX-112 selectivity, Analgesics and Pain and other features, and they carry somewhat different degrees oi cardiovascular and other risks; having experience with sev Pathway Modulators eral different NSAIDs is beneficial in clinical practice. Pain is a central symptom for patients with inflammatory A topical preparation of the NSAID diclofenac is available arthritis and osteoarthritis. It is important to use a patient both by prescription and over the counter fbr arthritis. It poses centered approach while managing pain in these patients. ln a lower risk for systemic adverse effects compared with oral addition to pharmacologic interventions, treatment should NSAlDs. Topical NSAIDs are strongly recommended fbr include patient education, guidance on physical activity and patients with knee osteoarthritis and conditionally recom exercise, orthotics, psychological and social interventions, mended for patients with hand osteoarthritis. Topical sleep hygiene education, and, il'indicated, sleep interventions. TABLE 8. Potential Toxicities of NSAID Use Category Toxicity Cardiovascular Myocardial infarction; exacerbation of heart failure Hemostatic Platelet dysfunction Gastrointestina I Dyspepsia; reflux; peptic ulcer disease; gastrointestinal bleeding Obstetric/Gyn eco log ic Bleeding; delayed labor; premature ductus arteriosus closure Pulmonary Asthma exacerbation Renal Hypertension; decreased glomerular filtration; increased salt and water retention; increased renin produ uncommonly, allergic interstitial nephritis or acute tubular necrosis

TABLE 8. Potential Toxicities of NSAID Use Category Toxicity Cardiovascular Myocardial infarction; exacerbation of heart failure Hemostatic Platelet dysfunction Gastrointestina I Dyspepsia; reflux; peptic ulcer disease; gastrointestinal bleeding Obstetric/Gyn eco log ic Bleeding; delayed labor; premature ductus arteriosus closure Pulmonary Asthma exacerbation Renal Hypertension; decreased glomerular filtration; increased salt and water retention; increased renin produ uncommonly, allergic interstitial nephritis or acute tubular necrosis 9

Principles of Therapeutics Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent

Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent Anakinra Macrophage

Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent Anakinra Macrophage Dendritic cell Neutrophil z'Ji-:',ii,"' tL-1

Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent Anakinra Macrophage Dendritic cell Neutrophil z'Ji-:',ii,"' tL-1 proteases

Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent Anakinra Macrophage Dendritic cell Neutrophil z'Ji-:',ii,"' tL-1 proteases tL-6

Mycophenolate Mofetil Apremilast Mycophenolate mofetil is the first-line agent for lupus nephri- Apremilast is modestly elfective for psoriasis and psoriatic tis and may be effective for systemic sclerosis with associated arthritis. It does not cause immunosuppression or myelosup interstitial lung disease. Gastrointestinal adverse effects, pression. However, apremilast is less efficacious than biologic including diarrhea, are common. Myelosuppression may DMARDs and has a slow onset of action, and its effect on pro occur. gression of erosive damage is unknown. Risks include gastro intestinal adverse effects (mainly nausea and diarrhea) and weight loss. It should be used with caution in patients with a Calcineurin Inhibitors Calcineurin inhibitors include cyclosporine, tacrolimus, and history of depression. Apremilast is also FDA approved for voclosporin. Cyclosporine is now rarely used for rheumato treatment of oral ulcers in Behget syndrome. logic conditions because of renal adverse effects, hyperten TEY POIl{IT sion, hyperuricemia (often presenting as gout), and need for . Methotrexate is a first-line medication for rheumatoid frequent drug level monitoring. Tacrolimus may be considered arthritis and other autoimmune diseases. as alternative therapy for some patients with lupus nephritis. Voclosporin, a next generation calcineurin inhibitor with . Hydroxychloroquine decreases mortality and the likeli- hood of developing nephritis in patients with systemic higher potency and improved side effect profile, is FDA lupus erythematosus. approved for lupus nephritis. r Cyclophosphamide is used in severe cases of vasculitis and lupus nephritis or when other agents fail. Janus Kinase Inhibitors Tofacitinib is an oral agent that inhibits Janus kinase (JAK) o The oral Janus kinase inhibitor tofacitinib is FDA 1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori approved for rheumatoid arthritis and psoriatic arthritis atic arthritis, with efTicacy equal to that of biologic DMARDs. and has efficacy equal to that ofbiologic agents. Risks include hyperlipidemia, hepatotoxicity, leukopenia, reactivation of zoster (at a rate higher than seen with bio- Biologic Disease-Modifying Antirheumatic Drugs logic therapies), and thrombotic events when used at higher Biologic DMARDs are highly specitic, parenterally adminis doses. Newer JAK inhibitors approved for rheumatologic tered, protein based agents with extracellular targets (cytokines, diseases include baricitinib (JAKI/2) and upadacitinib cytokine receptors, or cell surface molecules on immune cells) (JAK1). (Flgure 1). The end of the generic name of a biologic agent Anakinra Macrophage Dendritic cell Neutrophil z'Ji-:',ii,"' tL-1 proteases tL-6 k/'INF-a rilumab T cell Cartilage MMPs Synovial Tocacitini f-Abatacept Baricitinib Upadacitinib Bone B cell MMPs TNF Rituximab Osteoclast T lnf liximab \ RF, anti-CCP Etanercept anti bod ies Adalimumab Golimumab Certilizumab tIGURE l.Thein{lammatorycascadeinrheumatoidarthritis(RA).Dendriticcells,macrophages,andBcellspresentincitingantigenstoTcells.Macrophagessecrete

k/'INF-a rilumab T cell Cartilage MMPs Synovial Tocacitini f-Abatacept Baricitinib Upadacitinib Bone B cell MMPs TNF Rituximab Osteoclast T lnf liximab \ RF, anti-CCP Etanercept anti bod ies Adalimumab Golimumab Certilizumab tIGURE l.Thein{lammatorycascadeinrheumatoidarthritis(RA).Dendriticcells,macrophages,andBcellspresentincitingantigenstoTcells.Macrophagessecrete and other enzymes that contribute to the degradation of articular cartilage and activate neutrophils, which mediate joint damage through proteases and other enzymes. Activated osteoclasts additionally secrete MMPs that contribute to marginal erosions of bone. lLs, TNF, T cells, and B cells may all be targeted for inhibition by the various disease-modifying antirheumatic drugs useful in RA. CCP = cyclic citrullinated peptide; lL= interleukin; LTB4 = leukotriene Ba; MMP = matrix metalloproteinase; 02 = oxygen; PG E2 = prostag la ndi n Ez; RF = rheu matoid factor; IN F = tu mor necrosis factor.

and other enzymes that contribute to the degradation of articular cartilage and activate neutrophils, which mediate joint damage through proteases and other enzymes. Activated osteoclasts additionally secrete MMPs that contribute to marginal erosions of bone. lLs, TNF, T cells, and B cells may all be targeted for inhibition by the various disease-modifying antirheumatic drugs useful in RA. CCP = cyclic citrullinated peptide; lL= interleukin; LTB4 = leukotriene Ba; MMP = matrix metalloproteinase; 02 = oxygen; PG E2 = prostag la ndi n Ez; RF = rheu matoid factor; IN F = tu mor necrosis factor. 12

Principles of Therapeutics TABLE 1O. Tumor Necrosis Factor lnhibitors" Agent Agent Structure lndications lnflixima Er Chimeric (mouse-human) monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis; IBD Adalimumab Humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis; IBD Etanercept Fusion protein made of two p75 TNF receptors linked to RA; psoriatic arthritis; ankylosing spondylitis lgG Fc segment Certolizumab pegol Fab'segment of humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis attached to polyethylene glycol strands Golimumab Humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis IBD = inf ammatory bowel d sease; RA = rheumatord arthr t s; TNF - tumor necrosis factor. at baseline and every 3 to 6 months thereafter.

TABLE 1O. Tumor Necrosis Factor lnhibitors" Agent Agent Structure lndications lnflixima Er Chimeric (mouse-human) monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis; IBD Adalimumab Humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis; IBD Etanercept Fusion protein made of two p75 TNF receptors linked to RA; psoriatic arthritis; ankylosing spondylitis lgG Fc segment Certolizumab pegol Fab'segment of humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis attached to polyethylene glycol strands Golimumab Humanized monoclonal antibody RA; psoriatic arthritis; ankylosing spondylitis IBD = inf ammatory bowel d sease; RA = rheumatord arthr t s; TNF - tumor necrosis factor. at baseline and every 3 to 6 months thereafter. indicates what type of molecule it is: mcrb indicates a monoclo- term "biosimilar"); therefbre, they must undergo phase III nal antibody, -kin indicates an interleukin |lpe substance. ro testing to prove equivalent efficacy to the parent biologic. In is for a receptor antagonist, and .cept is for receptor based the United States, biosimilars are distinguished from their molecule. A11 biologics require parenteral administration. originator molecules by the presence of a four character Table l0 and Table 11 summarize the structures. targets. alphabetic suffix. Biosimilars hoid promise lbr decreasing cost indications, and common monitoring parameters of various and improving access, but those benelits have rarely been real biologic DN4ARDs. See Medications and Pregnancy fbr inlor ized because of regulatory and market factors. mation on these drugs in pregnancy. Biologic DMARDs increase r(tY P0 t llTs the risk fbr infection to varying degrees. Targeted screening is therefore necessary before initiation (see Vaccination and . All biologic agents increase the risk for infection; there fore, targeted screening is necessary before initiation. Screening in Immunosuppression). The cost of biologic agents is significant and may be a bar . Tumor necrosis factor inhibitors pose a particularly rier to access. high risk for reactivation of tuberculosis, and patients must be screened for latent infection befbre initiation of Tumor Necrosis Factor Inhibitors therapy. Tumor necrosis factor (TNF) inhibitors (see Table 10) are . Biologic agents that are not directed at tumor necrosis HVC widely used for treating RA. psoriasis. psoriatic arthritis, and factor (TNF) are usually started after one or two TNF ankylosing spondylitis, as well as several nonrheumatologic inhibitors have failed. diseases. TNF inhibitors are generally well tolerated; increased risk for infection is the primary safety concern. Because TNF U rate-Loweri n g TheraPY inhibitors pose a particul:rrly high risk for reactivation of tuberculosis, all patients being considered for treatment must Allopurinol be screened for latent infection and, if needed, receive treat Allopurinol is the recommended tjrst line urate lon'ering agent. lt competitively inhibits the enzyme xanthine oxidase, ment. Except for nonmelanoma skin cancer and possibly mel blocking the conversion of hypoxanthine (a breakdown prod anoma, l'NF inhibitors do not appear to increase the risk for uct of purines) to uric acid. Allopurinol is metabolized kr oxy- new cancers; the risk for malignant recurrence remains purinol, which also inhibits xanthine oxidase. Allopurinol is unclear. TNF inhibitors may exacerbate heart failure and rarely FDA approved fbr dosages up to 800 mg/d. Allopurinol should provoke a demyelinating condition. Over time, individual TNF be initiated at 100 mg/d and titrated in 100 mg increments inhibitors may lose efficacy owing to fbrmation of antidrug until the therapeutic target is achieved. For patients with stage antibodies. 4 or 5 chronic kidney disease, allopurinol should be initiated at 50 mg/d and titrated in 50 to 100 mg increments as needed. Other Biologic Disease-Modiffing Antirheumatic Drugs Multiple biologic DMARDs with non TNF extracellular and Allopurinol use is rarely associated with a hypersensitivity cell surface targets have been approved by the FDA. Most of syndrome, most severely as DRESS (drug reaction with eosino- these agents are started after one or two TNF inhibitors have philia and systemic symptoms), a potentially latal reaction' DRESS is also increasingly being reterred to as drug induced tailed. See Table 11 for more information. hypersensitiuity syndrome (DIHS) to emphasize the lact that Biosimilars eosinophilia is not always present. Risk factors include chronic Biosimilar agents are "copycat" versions of brand name bio kidney disease and diuretic use; allopurinol dosage titration logic medications. The drugs are not exact replicas (hence the appears to substantially reduce the risk. Anclther DRESS risk

indicates what type of molecule it is: mcrb indicates a monoclo- term "biosimilar"); therefbre, they must undergo phase III nal antibody, -kin indicates an interleukin |lpe substance. ro testing to prove equivalent efficacy to the parent biologic. In is for a receptor antagonist, and .cept is for receptor based the United States, biosimilars are distinguished from their molecule. A11 biologics require parenteral administration. originator molecules by the presence of a four character Table l0 and Table 11 summarize the structures. targets. alphabetic suffix. Biosimilars hoid promise lbr decreasing cost indications, and common monitoring parameters of various and improving access, but those benelits have rarely been real biologic DN4ARDs. See Medications and Pregnancy fbr inlor ized because of regulatory and market factors. mation on these drugs in pregnancy. Biologic DMARDs increase r(tY P0 t llTs the risk fbr infection to varying degrees. Targeted screening is therefore necessary before initiation (see Vaccination and . All biologic agents increase the risk for infection; there fore, targeted screening is necessary before initiation. Screening in Immunosuppression). The cost of biologic agents is significant and may be a bar . Tumor necrosis factor inhibitors pose a particularly rier to access. high risk for reactivation of tuberculosis, and patients must be screened for latent infection befbre initiation of Tumor Necrosis Factor Inhibitors therapy. Tumor necrosis factor (TNF) inhibitors (see Table 10) are . Biologic agents that are not directed at tumor necrosis HVC widely used for treating RA. psoriasis. psoriatic arthritis, and factor (TNF) are usually started after one or two TNF ankylosing spondylitis, as well as several nonrheumatologic inhibitors have failed. diseases. TNF inhibitors are generally well tolerated; increased risk for infection is the primary safety concern. Because TNF U rate-Loweri n g TheraPY inhibitors pose a particul:rrly high risk for reactivation of tuberculosis, all patients being considered for treatment must Allopurinol be screened for latent infection and, if needed, receive treat Allopurinol is the recommended tjrst line urate lon'ering agent. lt competitively inhibits the enzyme xanthine oxidase, ment. Except for nonmelanoma skin cancer and possibly mel blocking the conversion of hypoxanthine (a breakdown prod anoma, l'NF inhibitors do not appear to increase the risk for uct of purines) to uric acid. Allopurinol is metabolized kr oxy- new cancers; the risk for malignant recurrence remains purinol, which also inhibits xanthine oxidase. Allopurinol is unclear. TNF inhibitors may exacerbate heart failure and rarely FDA approved fbr dosages up to 800 mg/d. Allopurinol should provoke a demyelinating condition. Over time, individual TNF be initiated at 100 mg/d and titrated in 100 mg increments inhibitors may lose efficacy owing to fbrmation of antidrug until the therapeutic target is achieved. For patients with stage antibodies. 4 or 5 chronic kidney disease, allopurinol should be initiated at 50 mg/d and titrated in 50 to 100 mg increments as needed. Other Biologic Disease-Modiffing Antirheumatic Drugs Multiple biologic DMARDs with non TNF extracellular and Allopurinol use is rarely associated with a hypersensitivity cell surface targets have been approved by the FDA. Most of syndrome, most severely as DRESS (drug reaction with eosino- these agents are started after one or two TNF inhibitors have philia and systemic symptoms), a potentially latal reaction' DRESS is also increasingly being reterred to as drug induced tailed. See Table 11 for more information. hypersensitiuity syndrome (DIHS) to emphasize the lact that Biosimilars eosinophilia is not always present. Risk factors include chronic Biosimilar agents are "copycat" versions of brand name bio kidney disease and diuretic use; allopurinol dosage titration logic medications. The drugs are not exact replicas (hence the appears to substantially reduce the risk. Anclther DRESS risk 13

a t I Principles of Therapeutics ! ! t I I 1 Agent Agent Structure Target lndications Comments I I I Abatacept Soluble CTLA4 receptor/lgG CD8O/CD86; RA Preferred for patients with history of Fc segment chimera blocks T-cell severe i n{ection; relatively ! costimulation contraindicated in COPD 1 Rituximab Chimeric (mouse-human) CD20* B cells RA; ANCA-associated Given as intravenous infusion over l i monoclonal antibody vasculitis; occasionally several hours; has higher risk for infusion I

Rituximab Chimeric (mouse-human) CD20* B cells RA; ANCA-associated Given as intravenous infusion over l i monoclonal antibody vasculitis; occasionally several hours; has higher risk for infusion I I for SLE (off-label); reactions than other biologic DMARDs; lgG4-related disease can cause hypogammaglobulinemia Tocilizumab Humanized monoclonal lL-6 receptor RA; JIA; Castleman Can cause elevated aminotransferase I antibody disease; GCA levels, hyperlipidemia, leukopenia, thrombocytopenia; avoid in patients with history of diverticulitis because of I attendant risk for bowel perforation Sarilumab Human monoclonal antibody lL-6 receptor RA Can cause elevated aminotransferase levels, hyperlipidemia, leukopenia, throm bocytopenia

antibody disease; GCA levels, hyperlipidemia, leukopenia, thrombocytopenia; avoid in patients with history of diverticulitis because of I attendant risk for bowel perforation Sarilumab Human monoclonal antibody lL-6 receptor RA Can cause elevated aminotransferase levels, hyperlipidemia, leukopenia, throm bocytopenia Belimumab Human monoclonal antibody BLyS/BAFF SLE; lupus nephritis Phase llltrials showed small but statistical ly significant im provement versus standard therapy alone, with glucocorticoid-sparing effect Ustekinumab Humanmonoclonalantibody tL-12/lL-23 Psoriasis; psoriatic lnjectable; less robust effect than other a rth ritis biologic DMARDs Secukinumab Humanmonoclonalantibody lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy egual to ankylosing spondylitis that of TNF inhibitors; can cause IBD flares

Belimumab Human monoclonal antibody BLyS/BAFF SLE; lupus nephritis Phase llltrials showed small but statistical ly significant im provement versus standard therapy alone, with glucocorticoid-sparing effect Ustekinumab Humanmonoclonalantibody tL-12/lL-23 Psoriasis; psoriatic lnjectable; less robust effect than other a rth ritis biologic DMARDs Secukinumab Humanmonoclonalantibody lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy egual to ankylosing spondylitis that of TNF inhibitors; can cause IBD flares lxekizumab Humanized monoclonal lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy equal to antibody ankylosing spondylitis that of TNF inhibitors; can cause IBD flares

lxekizumab Humanized monoclonal lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy equal to antibody ankylosing spondylitis that of TNF inhibitors; can cause IBD flares Guselkumab Human monoclonal antibody lL-23 Psoriasis; psoriatic Selective lL-23 inhibitor afthritis Anakinra Recombinant receptor lL-1 B receptor RA; CAPSb; AOSD(off Rarely used in RA because efficary is antagonist label); acute gouty inferior to that of other biologic DMARDs; arthritis (off-label) reversible neutropenia can develop Canakinumab Human monoclonal antibody rL-1 p CAPSb More expensive lL-1p inhibitor Ri lonacept Dual lL-1B receptors chimerically tL-1 CAPSb; refractory More expensive lL-1 inhibitor attached to lgG Fc segment gout Mepolizumab Humanized monoclonal tL-5 EGPA; eosinophilic Only biologic approved fortreatment of antibody asthma EGPA arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor.

Canakinumab Human monoclonal antibody rL-1 p CAPSb More expensive lL-1p inhibitor Ri lonacept Dual lL-1B receptors chimerically tL-1 CAPSb; refractory More expensive lL-1 inhibitor attached to lgG Fc segment gout Mepolizumab Humanized monoclonal tL-5 EGPA; eosinophilic Only biologic approved fortreatment of antibody asthma EGPA arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor. 'Before initiation of any biologic, tuberculosis screening must be performed. Complete blood counts should be performed every 3 to 6 months for all biologics, and aspartate aminotransferase/alanine aminotransferase and a lipid panel should be checked every 2 to 3 months for tocilizumab. blhe cropyrin-associated periodic syndromes (CAPS) include familial cold autoin{lammator syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammator disease (chronic infantile neurologic, cutaneous, articular syndrome).

'Before initiation of any biologic, tuberculosis screening must be performed. Complete blood counts should be performed every 3 to 6 months for all biologics, and aspartate aminotransferase/alanine aminotransferase and a lipid panel should be checked every 2 to 3 months for tocilizumab. blhe cropyrin-associated periodic syndromes (CAPS) include familial cold autoin{lammator syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammator disease (chronic infantile neurologic, cutaneous, articular syndrome). factor is the HLA-B'58:01 allele, which is more common in enzymes should be monitored. Concomitant use with purine Black persons and persons of Han Chinese, Thai, and Korean analogues is contraindicated. Incidence of hypersensitivity is descent and increases the risk for hypersensitivity by several rarer and usually less severe than with allopurinol. In a 2018 hundred-fold. Screening for HLA 8'58:01 in these populations safety study, febuxostat users had an increased risk for cardio is conditionally recommended before initiation of allopurinol. vascular death and all-cause mortality compared with patients Xanthine oxidase inhibitors should not be coadministered with receiving allopurinol. These data do not define febuxostat purine analogues (such as azathioprine). See MKSAP 19 General as raising risk compared with no treatment, and other studies Internal Medicine 2 for more information on DRESS. have failed to support this observation; however, the results prompted the FDA to mandate a boxed warning for febuxostat Febuxostat regarding increased risk compared with allopurinol. The FDA Febuxostat is a noncompetitive xanthine oxidase inhibitor. has also limited the approved use of febuxostat to patients who Elevated aminotransferase levels can rarely occur, and liver are unresponsive to or cannot tolerate allopurinol.

factor is the HLA-B'58:01 allele, which is more common in enzymes should be monitored. Concomitant use with purine Black persons and persons of Han Chinese, Thai, and Korean analogues is contraindicated. Incidence of hypersensitivity is descent and increases the risk for hypersensitivity by several rarer and usually less severe than with allopurinol. In a 2018 hundred-fold. Screening for HLA 8'58:01 in these populations safety study, febuxostat users had an increased risk for cardio is conditionally recommended before initiation of allopurinol. vascular death and all-cause mortality compared with patients Xanthine oxidase inhibitors should not be coadministered with receiving allopurinol. These data do not define febuxostat purine analogues (such as azathioprine). See MKSAP 19 General as raising risk compared with no treatment, and other studies Internal Medicine 2 for more information on DRESS. have failed to support this observation; however, the results prompted the FDA to mandate a boxed warning for febuxostat Febuxostat regarding increased risk compared with allopurinol. The FDA Febuxostat is a noncompetitive xanthine oxidase inhibitor. has also limited the approved use of febuxostat to patients who Elevated aminotransferase levels can rarely occur, and liver are unresponsive to or cannot tolerate allopurinol. 14

Principles of Therapeutics Uricosuric Agents DMARDs and/or JAK inhibitors, such as tofacitinib, should not Probenecid is an organic acid transport inhibitor that decreases receive live attenuated vaccines (e.g., for measles. mumps and renal reuptake of uric acid. It is uncornmonly used because of rubella; varicella herpes zoster; influenza; and yellor,r, fever) limited eflficacy, inconvenience, and limitations on use (e.g., because of risk fbr active inf'ection. Such patients can receive drug interactions and adverse effects). the killed influenza and pneumococcal vaccines, as rtell as recombinant herpes zoster vaccine as needed. Other non live Pegloticase vaccines that are indicated should be administered as per Unlike most other mammals, humans lack a functioning standard care (see MKSAP 19 General lnternal N4edicine 2 lbr uricase to break down uric acid. Pegloticase is a recombinant, more information). Patients receiving traditional oral DMARDs nonhuman, infusible pegzlated uricase that is highly efl'ective (e.g., hldroxychloroquine, methotrexate, and sulfasalazine) at lowering serum urate. Pegloticase is reserved fbr severe may receive any vaccines as needed. and/or refractory gout. Because of its extreme potency, mobi Before initiation ot immunosuppressive therapy, the fbl lization flares of gout are common, and prophytaxis against lowing screening is recommended: acute gouty attacks is required. Pegloticase is administered o Tuberculosis screening with tuberculin skin testing or intravenously every 2 weeks; if the preinfusion serum urate interferon y release assay, particularly for patients initiat increases to more than 6.0 mg/dl (0.35 nrnroll[-) on two occa ing biologic DMARDs sions, antibodies have probably formed. and the drug should . Hepatitis B and C virus serologic testing (for patients initi be discontinued to prevent infusion reactions. ating biologic DMARDs and drugs that can cause hepato I(EY POIilIS toxicity) . Allopurinol is the first line urate-lowering agent; the o HIV screening biggest risk the drug poses is DRESS (drug reaction Patients with latent or active tuberculosis, active hepatitis with eosinophilia and systemic symptoms). B virus infection, or untreated HIV infection require initiation o Concomitant use of xanthine oxidase inhibitors (allo of appropriate therapy befbre initiating immunosuppression. purinol or febuxostat) with purine analogues is contra- Patients with risk firctors fbr ongoing tuberculosis exposure indicated. should have annual tuberculosis screening.

Uricosuric Agents DMARDs and/or JAK inhibitors, such as tofacitinib, should not Probenecid is an organic acid transport inhibitor that decreases receive live attenuated vaccines (e.g., for measles. mumps and renal reuptake of uric acid. It is uncornmonly used because of rubella; varicella herpes zoster; influenza; and yellor,r, fever) limited eflficacy, inconvenience, and limitations on use (e.g., because of risk fbr active inf'ection. Such patients can receive drug interactions and adverse effects). the killed influenza and pneumococcal vaccines, as rtell as recombinant herpes zoster vaccine as needed. Other non live Pegloticase vaccines that are indicated should be administered as per Unlike most other mammals, humans lack a functioning standard care (see MKSAP 19 General lnternal N4edicine 2 lbr uricase to break down uric acid. Pegloticase is a recombinant, more information). Patients receiving traditional oral DMARDs nonhuman, infusible pegzlated uricase that is highly efl'ective (e.g., hldroxychloroquine, methotrexate, and sulfasalazine) at lowering serum urate. Pegloticase is reserved fbr severe may receive any vaccines as needed. and/or refractory gout. Because of its extreme potency, mobi Before initiation ot immunosuppressive therapy, the fbl lization flares of gout are common, and prophytaxis against lowing screening is recommended: acute gouty attacks is required. Pegloticase is administered o Tuberculosis screening with tuberculin skin testing or intravenously every 2 weeks; if the preinfusion serum urate interferon y release assay, particularly for patients initiat increases to more than 6.0 mg/dl (0.35 nrnroll[-) on two occa ing biologic DMARDs sions, antibodies have probably formed. and the drug should . Hepatitis B and C virus serologic testing (for patients initi be discontinued to prevent infusion reactions. ating biologic DMARDs and drugs that can cause hepato I(EY POIilIS toxicity) . Allopurinol is the first line urate-lowering agent; the o HIV screening biggest risk the drug poses is DRESS (drug reaction Patients with latent or active tuberculosis, active hepatitis with eosinophilia and systemic symptoms). B virus infection, or untreated HIV infection require initiation o Concomitant use of xanthine oxidase inhibitors (allo of appropriate therapy befbre initiating immunosuppression. purinol or febuxostat) with purine analogues is contra- Patients with risk firctors fbr ongoing tuberculosis exposure indicated. should have annual tuberculosis screening. KtY POIlITS o Whenever possible, vaccinations should be updated Medications and Pregnancy before initiating biologic disease modifying antirheu- Some rheumatologic medications can have adverse effects matic drug regimens. on pregnancy. Table 12 lists these agents and tl.reir relative o Screening (and therapy ifneeded) for tuberculosis, risks. hepatitis B and C virus, and HIV is appropriate before I(EY PO IilIS initiation of immunosuppressive therapy. o Methotrexate is highly teratogenic and abortifacient; it must be discontinued at least 3 months before pregnancy. . Hydroxychloroquine is relatively safe in pregnancy and Nonpharmacologic and should not be discontinued ifit is needed. Nontraditional Management r Leflunomide is extremely teratogenic and must not be Because rheumatologic diseases fiequently aflect the muscu used before or during pregnancy; upon discontinuation, loskeletal system. nonpharmacologic measures are ofter.r cholestyramine is required to remove the drug fiom the used to address pain not eliminirted by medications. 'fhese body in all women of childbearing potential and specifi- measures include physical therapy, occupational therapy. cally in those wishing to become pregnant. surgery, weight reductior.r, psychosocial support, and self management programs. Many patients turn to complemen tary and alternative medicine as adjuncts to traditional Vaccination and Screening in medical interventions. lmmunosuppression Patients with autoimmune diseases should be assessed fbr Physical and Occupational Therapy immunization status at diagnosis and/or initiation ol treat Physical therapists can help primary care physicians assess ments. Whenever possible, patients should be updated with aerobic fitness and conditioning as well as ability to carry out vaccinations at least 2 to 4 weeks before initiating biologic activities of daily livir.rg. Pain and lunctional limitation can be DMARD regimens. Vaccine response may be diminished addressed through manual therapy, assistive devices, joint during biologic immunosuppressive treatment (particularly protection techniques, irnd therntal treatments. A targeted with B-cell depleting therapy). and patients receiving biologic exercise program can be initiated, and adapting the program

KtY POIlITS o Whenever possible, vaccinations should be updated Medications and Pregnancy before initiating biologic disease modifying antirheu- Some rheumatologic medications can have adverse effects matic drug regimens. on pregnancy. Table 12 lists these agents and tl.reir relative o Screening (and therapy ifneeded) for tuberculosis, risks. hepatitis B and C virus, and HIV is appropriate before I(EY PO IilIS initiation of immunosuppressive therapy. o Methotrexate is highly teratogenic and abortifacient; it must be discontinued at least 3 months before pregnancy. . Hydroxychloroquine is relatively safe in pregnancy and Nonpharmacologic and should not be discontinued ifit is needed. Nontraditional Management r Leflunomide is extremely teratogenic and must not be Because rheumatologic diseases fiequently aflect the muscu used before or during pregnancy; upon discontinuation, loskeletal system. nonpharmacologic measures are ofter.r cholestyramine is required to remove the drug fiom the used to address pain not eliminirted by medications. 'fhese body in all women of childbearing potential and specifi- measures include physical therapy, occupational therapy. cally in those wishing to become pregnant. surgery, weight reductior.r, psychosocial support, and self management programs. Many patients turn to complemen tary and alternative medicine as adjuncts to traditional Vaccination and Screening in medical interventions. lmmunosuppression Patients with autoimmune diseases should be assessed fbr Physical and Occupational Therapy immunization status at diagnosis and/or initiation ol treat Physical therapists can help primary care physicians assess ments. Whenever possible, patients should be updated with aerobic fitness and conditioning as well as ability to carry out vaccinations at least 2 to 4 weeks before initiating biologic activities of daily livir.rg. Pain and lunctional limitation can be DMARD regimens. Vaccine response may be diminished addressed through manual therapy, assistive devices, joint during biologic immunosuppressive treatment (particularly protection techniques, irnd therntal treatments. A targeted with B-cell depleting therapy). and patients receiving biologic exercise program can be initiated, and adapting the program 15

Principles of Therapeutics TABLE 12. Rheumatologic Medications and Pregnancy Medication/Class Comments Anti-l nflammatory Agents NSAIDs May impede implantation and be associated with small increased risk for miscarriage when used before 20 weeks' gestation. NSAID use after 30 weeks' gestation can lead to premature closure of ductus arteriosus. G lucocorticoids Whentakeninfirsttrimester,canincreaseriskforfetalcleftpalateandraiseriskformaternalgestational diabetes throughout the pregnancy. Useful in managing active autoimmune disease in pregnancy. Nonfluorinated glucocorticoids (e.9., prednisone, prednisolone, methylprednisolone) have limited ability to cross placenta and are preferred, except when treating the fetus (e.g., neonatal lupus erythematosus). Colchicine Should be used only i{ I benefit justifies potential risk to fetus. Analgesics and Pain Pathway Modulators Acetaminophen Generally considered safe at standard dosing but does cross the placenta. Opiates Some opiates/opioids cross placenta; may cause fetal opioid withdrawal at birth. Tramadol Should be used only if potential benefit justifies potential risk to fetus; postmarketing reports suggest possibility of neonatal seizures, withdrawal syndrome, and stillbirth. Topical agents Topical use may limit serum levels; individual agents should be reviewed {or pregnancy impact before use Nonbiologic DMARDs Methotrexate Highly teratogenic and abortifacient; must be discontinued at least 3 months before pregnancy. Hyd roxych loroquine Relatively safe in pregnancy and should not be discontinued if it is needed. Sulfasalazine Relatively safe during pregnancy.

Analgesics and Pain Pathway Modulators Acetaminophen Generally considered safe at standard dosing but does cross the placenta. Opiates Some opiates/opioids cross placenta; may cause fetal opioid withdrawal at birth. Tramadol Should be used only if potential benefit justifies potential risk to fetus; postmarketing reports suggest possibility of neonatal seizures, withdrawal syndrome, and stillbirth. Topical agents Topical use may limit serum levels; individual agents should be reviewed {or pregnancy impact before use Nonbiologic DMARDs Methotrexate Highly teratogenic and abortifacient; must be discontinued at least 3 months before pregnancy. Hyd roxych loroquine Relatively safe in pregnancy and should not be discontinued if it is needed. Sulfasalazine Relatively safe during pregnancy. Leflunomide Extremely teratogenic; must not be used before/during pregnancy; upon discontinuation, cholestyramine administration is required to remove drug from the body in all women of childbearing potential and specifically in those wishing to become pregnanU should be followed up with measurement of le{lunomide and its metabolite levels to ensure removal of drug. Azathioprine Routine use in pregnancy is not recommended; however, azathioprine may be safer than some other DMARDs and may be used if immunosuppressive agent is imperative. Cyclophospha m ide Not used in pregnancy unless absolutely necessary. Mycophenolate mofetil Teratogenic; should not be used in pregnancy; discontinue for 3 months before pregnancy is attempted. Cyclosporine May be used in pregnancy only if benefits outweigh risks. Tofaciti ni b; baricitinib; May be teratogenic at high doses. U citin ib Biologic DMARDs TNF inhibitors Accumulating retrospective data suggest low risk in pregnancy, but evidence is limited; can be continued if absolutely needed; different agents may have different considerations regarding crossing placenta. Ustekinumab; anakinra; Should be used only if potential benefit justifies undefined risk to fetus. secukinumab; sarilumab; ixekizumab; guselkumab Abatacept; belimumab; Should be used only if potential benefit justifies potential risk to fetus. canakinumab; rilonacept; rituxi mab; tocilizumab

Leflunomide Extremely teratogenic; must not be used before/during pregnancy; upon discontinuation, cholestyramine administration is required to remove drug from the body in all women of childbearing potential and specifically in those wishing to become pregnanU should be followed up with measurement of le{lunomide and its metabolite levels to ensure removal of drug. Azathioprine Routine use in pregnancy is not recommended; however, azathioprine may be safer than some other DMARDs and may be used if immunosuppressive agent is imperative. Cyclophospha m ide Not used in pregnancy unless absolutely necessary. Mycophenolate mofetil Teratogenic; should not be used in pregnancy; discontinue for 3 months before pregnancy is attempted. Cyclosporine May be used in pregnancy only if benefits outweigh risks. Tofaciti ni b; baricitinib; May be teratogenic at high doses. U citin ib Biologic DMARDs TNF inhibitors Accumulating retrospective data suggest low risk in pregnancy, but evidence is limited; can be continued if absolutely needed; different agents may have different considerations regarding crossing placenta. Ustekinumab; anakinra; Should be used only if potential benefit justifies undefined risk to fetus. secukinumab; sarilumab; ixekizumab; guselkumab Abatacept; belimumab; Should be used only if potential benefit justifies potential risk to fetus. canakinumab; rilonacept; rituxi mab; tocilizumab Urate-Lowering Therapy (rarely needed in premenopausal women) Allopurinol Should be used only if potential benefit justifies potential risk to fetus. Fe bu xostat Should be used only if potential benefit justifies potential risk to fetus. Probenecid No current evidence for adverse impact on pregnancy. Peg loticase Should be used only if potential benefit justifies potential risk to fetus.

Urate-Lowering Therapy (rarely needed in premenopausal women) Allopurinol Should be used only if potential benefit justifies potential risk to fetus. Fe bu xostat Should be used only if potential benefit justifies potential risk to fetus. Probenecid No current evidence for adverse impact on pregnancy. Peg loticase Should be used only if potential benefit justifies potential risk to fetus. Dl\,4ARD = d sease mod fying antirheumatlc drug; TNF = tumor necrosis factor t for home use is critical. Physical therapy ref'erral is appropriate Occupational therapists assess upper extremity function for tendinitis; bursitis: many forms of arthritis; and chronic ing, including the ability to perform self care and job related soft tissue pain due to overuse, injury and chronic pain syn tasks. Braces and splints may be provided for painful or unsta dromes (e.g.. fibromyalgia). ble joints. An ergonomic evaluation of the workstation may 16

Rheumatoid Arthritis accompany instruction in improved body mechanics and most important is the class II HLA group, especially HLA D avoidance of repetitir,,e trauma. alleles. These risk alleles code for the shared epitope, a flve amino acid sequence that preferentially binds and presents Complementary and Alternative Medicine citrullinated peptide antigens important in the pathophysiol- Nontraditionai options for symptom management are used by ogr of RA. Citrullinated proteins are immunogenic, especially about one third of patients overall and up to 90'l. of patients in people who have the shared epitope. with chronic pain, including arthritis and rheumatologic dis Citrulline is not a native amino acid in humans; instead, eases. Commonly used over the counter supplements include it is formed by the action of the enzyme peptidylarginine fish oil. vitamins, glucosamine, and chondroitin. Providers deiminase (PADI), which deiminates arginine to form citrul- should ask about supplement use because patients rarely vol- linated peptides. PADI expression is typically limited to sites of unteer this information. Significant drug interactions may inflammation and may therefore provide a link between early occur! for example, some herbal preparations can interact inflammation and subsequent autoimmunity. Many of the with anticoagulants. See MKSAP 19 General Internal Medicine other genes associated with RA modiflz immune responses to 1 for discussion of cannabis for pain management. provide a milieu for the development of autoantibodies. 1\4ind body interuentions, such as tai chi, meditation, and yoga, can improve psychological well being, strength, balance, Environmental Factors and pain level. Chiropractic and osteopathic manipulation as Environmental factors are responsible for the other,l0% of the well as massage remain popular. Randomized controlled trials risk for RA. One of the most provocative environmental factors support the use of tai chi for arthritis; smaller trials suggest is smoking. Smoking can lead to lung inflammation, which benefit from meditation techniques, yoga, massage, acupunc activates enzymes (including PADI), and may promote local ture, and manipulative medicine for various musculoskeletal protein citrullination. Patients who smoke are at increased problems. risk for RA, particularly those with a family history of RA, and should be counseled about smoking cessation. Exposure to Role of Surgery silica dust has also been associated with increased risk. Surgical procedures, such as carpal tunnel release or rotator cuff tendon repair, can address conditions that arise from lnfectious Agents repetitive trauma, injury and degenerative changes in the soft One potential risk factor for RA is periodontal disease. tissue. Synovectomy of inflammatory pannus is occasionally Porphyromonos gingiuolis, a bacterium associated with peri used when a single or limited number ofjoints in patients with odontitis, expresses its own PADI enzyme and provides a RA do not respond to medications. Total joint arthroplasty, potential link to formation of citrullinated peptide. Other particularly of the knee or hip, can reduce or eliminate pain infectious agents implicated in RA include Mycoplasma spe- and restore function in patients with an inadequate response cies, Epstein Barr virus, and parvovirus B19. However, a direct to medication and physical or occupational therapy. infectious cause of RA has not been identified. There is also rEY POITI interest in the role of the intestinal microbiome in RA. Gut . Nonpharmacologic measures used in rheumatologic dysbiosis has been postulated to promote early RA, possibly by activating proinfl ammatory lymphocytes. diseases include physical or occupational therapy, surgery weight reduction, psychosocial support, and Hormones self management programs. Women are tvvo to three times as likely as men to develop RA. The role of estrogen and other sex-specific factors is incom- pletely understood, and estrogen and other sex hormones have Rheumatoid Arthritis both stimulatory and inhibitory effects on the immune sys tem. Estrogen receptors are present on synovial fibroblasts and Pathophysiology and Risk Factors may drive the production of carlilage-damaging metallopro- Rheumatoid arthritis (RA) is a systemic autoimmune disease teinases. Stimulation of estrogen receptors on macrophages

accompany instruction in improved body mechanics and most important is the class II HLA group, especially HLA D avoidance of repetitir,,e trauma. alleles. These risk alleles code for the shared epitope, a flve amino acid sequence that preferentially binds and presents Complementary and Alternative Medicine citrullinated peptide antigens important in the pathophysiol- Nontraditionai options for symptom management are used by ogr of RA. Citrullinated proteins are immunogenic, especially about one third of patients overall and up to 90'l. of patients in people who have the shared epitope. with chronic pain, including arthritis and rheumatologic dis Citrulline is not a native amino acid in humans; instead, eases. Commonly used over the counter supplements include it is formed by the action of the enzyme peptidylarginine fish oil. vitamins, glucosamine, and chondroitin. Providers deiminase (PADI), which deiminates arginine to form citrul- should ask about supplement use because patients rarely vol- linated peptides. PADI expression is typically limited to sites of unteer this information. Significant drug interactions may inflammation and may therefore provide a link between early occur! for example, some herbal preparations can interact inflammation and subsequent autoimmunity. Many of the with anticoagulants. See MKSAP 19 General Internal Medicine other genes associated with RA modiflz immune responses to 1 for discussion of cannabis for pain management. provide a milieu for the development of autoantibodies. 1\4ind body interuentions, such as tai chi, meditation, and yoga, can improve psychological well being, strength, balance, Environmental Factors and pain level. Chiropractic and osteopathic manipulation as Environmental factors are responsible for the other,l0% of the well as massage remain popular. Randomized controlled trials risk for RA. One of the most provocative environmental factors support the use of tai chi for arthritis; smaller trials suggest is smoking. Smoking can lead to lung inflammation, which benefit from meditation techniques, yoga, massage, acupunc activates enzymes (including PADI), and may promote local ture, and manipulative medicine for various musculoskeletal protein citrullination. Patients who smoke are at increased problems. risk for RA, particularly those with a family history of RA, and should be counseled about smoking cessation. Exposure to Role of Surgery silica dust has also been associated with increased risk. Surgical procedures, such as carpal tunnel release or rotator cuff tendon repair, can address conditions that arise from lnfectious Agents repetitive trauma, injury and degenerative changes in the soft One potential risk factor for RA is periodontal disease. tissue. Synovectomy of inflammatory pannus is occasionally Porphyromonos gingiuolis, a bacterium associated with peri used when a single or limited number ofjoints in patients with odontitis, expresses its own PADI enzyme and provides a RA do not respond to medications. Total joint arthroplasty, potential link to formation of citrullinated peptide. Other particularly of the knee or hip, can reduce or eliminate pain infectious agents implicated in RA include Mycoplasma spe- and restore function in patients with an inadequate response cies, Epstein Barr virus, and parvovirus B19. However, a direct to medication and physical or occupational therapy. infectious cause of RA has not been identified. There is also rEY POITI interest in the role of the intestinal microbiome in RA. Gut . Nonpharmacologic measures used in rheumatologic dysbiosis has been postulated to promote early RA, possibly by activating proinfl ammatory lymphocytes. diseases include physical or occupational therapy, surgery weight reduction, psychosocial support, and Hormones self management programs. Women are tvvo to three times as likely as men to develop RA. The role of estrogen and other sex-specific factors is incom- pletely understood, and estrogen and other sex hormones have Rheumatoid Arthritis both stimulatory and inhibitory effects on the immune sys tem. Estrogen receptors are present on synovial fibroblasts and Pathophysiology and Risk Factors may drive the production of carlilage-damaging metallopro- Rheumatoid arthritis (RA) is a systemic autoimmune disease teinases. Stimulation of estrogen receptors on macrophages characterized by chronic inflammatory polyarlhritis affecting can increase production of tumor necrosis factor, a key RA both large and small joints, with a characteristic predilection inflammatory cytokine. for the joints of the hands and feet. RA has a prevalence of t( EY P0 t t{Ts 0.5u1, to 1'2, in the general population; some specific popula- o Potential risk factors for rheumatoid arthritis include tions have rates as high as 77,. genetic and environmental factors, infectious agents, and hormones; genes make up 60% of the risk. Genetic Factors . Smoking is an important and modifiable risk factor for Genes are responsible lbr 60'/. of the risk for RA. Among some rheumatoid arthritis. 100 genetic loci recognized as associated with RA risk, the

characterized by chronic inflammatory polyarlhritis affecting can increase production of tumor necrosis factor, a key RA both large and small joints, with a characteristic predilection inflammatory cytokine. for the joints of the hands and feet. RA has a prevalence of t( EY P0 t t{Ts 0.5u1, to 1'2, in the general population; some specific popula- o Potential risk factors for rheumatoid arthritis include tions have rates as high as 77,. genetic and environmental factors, infectious agents, and hormones; genes make up 60% of the risk. Genetic Factors . Smoking is an important and modifiable risk factor for Genes are responsible lbr 60'/. of the risk for RA. Among some rheumatoid arthritis. 100 genetic loci recognized as associated with RA risk, the 17