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; I Rheumatoid Arthritis TABLE 13. 2010 American College of Rheumatology/ Another sign of early RA is the inability to make a fist, which European League Against Rheumatism Classification Criteria is due to flexor tenosynovitis. \ for Rheumatoid Arthritis The pattern of joint involvement is useful for diagnosing Criteria 5core" RA. RA most characteristically affects the metacarpophalan . geal joints, metatarsophalangeal joints, and proximal inter- Joint lnvolvementb phalangeal joints of the hands and feet but spares the distal : 1 large joint (shoulders, elbows, hips, knees, ankles) U interphalangeal joints of both the upper and lower extremities r 2-10 large joints 1 (Figure 2 and Figure 3). Wrists, elbows, shoulders, hips, knees, : 1-3 smalljoints (MCPs, PlPs, wrists, 2-5 MTPs) 2 and ankles also can be involved. RA tends to affect joints sym- metrically (i.e., joints on both sides of the body are generally ! 4-10 smalljoints 3

1 large joint (shoulders, elbows, hips, knees, ankles) U interphalangeal joints of both the upper and lower extremities r 2-10 large joints 1 (Figure 2 and Figure 3). Wrists, elbows, shoulders, hips, knees, : 1-3 smalljoints (MCPs, PlPs, wrists, 2-5 MTPs) 2 and ankles also can be involved. RA tends to affect joints sym- metrically (i.e., joints on both sides of the body are generally ! 4-10 smalljoints 3 >10 smalljoints 5 involved), but severity may be asymmetric. RA may occasion ally present as persistent involvement in a single joint. RA Serology spares the thoracic and lumbar spine but affects the cervical : Negativity for RF or anti-CCP antibodies 0 spine, especially the C1-C2 (atlantoaxial) articulation. See Low levels of RF or anti-CCP antibodies (<3 times 2 Table 14 for more information. the upper limit of normal) High levels of RF or anti-CCP antibodies (>3 times 3 the upper limit of normal) : Acute Phase Reactants Normal CRP or ESR 0

>10 smalljoints 5 involved), but severity may be asymmetric. RA may occasion ally present as persistent involvement in a single joint. RA Serology spares the thoracic and lumbar spine but affects the cervical : Negativity for RF or anti-CCP antibodies 0 spine, especially the C1-C2 (atlantoaxial) articulation. See Low levels of RF or anti-CCP antibodies (<3 times 2 Table 14 for more information. the upper limit of normal) High levels of RF or anti-CCP antibodies (>3 times 3 the upper limit of normal) : Acute Phase Reactants Normal CRP or ESR 0 Abnormal CRP or ESR 1 : Duration" ) <6 weeks 0 : >6 weeks 1 -\ CCP = cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; N4CP = metacarpophalangeal; IVlTP = metatarsophalangeal; PIP = proximal interphalangeal; RF = rheumatoid facton

Duration" ) <6 weeks 0 : >6 weeks 1 -\ CCP = cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; N4CP = metacarpophalangeal; IVlTP = metatarsophalangeal; PIP = proximal interphalangeal; RF = rheumatoid facton "Six points needed {or classification as rheumatoid arthritis. : bAt least one joint with definite clinical synovitis that is not better explained by another disease. Joints excluded from this classification schema: first carpometacarpal, distal interphalangeal, and {irst metatarsophalangeal. I 'A duration of 6 weeks or longer is less often seen with crystalline or viral causes. l From Aletaha D, Neogi T, Silman AJ, et al. 201 0 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against t Rheumatism collaborative initiative. Arthritis Rheum. 201 0 Sep;62(9):2569-81. doi:1 0.1 002/art.27584. IPMID: 20872595] Copyright 20 1 0, American Col ege of Rheumatology.Adapted with permission from John Wiley & Sons, lnc.

'A duration of 6 weeks or longer is less often seen with crystalline or viral causes. l From Aletaha D, Neogi T, Silman AJ, et al. 201 0 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against t Rheumatism collaborative initiative. Arthritis Rheum. 201 0 Sep;62(9):2569-81. doi:1 0.1 002/art.27584. IPMID: 20872595] Copyright 20 1 0, American Col ege of Rheumatology.Adapted with permission from John Wiley & Sons, lnc. FIGURE 2. Earlyrheumatoidarthritisofthehands,withswellingmostprominently Diagnosis in the third and fourth proximal interphalangeal joints. ) The 2010 American College of Rheumatolos/ (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA are sensitive and emphasize early diagnosis and treat- ment to prevent permanent consequences of chronic inflam . mation (Table 13). ., :

FIGURE 2. Earlyrheumatoidarthritisofthehands,withswellingmostprominently Diagnosis in the third and fourth proximal interphalangeal joints. ) The 2010 American College of Rheumatolos/ (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA are sensitive and emphasize early diagnosis and treat- ment to prevent permanent consequences of chronic inflam . mation (Table 13). ., : Clinical Manifestations RA is a chronic disorder, and onset of symptoms is usually gradual. Patients with RA typically report joint pain and inflammatory symptoms, including swelling and morning stiffness lasting at least 30 to 45 minutes and commonly sev- eral hours. Stiffness is also worse following rest and alleviated by ongoing activity. Slmovitis is palpable on joint examination, ) manifesting as softness or bogginess of the affected joint. l Gently squeezing the joints may also elicit tenderness. As part \ of screening examination, the metacarpophalangeal and/or t IGU R E 3. Severe rheumatoid arthritis 0f the hands, with ulnar deviation and the metatarsophalangeal joints can together be squeezed. subluxation at the metacarpophalangeal joints on both sides. 18

Rheumatoid Arthritis TAgLE 14, Consequences of Persistent lnflammation on nor anti-CCP antibodies). Although categorized as having RA, Joints and Supporting Structures these patients have somewhat different genetics and risk fac Joint Area lmplications tors and generally have a better prognosis than those with seropositive RA. C1-C2 articulation Laxity of transverse ligament resuhs in and transverse increased posterior motion of dens on Erythrocy.te sedimentation rate and C-reactive protein ligament C2 because of atlantoaxial subluxation. level are elevated in 75% ofpatients with RA and can be used Rheumatoid synovitis may lead to to monitor treatment response. The systemic inflammation erosion of dens; with neck flexion, dens can affectthe midbrain and other inherent to RA is also commonly reflected by anemia of vital neurologic structures. This must inflammation and modest thrombocytosis. be evaluated before intubation or neck manipulation in patients with long- standing RA. lmaging Studies Shoulder and rotator Restricted range of motion of Plain radiography of the hands and/or feet is the standard imag cuff tendons glenohumeral joint and rotator cuff ing study for RA and can aid in diagnosis and assessing progres tears sion. However, radiographs obtained early in the disease may be Elbow joint Elbow contractures and difficulty with normal or reveal soft-tissue swelling only. Tlpical radiographic hand pronation and supination changes include periarticular osteopenia, marginal erosions, Wrist carpaljoints Restricted range of motion of wrist; and joint-space narrowing (Figure 4 and Figure 5). Radiography and finger tendons carpal tunnel syndrome; rupture of of the cervical spine with flexion/extension views is appropriate finger extensor tendons, especially fourth and fifth ifCl-C2 subluxation is suspected. MCPs and surrounding Ulnar deviation and subluxation of MRI and ultrasonography are more sensitive than plain structures MCPs radiography for detecting abnormalities in joints and soft tis- PlPs and surrounding Swan neck or boutonniere deformity sues and may have utility in monitoring disease, assessing risk structu res due to inflammatory disruption of periarticular su pport structures Hip joint Axial migration of femoral head in acetabulum (protrusio acetabuli) Knee joint Tricompartmental joint-space narrowing Ankle and mid-foot Restricted range of motion of ankle; joints and tendons progressive pronated fl at foot deformity MTPs and Fibular deviation of MTPs; cock-up surrounding deformities; skin ulceration underneath stru ctu res subluxed MTP heads MCP = metacarpophalangeal; N4TP = metatarsophalangeal; PIP = proximal interphalanqeal; RA = rheumatoid arthritis.

TAgLE 14, Consequences of Persistent lnflammation on nor anti-CCP antibodies). Although categorized as having RA, Joints and Supporting Structures these patients have somewhat different genetics and risk fac Joint Area lmplications tors and generally have a better prognosis than those with seropositive RA. C1-C2 articulation Laxity of transverse ligament resuhs in and transverse increased posterior motion of dens on Erythrocy.te sedimentation rate and C-reactive protein ligament C2 because of atlantoaxial subluxation. level are elevated in 75% ofpatients with RA and can be used Rheumatoid synovitis may lead to to monitor treatment response. The systemic inflammation erosion of dens; with neck flexion, dens can affectthe midbrain and other inherent to RA is also commonly reflected by anemia of vital neurologic structures. This must inflammation and modest thrombocytosis. be evaluated before intubation or neck manipulation in patients with long- standing RA. lmaging Studies Shoulder and rotator Restricted range of motion of Plain radiography of the hands and/or feet is the standard imag cuff tendons glenohumeral joint and rotator cuff ing study for RA and can aid in diagnosis and assessing progres tears sion. However, radiographs obtained early in the disease may be Elbow joint Elbow contractures and difficulty with normal or reveal soft-tissue swelling only. Tlpical radiographic hand pronation and supination changes include periarticular osteopenia, marginal erosions, Wrist carpaljoints Restricted range of motion of wrist; and joint-space narrowing (Figure 4 and Figure 5). Radiography and finger tendons carpal tunnel syndrome; rupture of of the cervical spine with flexion/extension views is appropriate finger extensor tendons, especially fourth and fifth ifCl-C2 subluxation is suspected. MCPs and surrounding Ulnar deviation and subluxation of MRI and ultrasonography are more sensitive than plain structures MCPs radiography for detecting abnormalities in joints and soft tis- PlPs and surrounding Swan neck or boutonniere deformity sues and may have utility in monitoring disease, assessing risk structu res due to inflammatory disruption of periarticular su pport structures Hip joint Axial migration of femoral head in acetabulum (protrusio acetabuli) Knee joint Tricompartmental joint-space narrowing Ankle and mid-foot Restricted range of motion of ankle; joints and tendons progressive pronated fl at foot deformity MTPs and Fibular deviation of MTPs; cock-up surrounding deformities; skin ulceration underneath stru ctu res subluxed MTP heads MCP = metacarpophalangeal; N4TP = metatarsophalangeal; PIP = proximal interphalanqeal; RA = rheumatoid arthritis. Laboratory Studies The most useful laboratory studies to aid in the diagnosis of RA are rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies. Rheumatoid factor is an immunoglobulin, usually IgM, directed against the Fc portion of IgG. Rheumatoid factor occurs in approximately 70"/,, of patients with RA. Because rheumatoid factor can be associated with other dis- eases (e.g., viral hepatitis, endocarditis) and because its pres ence increases with age, the specificity of rheumatoid factor is limited at about 857,. Anti-CCP antibodies are also present in 7ou/,, of patients with RA but have a specificity of 95'/u. Nonetheless, a high pretest probability is required to make both of these autoantibodies optimally useful for diagnosing RA. Both of these antibodies may predate the onset of clinical F IG U R E4. Radiograph showing advanced rheumatoid arthritis in the hand. disease, but anti-CCP antibodies are more predictive than Shown are ulnar deviation at the metacarpophalangeal joints; marginal erosions most prominently at the second through fifth metacarpophalangeal joints and the rheumatoid factor for erosive disease in patients already diag second and third proximal interphalangeal joints (arows); and joint-space nanowing nosed with RA. at the wrist, metacarpophalangeal, and proximal interphalangeal joints and within Approximately 70"/,' to 2O"/,, of patients diagnosed with RA the carpus, which also represents erosive disease. Note the loss of the ulnar styloid are seronegative (i.e., positive for neither rheumatoid factor (anowhead), anolher common sign of bony erosion in rheumatoid arthritis.

Laboratory Studies The most useful laboratory studies to aid in the diagnosis of RA are rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies. Rheumatoid factor is an immunoglobulin, usually IgM, directed against the Fc portion of IgG. Rheumatoid factor occurs in approximately 70"/,, of patients with RA. Because rheumatoid factor can be associated with other dis- eases (e.g., viral hepatitis, endocarditis) and because its pres ence increases with age, the specificity of rheumatoid factor is limited at about 857,. Anti-CCP antibodies are also present in 7ou/,, of patients with RA but have a specificity of 95'/u. Nonetheless, a high pretest probability is required to make both of these autoantibodies optimally useful for diagnosing RA. Both of these antibodies may predate the onset of clinical F IG U R E4. Radiograph showing advanced rheumatoid arthritis in the hand. disease, but anti-CCP antibodies are more predictive than Shown are ulnar deviation at the metacarpophalangeal joints; marginal erosions most prominently at the second through fifth metacarpophalangeal joints and the rheumatoid factor for erosive disease in patients already diag second and third proximal interphalangeal joints (arows); and joint-space nanowing nosed with RA. at the wrist, metacarpophalangeal, and proximal interphalangeal joints and within Approximately 70"/,' to 2O"/,, of patients diagnosed with RA the carpus, which also represents erosive disease. Note the loss of the ulnar styloid are seronegative (i.e., positive for neither rheumatoid factor (anowhead), anolher common sign of bony erosion in rheumatoid arthritis. 19

Rheumatoid Arthritis bone marrow edema, synovitis, and erosions but in clinical practice is generally reserved for assessment of soft-tissue derangements, such as tendon ruptures. MRI of the cervical spine is specifically indicated if atlantoaxial involvement is suspected.

bone marrow edema, synovitis, and erosions but in clinical practice is generally reserved for assessment of soft-tissue derangements, such as tendon ruptures. MRI of the cervical spine is specifically indicated if atlantoaxial involvement is suspected. TEY POIIITI . Tlpical clinical manifestations of rheumatoid arthritis include pain, swelling, and prolonged morning stiffness in a symmetric pattern, particularly in the joints of the hands and feet. o The most useful laboratory studies to aid in the diagno- HVC sis of rheumatoid arthritis (RA) are rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies; anti-CCP antibodies have a specificity of 95% for RA. . Plain radiography ofthe hands and/or feet is the stand- HVC ard imaging study for rheumatoid arthritis; radiographic changes include periarticular osteopenia, marginal ero- sions, and joint-space narrowing, although early radio graphs may be normal.

TEY POIIITI . Tlpical clinical manifestations of rheumatoid arthritis include pain, swelling, and prolonged morning stiffness in a symmetric pattern, particularly in the joints of the hands and feet. o The most useful laboratory studies to aid in the diagno- HVC sis of rheumatoid arthritis (RA) are rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies; anti-CCP antibodies have a specificity of 95% for RA. . Plain radiography ofthe hands and/or feet is the stand- HVC ard imaging study for rheumatoid arthritis; radiographic changes include periarticular osteopenia, marginal ero- sions, and joint-space narrowing, although early radio graphs may be normal. Com pl ications a nd Bcra-Articu la r Manifestations Joints RA joint damage is a consequence of synovitis within the joint. The synovial lining, normally only a few cells thick, becomes significantly expanded through proliferation of resident fibro blast-like synoviocytes and immune system cells (T cells, B cells, macrophages), as well as angiogenesis. Various cl.tokines (tumor necrosis factor, interleukins), often signaling through Janus kinases, and cartilage-damaging metalloproteinases are produced. Receptor activator ofnuclear factor kappa B ligand (RANKL), produced by inflammatory cells, activates osteoclasts to erode bone. The metalloproteinases and activated osteoclasts result in various irreversible changes to the joints (see Table 14).

Com pl ications a nd Bcra-Articu la r Manifestations Joints RA joint damage is a consequence of synovitis within the joint. The synovial lining, normally only a few cells thick, becomes significantly expanded through proliferation of resident fibro blast-like synoviocytes and immune system cells (T cells, B cells, macrophages), as well as angiogenesis. Various cl.tokines (tumor necrosis factor, interleukins), often signaling through Janus kinases, and cartilage-damaging metalloproteinases are produced. Receptor activator ofnuclear factor kappa B ligand (RANKL), produced by inflammatory cells, activates osteoclasts to erode bone. The metalloproteinases and activated osteoclasts result in various irreversible changes to the joints (see Table 14). Skin The most common RA skin changes are rheumatoid nodules (Figure 6), present in up to 30% of patients. Nodules typically occur in the olecranon region and can be confused with gouty tophi, but they can also occur over the hand and feet joints and even in the lungs. Nodulosis can rarely be induced by certain drugs (e.9., methotrexate). Patients with RA are also at an increased risk for neutro t I G U R E 5. Radiograph of rheumatoid arthritis in the foot showinq marginal philic dermatoses, such as pyoderma gangrenosum or Sweet erosions and joint,space nanowing at the third, fourth, and fifth metaiarsophalangeal syndrome (see MKSAP 19 General Internal Medicine 2). joints (arows). Erosion at the fifth metatarsophalangeal joint is often the first Palpable purpura and skin ulcers may rarely result from small- radiographic sign of rheumatoid arthritis foot involvement. vessel cutaneous vasculitis.

Skin The most common RA skin changes are rheumatoid nodules (Figure 6), present in up to 30% of patients. Nodules typically occur in the olecranon region and can be confused with gouty tophi, but they can also occur over the hand and feet joints and even in the lungs. Nodulosis can rarely be induced by certain drugs (e.9., methotrexate). Patients with RA are also at an increased risk for neutro t I G U R E 5. Radiograph of rheumatoid arthritis in the foot showinq marginal philic dermatoses, such as pyoderma gangrenosum or Sweet erosions and joint,space nanowing at the third, fourth, and fifth metaiarsophalangeal syndrome (see MKSAP 19 General Internal Medicine 2). joints (arows). Erosion at the fifth metatarsophalangeal joint is often the first Palpable purpura and skin ulcers may rarely result from small- radiographic sign of rheumatoid arthritis foot involvement. vessel cutaneous vasculitis. for progression, and determining response to therapy. Eyes Ultrasonography is becoming a common tool for detecting The most common eye manifestation in RA is dry eye (kerato- joint fluid (effusion), synovial tissue thickening, early ero- conjunctivitis sicca). It occurs in 10% to 15% ofpatients and can sions, and increased vascularity. MRI can be used to assess be severe. Most of these patients also have dry mouth and are 20

Rheumatoid Arthritis 7- such as dyslipidemia and hypertension, should be addressed. v" Clinically significant pericarditis is rare. Granulomatous myo carditis, valvular disease (mainly mitral), conduction block, and aortitis can occur but are very rare. Hematologic Anemia of inflammation is the most common RA hematologic abnormality Felty syndrome is a rare condition consisting of neutropenia and splenomegaly; it occurs in patients with long- standing, severe, seropositive RA. Patients with Felty syndrome are at risk for serious bacterial infections, Iower extremity ulcer- ation, lymphoma, and vasculitis. Patients with RA can also have large granular lymphocyte syndrome, which can progress to large granular lymphoqte leukemia. Findings overlap with Felty syndrome and include neutropenia, anemia, thrombocy F I G UR E 5. Rheumatoid nodules appear as slowly developing, firm, painless, topenia, splenomegaly, and recurrent infections. Patients with subcutaneous nodules (arows) located al pressure points or over the extensor RA are at increased risk for lymphomas (particularly large B-cell surfaces of joints and tendons. lymphomas), and risk is correlated with disease activity.

Hematologic Anemia of inflammation is the most common RA hematologic abnormality Felty syndrome is a rare condition consisting of neutropenia and splenomegaly; it occurs in patients with long- standing, severe, seropositive RA. Patients with Felty syndrome are at risk for serious bacterial infections, Iower extremity ulcer- ation, lymphoma, and vasculitis. Patients with RA can also have large granular lymphocyte syndrome, which can progress to large granular lymphoqte leukemia. Findings overlap with Felty syndrome and include neutropenia, anemia, thrombocy F I G UR E 5. Rheumatoid nodules appear as slowly developing, firm, painless, topenia, splenomegaly, and recurrent infections. Patients with subcutaneous nodules (arows) located al pressure points or over the extensor RA are at increased risk for lymphomas (particularly large B-cell surfaces of joints and tendons. lymphomas), and risk is correlated with disease activity. classified as having secondary Sj6gren syndrome (see Sjogren Blood Vessels Syndrome). Less common (1'l.) are episcleritis (inflammation of Small-vessel cutaneous vasculitis occurs in a small percentage superficial scleral vessels) and scleritis (inflammation of deep of patients with RA, leading to palpable purpura or periungual scleral vessels). RA is one of the most common diseases associ- infarcts. A rare, larger-vessel vasculitis similar to po$arteritis ated with scleritis, which can be vision threatening and lead to nodosa can affect multiple organ systems; before current ther- thinning of the sclera and perforation. Keratitis (comeal inflam- apy, it had a s-year mortality rate of 30% to 50'2,. mation) can occur; it is ulcerative and occurs at the periphery of the comea. Severe keratitis is known as corneal melt. Both IEY POIilT' scleritis and keratitis require immediate referral to an ophthal o Extra-articular manifestations and complications of mologist (see MKSAP 1g General Internal Medicine 2). rheumatoid arthritis include rheumatoid nodules, dry eye, interstitial lung disease, pleural effusions, and ane- Lungs mia of inflammation. Interstitial lung disease may develop in 507, of patients with . Rheumatoid arthritis conveys a significantly increased RA; clinically significant disease is seen in 10'/. of patients and risk for cardiovascular disease. contributes to excess mortality. Bronchiectasis and bronchioli tis occur, and the bronchiolitis can be obliterative and/or constrictive. Pleural disease occurs in up to 5% of patients; pleural effusions are exudative and can be large. RA pleural Management effusions are characterized by low glucose and pH (mimicking See Principles ofTherapeutics for details on the uses, mecha bacterial or tubercular infection and malignancy) and low nisms of action, major toxicities, and/or monitoring require- complement levels, as well as elevated levels of total protein, ments of the medications used in RA, as well as recommended rheumatoid factor, and lactate dehydrogenase. Infl ammatory vaccines. cells in the RA effusion are characteristically mononuclear; a neutrophil predominant effusion suggests infection. Upper General Considerations airway involvement from cricoarytenoid arthritis occurs The 2015 ACR RA treatment guidelines advocate for early diag- rarely; symptoms include hoarseness, sore throat, dysphagia, nosis and aggressive early therapy ofRA to prevent irreversible and stridor. Cricoarytenoid arthritis can pose problems for cartilage and bone damage. A key treatment goal is to treat to endotracheal intubation. target, with the target being achievement of remission or low disease activity. Disease activity assessment involves making a Heart measured determination using combinations of numbers of Atherosclerotic heart disease remains the major cause of tender and swollen joints (typically by using 28 joints that excess death in patients with RA, although some data suggest exclude the feet); patient and physician impressions of disease that risk for cardiovascular disease may be decreasing toward activity; and, in some activity scoring systems, measurement that of the general population. Patients with RA should be of the erythrocyte sedimentation rate or C reactive protein. considered at high cardiovascular risk for purposes ofperiop- These parameters are combined into a composite score, thus erative evaluation, and cardiovascular disease risk factors, assigning a disease activity ranging from remission to Iow

classified as having secondary Sj6gren syndrome (see Sjogren Blood Vessels Syndrome). Less common (1'l.) are episcleritis (inflammation of Small-vessel cutaneous vasculitis occurs in a small percentage superficial scleral vessels) and scleritis (inflammation of deep of patients with RA, leading to palpable purpura or periungual scleral vessels). RA is one of the most common diseases associ- infarcts. A rare, larger-vessel vasculitis similar to po$arteritis ated with scleritis, which can be vision threatening and lead to nodosa can affect multiple organ systems; before current ther- thinning of the sclera and perforation. Keratitis (comeal inflam- apy, it had a s-year mortality rate of 30% to 50'2,. mation) can occur; it is ulcerative and occurs at the periphery of the comea. Severe keratitis is known as corneal melt. Both IEY POIilT' scleritis and keratitis require immediate referral to an ophthal o Extra-articular manifestations and complications of mologist (see MKSAP 1g General Internal Medicine 2). rheumatoid arthritis include rheumatoid nodules, dry eye, interstitial lung disease, pleural effusions, and ane- Lungs mia of inflammation. Interstitial lung disease may develop in 507, of patients with . Rheumatoid arthritis conveys a significantly increased RA; clinically significant disease is seen in 10'/. of patients and risk for cardiovascular disease. contributes to excess mortality. Bronchiectasis and bronchioli tis occur, and the bronchiolitis can be obliterative and/or constrictive. Pleural disease occurs in up to 5% of patients; pleural effusions are exudative and can be large. RA pleural Management effusions are characterized by low glucose and pH (mimicking See Principles ofTherapeutics for details on the uses, mecha bacterial or tubercular infection and malignancy) and low nisms of action, major toxicities, and/or monitoring require- complement levels, as well as elevated levels of total protein, ments of the medications used in RA, as well as recommended rheumatoid factor, and lactate dehydrogenase. Infl ammatory vaccines. cells in the RA effusion are characteristically mononuclear; a neutrophil predominant effusion suggests infection. Upper General Considerations airway involvement from cricoarytenoid arthritis occurs The 2015 ACR RA treatment guidelines advocate for early diag- rarely; symptoms include hoarseness, sore throat, dysphagia, nosis and aggressive early therapy ofRA to prevent irreversible and stridor. Cricoarytenoid arthritis can pose problems for cartilage and bone damage. A key treatment goal is to treat to endotracheal intubation. target, with the target being achievement of remission or low disease activity. Disease activity assessment involves making a Heart measured determination using combinations of numbers of Atherosclerotic heart disease remains the major cause of tender and swollen joints (typically by using 28 joints that excess death in patients with RA, although some data suggest exclude the feet); patient and physician impressions of disease that risk for cardiovascular disease may be decreasing toward activity; and, in some activity scoring systems, measurement that of the general population. Patients with RA should be of the erythrocyte sedimentation rate or C reactive protein. considered at high cardiovascular risk for purposes ofperiop- These parameters are combined into a composite score, thus erative evaluation, and cardiovascular disease risk factors, assigning a disease activity ranging from remission to Iow 21

Rheumatoid Arthritis to doses as high as 25 mg per week in partial responders; the DMARD- naiVe RA treating physician should generally maximize methotrexate dosing before adding other agents. At doses greater than 15 mg weekly, methotrexate oral absorption approaches its effective DMARD Iimit; switching to subcutaneous administration allows for monotherapy (usually MTX) higher serum drug levels. Folic acid supplements minimize toxicity without diminishing efficacy. Of patients with RA tak ing methotrexate alone, 30% to 50'7, achieve remission or low disease activity. Moderate/high Low disease disease activity activity Leflunomide may be useful in patients who cannot toler ate methotrexate in both monotherapy and combination ther apy. Hydroxychloroquine and sulfasalazine are less potent Combination DMARD or Continue current agents and are rarely used as single agents since biologic TNFi +/- MTX or therapy; if in disease modi$zing antirheumatic drugs (DMARDs) became non-TNF biologic +/- MTX or remission, consider available. However, both can be used in combination with tofacitinib +/- MTX tapering medications" methotrexate as triple therapy. Data suggest that triple therapy is similar in efficacy to methotrexate combined with a tumor Moderate/high Low disease necrosis factor (TNF) inhibitor, except in the area of radio- disease activity activity graphic progression. Triple therapy, however, may be poorly tolerated. Tofacitinib, baricitinib, and upadacitinib constitute a class Consider alternate biologic/TNFi/small of FDA approved oral small molecule Janus kinase inhibitors molecule/MTX therapy whose efficacy in RA is similar to that of the biologics.

to doses as high as 25 mg per week in partial responders; the DMARD- naiVe RA treating physician should generally maximize methotrexate dosing before adding other agents. At doses greater than 15 mg weekly, methotrexate oral absorption approaches its effective DMARD Iimit; switching to subcutaneous administration allows for monotherapy (usually MTX) higher serum drug levels. Folic acid supplements minimize toxicity without diminishing efficacy. Of patients with RA tak ing methotrexate alone, 30% to 50'7, achieve remission or low disease activity. Moderate/high Low disease disease activity activity Leflunomide may be useful in patients who cannot toler ate methotrexate in both monotherapy and combination ther apy. Hydroxychloroquine and sulfasalazine are less potent Combination DMARD or Continue current agents and are rarely used as single agents since biologic TNFi +/- MTX or therapy; if in disease modi$zing antirheumatic drugs (DMARDs) became non-TNF biologic +/- MTX or remission, consider available. However, both can be used in combination with tofacitinib +/- MTX tapering medications" methotrexate as triple therapy. Data suggest that triple therapy is similar in efficacy to methotrexate combined with a tumor Moderate/high Low disease necrosis factor (TNF) inhibitor, except in the area of radio- disease activity activity graphic progression. Triple therapy, however, may be poorly tolerated. Tofacitinib, baricitinib, and upadacitinib constitute a class Consider alternate biologic/TNFi/small of FDA approved oral small molecule Janus kinase inhibitors molecule/MTX therapy whose efficacy in RA is similar to that of the biologics. FIGURE 7. Asimplifiedalgorithm presenting an initial approachtothe treatment of both early and established rheumatoid arthritis (RA). All patients with Biologic Disease-Modiffing Antirheumatic Drugs RA should receive a disease-modifying antirheumatic drug initially and be Biologic DMARDs can be used as monotherapy but are typi- advanced to more aggressive and/or combination therapy as needed to control cally added to methotrexate when moderate to high disease disease. Disease activity should be assessed, wherever possible, by using a Iormal, activity persists. TNF inhibitors are the most frequently used validated, and consistent disease activity index. Refer to the 201 5 American College of Rheumatology RA treatment guidelines for more complex algorithms biologic DMARDs; they have a relatively rapid onset of action accounting for differences between agents and patient-specific complexities. and demonstrate synerry with methotrexate. The combination DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; RA = of methotrexate and a TNF inhibitor slows the rate of radio- rheumatoid arthritis; TNF = tumor necrosis factor; TNFi = tumor necrosis factor graphic damage to cartilage and bone, even in the setting of in h ibitor. continued clinical disease activity. This effect also has been rDo nol disco0tinue all RA trealments. shown with other biologics in combination with methotrex ate. Other biologic DMARDs used in RA include abatacept (a moderate, or high. The Clinical Disease Activity Index (CDAI) selective T-cell costimulation modulator), tocilizumab (an and Disease Activity Score 28 (DAS28) are two commonly used anti-interleukin-6 receptor antibody), and rituximab (an instruments to assess disease activity and response to treat anti-B-cell antibody). ment. Treating to target in RA results in less radiographic Until better data are available to guide therapeutic deci damage, reduced cardiovascular risk, and increased work sions, choice of a biologic DMARD remains empiric and based productivity compared with conventional care. largely on patient characteristics, including what agents The 2015 ACR RA treatment guidelines can assist in mak- should be avoided because of patient comorbidity (e.g., avoid ing initial treatment decisions in early RA. Treatment is typi- ing abatacept in a patient with COPD). cally advanced at 12 week intervals with the goal of reaching remission or low disease activity as rapidly as possible. Patients who remain in remission or a state of low disease activity for NSAIDS 6 months or longer may be able to reduce treatment intensity. NSAIDs are used as adjunctive therapy to control symptoms Treatment decisions for established RA are more complex. An while the full effect of DMARDs is being awaited. These agents initial approach to the treatment of both early and established are not disease modifizing and do not prevent joint damage. RA is outlined in Figure 7. Use with glucocorticoids should be avoided and caution should be exercised with concomitant methotrexate. Disease-Modifying Antirheumatic Drugs Nonbiologic Disease-Modiffing Antirheumatic Drugs Glucocorticoids Methotrexate is the anchor drug in RA, used in both mono- Unlike NSAIDs, glucocorticoids can have a disease modi$zing therapy and combination therapy. Methotrexate can be titrated effect, in addition to their efficacy in symptom management.

FIGURE 7. Asimplifiedalgorithm presenting an initial approachtothe treatment of both early and established rheumatoid arthritis (RA). All patients with Biologic Disease-Modiffing Antirheumatic Drugs RA should receive a disease-modifying antirheumatic drug initially and be Biologic DMARDs can be used as monotherapy but are typi- advanced to more aggressive and/or combination therapy as needed to control cally added to methotrexate when moderate to high disease disease. Disease activity should be assessed, wherever possible, by using a Iormal, activity persists. TNF inhibitors are the most frequently used validated, and consistent disease activity index. Refer to the 201 5 American College of Rheumatology RA treatment guidelines for more complex algorithms biologic DMARDs; they have a relatively rapid onset of action accounting for differences between agents and patient-specific complexities. and demonstrate synerry with methotrexate. The combination DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; RA = of methotrexate and a TNF inhibitor slows the rate of radio- rheumatoid arthritis; TNF = tumor necrosis factor; TNFi = tumor necrosis factor graphic damage to cartilage and bone, even in the setting of in h ibitor. continued clinical disease activity. This effect also has been rDo nol disco0tinue all RA trealments. shown with other biologics in combination with methotrex ate. Other biologic DMARDs used in RA include abatacept (a moderate, or high. The Clinical Disease Activity Index (CDAI) selective T-cell costimulation modulator), tocilizumab (an and Disease Activity Score 28 (DAS28) are two commonly used anti-interleukin-6 receptor antibody), and rituximab (an instruments to assess disease activity and response to treat anti-B-cell antibody). ment. Treating to target in RA results in less radiographic Until better data are available to guide therapeutic deci damage, reduced cardiovascular risk, and increased work sions, choice of a biologic DMARD remains empiric and based productivity compared with conventional care. largely on patient characteristics, including what agents The 2015 ACR RA treatment guidelines can assist in mak- should be avoided because of patient comorbidity (e.g., avoid ing initial treatment decisions in early RA. Treatment is typi- ing abatacept in a patient with COPD). cally advanced at 12 week intervals with the goal of reaching remission or low disease activity as rapidly as possible. Patients who remain in remission or a state of low disease activity for NSAIDS 6 months or longer may be able to reduce treatment intensity. NSAIDs are used as adjunctive therapy to control symptoms Treatment decisions for established RA are more complex. An while the full effect of DMARDs is being awaited. These agents initial approach to the treatment of both early and established are not disease modifizing and do not prevent joint damage. RA is outlined in Figure 7. Use with glucocorticoids should be avoided and caution should be exercised with concomitant methotrexate. Disease-Modifying Antirheumatic Drugs Nonbiologic Disease-Modiffing Antirheumatic Drugs Glucocorticoids Methotrexate is the anchor drug in RA, used in both mono- Unlike NSAIDs, glucocorticoids can have a disease modi$zing therapy and combination therapy. Methotrexate can be titrated effect, in addition to their efficacy in symptom management. 22

Osteoarthritis Low dose prednisone (s-ts mg/d) can be used to rapidly xEY POtilts improve RA symptoms until long term medications become . There is an increased risk for developing rheumatoid effective, or they can be used short term for disease flares. arthritis in the first year after a first pregnancy. Although glucocorticoid use is associated with a reduction in . Among women with established rheumatoid arthritis radiographic progression, long term therapy with glucocorti- at the time of conception, two thirds will go into coitls has substantial potential adverse effects, including osteo- remission or a state of low disease activity during porosis, diabetes mellitus, and intbction. pregnancy, and one third will not improve or will get worse. Surgery Surgical therapy has become less common in RA because of current treatment strategies. Nonetheless, some patients may require synovectomy for a single persistently swollen joint, carpal tunnel release, repair of a ruptured tendon, Osteoarthritis total joint replacement (shoulder, metacarpophalangeal joints, hip, knee), or joint fusion lbr a painful damaged Pathophysiology joint (wrist or ankle). See MKSAP 19 General Internal Osteoarthritis (OA) is a chronic progressive multifactorial Medicine 2 for a discussion of perioperative RA medication disorder of maladaptive cellular repair responses to joint management. stress. Previously deemed a "wear and tear" disease and an inevitable consequence ofaging, OA is now recognized as a XEY POITIS disorder driven by a complex interplay of genetics; biome- . In rheumatoid arthritis, treating to a target of remis- chanics; cell stress; biochemical change in cartilage and sion or low disease activity results in less radio- extracellular matrix components; and degradation and graphic damage, reduced cardiovascular risk, and inllammation, which is usually subclinical. It affects all tis increased work productivity compared with conven- sues of the joint and is characterized by cartilage and tional care. meniscal degradation, subchondral bone changes (bone HVC o Methotrexate is the anchor drug in rheumatoid arthri- marrow lesions, subchondral sclerosis), and osteophyte tis; it is used as both monotherapy and a component of formation. OA is accompanied by low-grade synovitis and combination therapy. is driven by imbalanced anabolic and catabolic processes . Tumor necrosis factor inhibitors are the most fre that represent aberrant joint responses and result in joint quently used biologics to treat rheumatoid arthritis; tissue degeneration. they have a relatively rapid onset of action and demon- strate synerS/ with methotrexate. HVC o In rheumatoid arthritis, NSAIDs are not disease Epidemiology and Risk Factors modifying and do not prevent joint damage; they are OA is the most common form of arthritis worldwide and is a used primarily to control symptoms while the full leading cause of pain and disability, affecting approximately effect of disease-modifying antirheumatic drugs is 30 million U.S. adults. OA is the leading cause of lower extrem- awaited. ity disability among older adults, with an estimated lifetime . Low-dose prednisone can be used in rheumatoid risk for knee OA approaching 50%. Prevalence is projected to arthritis to rapidly improve symptoms until long,term more than double by 2030, Iargely because of increasing obe- medications become effective, but long-term glucocor- sity and the aging ofthe population. Incidence and prevalence ticoid use carries significant comorbid risk. vary by joint and depend on whether a clinical or a radio graphic definition is being applied. Epidemiologic risk factors for OA include age older than Pregnancy 55 years, female sex, obesity, genetics, and occupations that There is an increased risk for developing RA in the first year involve repetitive motions or physical labor. Age and female after a first pregnancy. Breastf'eeding may decrease this risk. sex are nonmodifiable risk factors for OA of different sites. Among women with established RA at the time of concep Obesity is the most important modifiable risk factor, especially tion, two thirds will go into remission or a state of low dis- for knee OA. Increased body mass is also a risk factor fbr hand ease activity during pregnancy, and one third will not OA, perhaps underscoring the systemic nature of obesity and improve or will get worse. Medication management is a a role for metabolic and/or inflammatory mechanisms in the major issue, and pregnancy plans should be discussed with pathogenesis of hand OA. Single inherited conditions rarely any woman of childbearing age who will be placed on ther predispose to OA; however, mutations in genes involved in apy. RA medications in pregnancy are discussed in Principles bone or articular cartilage structure or metabolism are possi of Therapeutics. ble risk factors.

Low dose prednisone (s-ts mg/d) can be used to rapidly xEY POtilts improve RA symptoms until long term medications become . There is an increased risk for developing rheumatoid effective, or they can be used short term for disease flares. arthritis in the first year after a first pregnancy. Although glucocorticoid use is associated with a reduction in . Among women with established rheumatoid arthritis radiographic progression, long term therapy with glucocorti- at the time of conception, two thirds will go into coitls has substantial potential adverse effects, including osteo- remission or a state of low disease activity during porosis, diabetes mellitus, and intbction. pregnancy, and one third will not improve or will get worse. Surgery Surgical therapy has become less common in RA because of current treatment strategies. Nonetheless, some patients may require synovectomy for a single persistently swollen joint, carpal tunnel release, repair of a ruptured tendon, Osteoarthritis total joint replacement (shoulder, metacarpophalangeal joints, hip, knee), or joint fusion lbr a painful damaged Pathophysiology joint (wrist or ankle). See MKSAP 19 General Internal Osteoarthritis (OA) is a chronic progressive multifactorial Medicine 2 for a discussion of perioperative RA medication disorder of maladaptive cellular repair responses to joint management. stress. Previously deemed a "wear and tear" disease and an inevitable consequence ofaging, OA is now recognized as a XEY POITIS disorder driven by a complex interplay of genetics; biome- . In rheumatoid arthritis, treating to a target of remis- chanics; cell stress; biochemical change in cartilage and sion or low disease activity results in less radio- extracellular matrix components; and degradation and graphic damage, reduced cardiovascular risk, and inllammation, which is usually subclinical. It affects all tis increased work productivity compared with conven- sues of the joint and is characterized by cartilage and tional care. meniscal degradation, subchondral bone changes (bone HVC o Methotrexate is the anchor drug in rheumatoid arthri- marrow lesions, subchondral sclerosis), and osteophyte tis; it is used as both monotherapy and a component of formation. OA is accompanied by low-grade synovitis and combination therapy. is driven by imbalanced anabolic and catabolic processes . Tumor necrosis factor inhibitors are the most fre that represent aberrant joint responses and result in joint quently used biologics to treat rheumatoid arthritis; tissue degeneration. they have a relatively rapid onset of action and demon- strate synerS/ with methotrexate. HVC o In rheumatoid arthritis, NSAIDs are not disease Epidemiology and Risk Factors modifying and do not prevent joint damage; they are OA is the most common form of arthritis worldwide and is a used primarily to control symptoms while the full leading cause of pain and disability, affecting approximately effect of disease-modifying antirheumatic drugs is 30 million U.S. adults. OA is the leading cause of lower extrem- awaited. ity disability among older adults, with an estimated lifetime . Low-dose prednisone can be used in rheumatoid risk for knee OA approaching 50%. Prevalence is projected to arthritis to rapidly improve symptoms until long,term more than double by 2030, Iargely because of increasing obe- medications become effective, but long-term glucocor- sity and the aging ofthe population. Incidence and prevalence ticoid use carries significant comorbid risk. vary by joint and depend on whether a clinical or a radio graphic definition is being applied. Epidemiologic risk factors for OA include age older than Pregnancy 55 years, female sex, obesity, genetics, and occupations that There is an increased risk for developing RA in the first year involve repetitive motions or physical labor. Age and female after a first pregnancy. Breastf'eeding may decrease this risk. sex are nonmodifiable risk factors for OA of different sites. Among women with established RA at the time of concep Obesity is the most important modifiable risk factor, especially tion, two thirds will go into remission or a state of low dis- for knee OA. Increased body mass is also a risk factor fbr hand ease activity during pregnancy, and one third will not OA, perhaps underscoring the systemic nature of obesity and improve or will get worse. Medication management is a a role for metabolic and/or inflammatory mechanisms in the major issue, and pregnancy plans should be discussed with pathogenesis of hand OA. Single inherited conditions rarely any woman of childbearing age who will be placed on ther predispose to OA; however, mutations in genes involved in apy. RA medications in pregnancy are discussed in Principles bone or articular cartilage structure or metabolism are possi of Therapeutics. ble risk factors. 23