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Systemic Lupus Erythematosus Psoriatic Arthritis For mild arthritic disease, NSAIDs or joint injections with Thble 18 lists agents available to treat psoriatic arthritis. In gen- glucocorticoids may be sufficient until the disease self eral, most ofthese agents are also effective for psoriasis. Because resolves. For more persistent or severe disease, sulfasalazine agents such as TNF inhibitors are often given in higher doses (preferred) or methotrexate may be required. There are few for skin disease than for joint disease, the predominant feature data from controlled studies for either agent, but case series of the disease may drive the prescribing dose. Weight loss and and reports suggest efficacy. TNF inhibitors may also be needed smoking cessation may positively affect disease activity. if these agents fail, but again data are scant. Given the mono- For limited disease, such as a single digit with dactylitis or phasic nature of reactive arthritis in many patients, a trial off a single swollen joint, an oral or topical NSAID or a local injec therapy is warranted 3 to 6 months after remission. tion of glucocorticoids may suffice. High dose oral glucocorti Topical glucocorticoids can be used to help address the coids should be avoided because eventual tapering of the skin manifestations, and topical ocular glucocorticoids are dosage raises the risk for erythrodermic psoriasis. useful for uveitis. For more active disease, the ACR suggests initiating a TNF KEY POITTS inhibitor, methotrexate, or an interleukin 17 inhibitor. If one . For ankylosing spondylitis, NSAIDs are recommended agent is insufficient, another may be tried. Combination ther- as the initial medication to relieve pain and improve apy does not have the same effect in psoriatic arthritis as in stiffness; physical therapy to maintain general range of rheumatoid arthritis. Surgery may be indicated for significant motion is essential. damage to larger joints. . Tumor necrosis factor inhibitors in patients with active HVC Enteropathic Arthritis ankylosing spondylitis are associated with improvements Enteropathic arthritis is best addressed by focusing on control of in clinical, radiographic, and MRI outcomes. bowel inflammation. For spondyloarthritis associated with o For psoriatic arthritis, limited disease can be treated with bowel involvement, medications to address both peripheral a topical NSAID or local glucocorticoid injection; for arthritis and bowel inflammation include sulfasalazine, azathio- more active disease, a tumor necrosis factor inhibitor, prine, methotrexate, and glucocorticoids. The TNF inhibitors are methotrexate, or interleukin-l7 inhibitor can be used. especially useful for bowel and joint symptoms, including . The peripheral arthritis tied to inflammatory bowel dis- spine disease. Interleukin 17 inhibitors may cause IBD to flare ease is best addressed by focusing on control ofbowel and are contraindicated in these patients. NSAIDs should be inflammation; for spondyloarthritis that is associated avoided when possible because ofthe potential for IBD flare. with bowel involvement, medications to address both peripheral arthritis and bowel inllammation include Reactive Anhritis sulfasalazine, azathioprine, methotrexate, and gluco- Because of a lack of benefit, antibiotic treatment of reactive corticoids. arthritis due to enteric organisms is not usually warranted. o Because of a lack of benefit, antibiotic treatment of However, patients with severe infections or immunosuppres- reactive arthritis due to enteric organisms is not usually sion or those with urogenital infection with C. trachomatis warranted; for mild arthritic disease, NSAIDs or joint may benefit from antibacterial therapy. injections with glucocorticoids may be sufficient, and for more persistent or severe disease, sulfasalazine or TABLE 1 8. Medications to Treat Psoriatic Arthritis methotrexate may be required. Category Medications Anti-inflammatory agents NSAIDs; oral or intra-articular glucocorticoids Non biologic disease-modiiying Methotrexate, leflu nomide, Systemic Lupus antirheumatic drugs sulfasalazine, cyclosporine, apremilast Erythematosus Tumor necrosis factor inhibitors Etanercep! adalimumab, infliximab, certolizumab, Epidemiology and golimumab Pathophysiology lnterleukin-1 7 inhibitors Secukinumab, ixekizumab, Systemic lupus erythematosus (SLE) is a multisystem autoim- brodalumab mune disease characterized by a heterogeneous constellation lnterleukin-1 2/interleukin-23 Ustekinumab inhibitor oforgan involvement and the presence ofantinuclear antibod ies (ANA) and other autoantibodies. Cytotoxic T-lym phocyte Abatacept antigen-4 immunoglobulin In SLE, a complex and varying interaction of genes, envi- ronment, and random events leads to a breakdown of self- Janus kinase inhibitor Tofacitinib tolerance and autoimmunilr. Defects in cellular apoptosis

Psoriatic Arthritis For mild arthritic disease, NSAIDs or joint injections with Thble 18 lists agents available to treat psoriatic arthritis. In gen- glucocorticoids may be sufficient until the disease self eral, most ofthese agents are also effective for psoriasis. Because resolves. For more persistent or severe disease, sulfasalazine agents such as TNF inhibitors are often given in higher doses (preferred) or methotrexate may be required. There are few for skin disease than for joint disease, the predominant feature data from controlled studies for either agent, but case series of the disease may drive the prescribing dose. Weight loss and and reports suggest efficacy. TNF inhibitors may also be needed smoking cessation may positively affect disease activity. if these agents fail, but again data are scant. Given the mono- For limited disease, such as a single digit with dactylitis or phasic nature of reactive arthritis in many patients, a trial off a single swollen joint, an oral or topical NSAID or a local injec therapy is warranted 3 to 6 months after remission. tion of glucocorticoids may suffice. High dose oral glucocorti Topical glucocorticoids can be used to help address the coids should be avoided because eventual tapering of the skin manifestations, and topical ocular glucocorticoids are dosage raises the risk for erythrodermic psoriasis. useful for uveitis. For more active disease, the ACR suggests initiating a TNF KEY POITTS inhibitor, methotrexate, or an interleukin 17 inhibitor. If one . For ankylosing spondylitis, NSAIDs are recommended agent is insufficient, another may be tried. Combination ther- as the initial medication to relieve pain and improve apy does not have the same effect in psoriatic arthritis as in stiffness; physical therapy to maintain general range of rheumatoid arthritis. Surgery may be indicated for significant motion is essential. damage to larger joints. . Tumor necrosis factor inhibitors in patients with active HVC Enteropathic Arthritis ankylosing spondylitis are associated with improvements Enteropathic arthritis is best addressed by focusing on control of in clinical, radiographic, and MRI outcomes. bowel inflammation. For spondyloarthritis associated with o For psoriatic arthritis, limited disease can be treated with bowel involvement, medications to address both peripheral a topical NSAID or local glucocorticoid injection; for arthritis and bowel inflammation include sulfasalazine, azathio- more active disease, a tumor necrosis factor inhibitor, prine, methotrexate, and glucocorticoids. The TNF inhibitors are methotrexate, or interleukin-l7 inhibitor can be used. especially useful for bowel and joint symptoms, including . The peripheral arthritis tied to inflammatory bowel dis- spine disease. Interleukin 17 inhibitors may cause IBD to flare ease is best addressed by focusing on control ofbowel and are contraindicated in these patients. NSAIDs should be inflammation; for spondyloarthritis that is associated avoided when possible because ofthe potential for IBD flare. with bowel involvement, medications to address both peripheral arthritis and bowel inllammation include Reactive Anhritis sulfasalazine, azathioprine, methotrexate, and gluco- Because of a lack of benefit, antibiotic treatment of reactive corticoids. arthritis due to enteric organisms is not usually warranted. o Because of a lack of benefit, antibiotic treatment of However, patients with severe infections or immunosuppres- reactive arthritis due to enteric organisms is not usually sion or those with urogenital infection with C. trachomatis warranted; for mild arthritic disease, NSAIDs or joint may benefit from antibacterial therapy. injections with glucocorticoids may be sufficient, and for more persistent or severe disease, sulfasalazine or TABLE 1 8. Medications to Treat Psoriatic Arthritis methotrexate may be required. Category Medications Anti-inflammatory agents NSAIDs; oral or intra-articular glucocorticoids Non biologic disease-modiiying Methotrexate, leflu nomide, Systemic Lupus antirheumatic drugs sulfasalazine, cyclosporine, apremilast Erythematosus Tumor necrosis factor inhibitors Etanercep! adalimumab, infliximab, certolizumab, Epidemiology and golimumab Pathophysiology lnterleukin-1 7 inhibitors Secukinumab, ixekizumab, Systemic lupus erythematosus (SLE) is a multisystem autoim- brodalumab mune disease characterized by a heterogeneous constellation lnterleukin-1 2/interleukin-23 Ustekinumab inhibitor oforgan involvement and the presence ofantinuclear antibod ies (ANA) and other autoantibodies. Cytotoxic T-lym phocyte Abatacept antigen-4 immunoglobulin In SLE, a complex and varying interaction of genes, envi- ronment, and random events leads to a breakdown of self- Janus kinase inhibitor Tofacitinib tolerance and autoimmunilr. Defects in cellular apoptosis 42

Systemic Lupus Erythematosus result in inadequate clearance of intracellular proteins, espe- cially nuclear antigens, promoting the generation of self directed T and B cells and the initiation/propagation of autoimmunity. Cytokine generation supports autoreactiviry with type I interf'erons playing a major role. Autoantibodies may directly induce tissue damage or promote the formation of immune complexes that lead to complement activation and tissue inflammation and damage. Inheritance of SLE risk is polygenic, including major histocompatibility complex genes. The risk for SLE is higher in those with a family history Incidence increases at pubefi and peaks in the third decade. The disease is more common and more severe in Black and Hispanic populations. Approximately 90% of adult patients are women; SLE is frequently more severe in men than women. tIGURE 29. Thefacial eruption of acutecutaneous lupuserythematosus f,lY POrilTt (malar or butterfly rash). This patient has fixed erythematous raised lesions over the . Systemic lupus erythematosus is a multisystem autoim malar eminences, the bridge of the nose with sparing of the nasolabial folds, and mune disease characterized by a heterogeneous constella- the chin.

result in inadequate clearance of intracellular proteins, espe- cially nuclear antigens, promoting the generation of self directed T and B cells and the initiation/propagation of autoimmunity. Cytokine generation supports autoreactiviry with type I interf'erons playing a major role. Autoantibodies may directly induce tissue damage or promote the formation of immune complexes that lead to complement activation and tissue inflammation and damage. Inheritance of SLE risk is polygenic, including major histocompatibility complex genes. The risk for SLE is higher in those with a family history Incidence increases at pubefi and peaks in the third decade. The disease is more common and more severe in Black and Hispanic populations. Approximately 90% of adult patients are women; SLE is frequently more severe in men than women. tIGURE 29. Thefacial eruption of acutecutaneous lupuserythematosus f,lY POrilTt (malar or butterfly rash). This patient has fixed erythematous raised lesions over the . Systemic lupus erythematosus is a multisystem autoim malar eminences, the bridge of the nose with sparing of the nasolabial folds, and mune disease characterized by a heterogeneous constella- the chin. tion oforgan involvement and the presence ofantinuclear antibodies and other autoantibodies. desquamation. The facial eruption of ACLE (the classic malar . Approximately 9O"/" of adult patients with systemic lupus or butterfly rash) is characterized by fixed, rather than tran- erythematosus are women. sient, erythema/edema over the cheeks and bridge ofthe nose, sparing the nasolabial folds (Figure 29), but the neck, upper chest, and dorsum ofthe arms and hands can also be involved. In some patients, a bullous eruption occurs. ACLE usually Clin ica I Manifestations responds to therapy and heals without scarring or atrophy. Mucocutaneous lnvolvement Subacute cutaneous lupus erythematosus (SCLE) is a Skin disease occurs in most patients with SLE and is classified photosensitive rash occurring especially on the arms, neck, as acute, subacute, or chronic. and upper trunk, usually sparing the central face (Figure 3o). Acute cutaneous lupus erythematosus (ACLE) presents as It consists of erythematous annular/polycyclic or patchy papu- an erythematous, macular, patchy eruption, sometimes with losquamous lesions, often with a fine scale, that may leave

tion oforgan involvement and the presence ofantinuclear antibodies and other autoantibodies. desquamation. The facial eruption of ACLE (the classic malar . Approximately 9O"/" of adult patients with systemic lupus or butterfly rash) is characterized by fixed, rather than tran- erythematosus are women. sient, erythema/edema over the cheeks and bridge ofthe nose, sparing the nasolabial folds (Figure 29), but the neck, upper chest, and dorsum ofthe arms and hands can also be involved. In some patients, a bullous eruption occurs. ACLE usually Clin ica I Manifestations responds to therapy and heals without scarring or atrophy. Mucocutaneous lnvolvement Subacute cutaneous lupus erythematosus (SCLE) is a Skin disease occurs in most patients with SLE and is classified photosensitive rash occurring especially on the arms, neck, as acute, subacute, or chronic. and upper trunk, usually sparing the central face (Figure 3o). Acute cutaneous lupus erythematosus (ACLE) presents as It consists of erythematous annular/polycyclic or patchy papu- an erythematous, macular, patchy eruption, sometimes with losquamous lesions, often with a fine scale, that may leave fIGURE 30. Subacutecutaneouslupuserythematosusischaracterizedbyerythematous,macular,orpatchyskinlesionsthatarescalyandcanevolveas(/)annular/polycyclic lesions or (B) papulosquamous plaques. 43

Systemic Lupus Erythematosus unexplained pain and/or reduced range of motion. Long- term and higher-dose (>20 mg/d) prednisone treatment, severe/active SLE, and vasculitis are associated with increased risk for osteonecrosis. MRI may be needed to iden- tiff early disease. Although small lesions can improve with out invasive treatment, larger areas of involvement can lead to bony collapse. Treatment requires extended non-weight- bearing and, in some cases, core decompression of the affected bone. In the wake of collapse, joint replacement may be necessary. Myalgia and subjective weakness are common, but true myositis is rare. Glucocorticoids often cause muscle weakness, and, rarely, antimalarial agents can affect muscle. Thus, medi- cation effects must be differentiated from active SLE disease. F t G Un E 3 I . Discoid lupus erythematosus.This patient has hyperpigmented, raised patches with keratotic scaling and follicular plugging involving the malar Fibromyalgia is a common comorbidity (30%); symptoms may and perioral areas as well as the bridge of the nose. Areas of atrophic scarring are overlap those of active SLE disease. also present. Kidney lnvolvement postinflammatory hypo- or hyperpigmentation. SCLE is asso- Kidney disease occurs frequently among patients with SLE and ciated with anti-Ro/SSA autoantibodies (prevalence >75%) and remains an important source of morbidity. Lupus nephritis can can occur in isolation or as a manifestation of underlying SLE. present with minimal laboratory abnormalities (non-nephrotic Discoid lupus erythematosus (DLE) is the most common proteinuria, hematuria), nephritis (hypertension, edema, manifestation of chronic cutaneous Iupus erythematosus active urine sediment, and elevated serum creatinine), and/or and can cause scarring, atrophy, and permanent alopecia nephrosis (nephrotic-range proteinuria, edema, hypoalbu- (Figure 31 and Figure 32). DLE presents as hlpo- or hyperpig- minemia, hypercholesterolemia, and, in some cases, thrombo- mented patches or plaques, with erythema during active dis- sis). Untreated active disease may progress to kidney failure, in ease, which may be variably atrophic or hyperkeratotic. Like severe cases requiring dialysis or transplant. SCLE, DLE can occur as an isolated flnding in the absence ofSLE and in such cases is typically limited to the neck, face, and scalp. Painless oral or nasopharyngeal ulcerations occur in 5'1, of patients with SLE. Involvement of the hard palate is characteristic. Rarely, DLE is associated with painful ulcers. Nonscarring alopecia is a common feature of active SLE, with hair regrowth a sign of disease control. Raynaud phenomenon occurs frequently, reflecting arte- rial vasospasm of digital arteries. Other vascular changes, including livedo reticularis or periungual erythema, may be present as well, although these findings are nonspecific. Some patients with SLE may develop cutaneous vasculitis, most often in the distal extremities.

unexplained pain and/or reduced range of motion. Long- term and higher-dose (>20 mg/d) prednisone treatment, severe/active SLE, and vasculitis are associated with increased risk for osteonecrosis. MRI may be needed to iden- tiff early disease. Although small lesions can improve with out invasive treatment, larger areas of involvement can lead to bony collapse. Treatment requires extended non-weight- bearing and, in some cases, core decompression of the affected bone. In the wake of collapse, joint replacement may be necessary. Myalgia and subjective weakness are common, but true myositis is rare. Glucocorticoids often cause muscle weakness, and, rarely, antimalarial agents can affect muscle. Thus, medi- cation effects must be differentiated from active SLE disease. F t G Un E 3 I . Discoid lupus erythematosus.This patient has hyperpigmented, raised patches with keratotic scaling and follicular plugging involving the malar Fibromyalgia is a common comorbidity (30%); symptoms may and perioral areas as well as the bridge of the nose. Areas of atrophic scarring are overlap those of active SLE disease. also present. Kidney lnvolvement postinflammatory hypo- or hyperpigmentation. SCLE is asso- Kidney disease occurs frequently among patients with SLE and ciated with anti-Ro/SSA autoantibodies (prevalence >75%) and remains an important source of morbidity. Lupus nephritis can can occur in isolation or as a manifestation of underlying SLE. present with minimal laboratory abnormalities (non-nephrotic Discoid lupus erythematosus (DLE) is the most common proteinuria, hematuria), nephritis (hypertension, edema, manifestation of chronic cutaneous Iupus erythematosus active urine sediment, and elevated serum creatinine), and/or and can cause scarring, atrophy, and permanent alopecia nephrosis (nephrotic-range proteinuria, edema, hypoalbu- (Figure 31 and Figure 32). DLE presents as hlpo- or hyperpig- minemia, hypercholesterolemia, and, in some cases, thrombo- mented patches or plaques, with erythema during active dis- sis). Untreated active disease may progress to kidney failure, in ease, which may be variably atrophic or hyperkeratotic. Like severe cases requiring dialysis or transplant. SCLE, DLE can occur as an isolated flnding in the absence ofSLE and in such cases is typically limited to the neck, face, and scalp. Painless oral or nasopharyngeal ulcerations occur in 5'1, of patients with SLE. Involvement of the hard palate is characteristic. Rarely, DLE is associated with painful ulcers. Nonscarring alopecia is a common feature of active SLE, with hair regrowth a sign of disease control. Raynaud phenomenon occurs frequently, reflecting arte- rial vasospasm of digital arteries. Other vascular changes, including livedo reticularis or periungual erythema, may be present as well, although these findings are nonspecific. Some patients with SLE may develop cutaneous vasculitis, most often in the distal extremities. M usculoskeletal I nvolvement Joints are affected in 90% of patients with SLE. Many patients have arthralgia, and a much smaller group exhibits arthritis. Many patients with SLE may have evidence of synovitis on imaging even with minimal symptoms or swelling on exami- nation. Typical distribution includes small peripheral joints, often resembling rheumatoid arthritis, but large joints are also affected. SLE arthritis is nonerosive, but reducible subluxation of the digits, swan neck deformities, and ulnar deviation (Jaccoud arthropathy) can occur, a result of damage to the tendons and ligaments. Osteonecrosis is a serious complication of SLE that most commonly affects the hips but can also involve other large FIGU RE 3 2. Active discoid lupus erythematosus ol the scalp with scaning hair joints. It should be suspected in patients with otherwise loss.

M usculoskeletal I nvolvement Joints are affected in 90% of patients with SLE. Many patients have arthralgia, and a much smaller group exhibits arthritis. Many patients with SLE may have evidence of synovitis on imaging even with minimal symptoms or swelling on exami- nation. Typical distribution includes small peripheral joints, often resembling rheumatoid arthritis, but large joints are also affected. SLE arthritis is nonerosive, but reducible subluxation of the digits, swan neck deformities, and ulnar deviation (Jaccoud arthropathy) can occur, a result of damage to the tendons and ligaments. Osteonecrosis is a serious complication of SLE that most commonly affects the hips but can also involve other large FIGU RE 3 2. Active discoid lupus erythematosus ol the scalp with scaning hair joints. It should be suspected in patients with otherwise loss. 44

Systemic Lupus Erythematosus All patients with SLE should be regularly evaluated for Pulmonary lnvolvement kidney involvement through assessment of serum creatinine Pulmonary involvement is common in SLE, with most patients and urine for protein and microscopic evaluation. Active kid- presenting with pleuritis (45"1, 6O'X,). Pleural effusions occur ney disease should be suspected when there is active urine in approximately half of these patients and are typically exu sediment or proteinuria greater than 500 mgl24 h (or a spot dative; fluid analysis may reveal lymphocytic pleocytosis and urine protein to creatine ratio >500 mg/g). Elevated or rising mildly depressed glucose levels. anti-double stranded DNA antibody titers or complement Parenchymal lung involvement occurs in less than 10'1, of consumption are commonly associated with active kidney patients with SLE. A nonspecific interstitial pneumonia pat- disease. tern is most common, and evaluation centers on assessing SLE Kidney biopsy defines both the histologic subtype and the activity and excluding other causes of diffuse parenchymal activity/chronicity of disease, which are important for thera lung disease. Two rare but potentially life threatening compli peutic decisions. Indications fbr kidney biopsy include an cations of SLE lung disease are acute lupus pneumonitis (pre- increase in serum creatinine level, unexplained decrease in senting as fever, cough, dyspnea, hypoxemia, pleuritic chest glomerular filtration rate, or proteinuria greater than pain, and infiltrates) and diffuse alveolar hemorrhage (pre- 5OO mgl24 h (or a spot urine protein-to-creatinine ratio senting with dyspnea, hypoxemia, diffuse alveolar infiltrates, >500 mg/g), especially in the presence of hematuria or an a dropping hematocrit, and a high Dr.co). Both carry a high active urine sediment. mortality rate (>50'X,). Early recognition, rapid evaluation (CT See MKSAP 19 Nephrologz fbr information on the classes and/or bronchoscopy with bronchoalveolar lavage or biopsy), and treatment of lupus nephritis. and aggressive respiratory support combined with high dose glucocorticoids and immunosuppression are required. With Neuropsychiatric lnvolvement new pulmonary infiltrates, differentiation between these dis Neuropsychiatric systemic lupus erythematosus (NPSLE) may orders and infection can be difficult. and antibiotics and involve the central and/or peripheral nervous systems. NPSLE immunosuppressive therapy are often administered simulta prevalence is high (75%), but most of the common manifesta neously until the diagnosis is clear. tions (headache, mild cognitive dysfunction, and mood disor Shrinking lung syndrome is a rare but characteristic syn der) are nonspecific. Peripheral neuropathy occurs in 10"/n to drome consisting of pleuritic chest pain and dyspnea, with 14% ofpatients. Severe acute presentations, including seizures progressive decrease in lung volumes. The cause is uncertain, and psychosis, are uncommon (<5'1,) but require aggressive but pleuropulmonary disease and/or diaphragmatic dysfunc symptomatic as well as disease speciflc treatment. tion may contribute. Immunosuppression may reverse the Patients suspected of having serious central NPSLE, process in some patients. such as meningitis, stroke, and psychosis, should undergo central nervous system imaging (CT, MRI, or PET) and cere- brospinal fluid analysis as appropriate. ln some patients Hematologic lnvolvement with severe disease, measurement of cerebrospinal fluid for In patients with SLE, normocytic, normochromic anemia of NPSLE associated autoantibodies (antineuronal, anti inflammation is common; autoimmune hemolytic anemia N methyl r) aspartate receptor, antiribosomal P, and others) occurs in approximately 10u1, of cases and correlates with SLE may be useful. For patients suspected of having peripheral activity. Lymphopenia/leukopenia is also common but usually neuropathies, electromyography and nerve conduction mild. Thrombocytopenia occurs in 30'1, to 50% of cases, and studies should be performed. Neuropsychologic testing may approximately 10'2, of patients develop severe thrombocytope help define and distinguish organic versus functional cogni nia (<50,000/pL [50 x 10e/L]) in isolation or in conjunction tive changes. with hemolytic anemia. Cytopenia in SLE may be caused by immune and non- Cardiovascular lnvolvement immune destructive mechanisms (including microangiopa- Asymptomatic pericarditis is the most frequent cardiac mani- thy), medications, and kidney and liver disease. Moderate and festation of acute SLE (40'1,). When symptomatic, features severe or rapidly progressive cytopenia requires prompt evalu- include chest pain, exudative effusion, and, rarely, tamponade ation with serologic studies and/or bone marrow biopsy. An or chronic constriction. Myocarditis occurs in 5'1, to 10% of exact cause of cytopenia may be diflicult to ascertain, and a patients with SLE and usually presents as insidious heart fail trial of medication adjustment in concert with evaluation for ure but can be acute. other causes is often necessary. Valvular abnormalities occurring in SLE include those Antiphospholipid antibodies and lupus anticoagulant are associated with antiphospholipid syndrome (nonspecific present in about 40'2, of patients with SLE and may be associ thickening of the mitral and aortic valve leaflets, vegetations, ated with a false positive result on a rapid plasma reagin test regurgitation, and stenosis). Libman Sacks endocarditis (non fbr syphilis. Most patients are asymptomatic. Thrombotic infectious verrucous vegetations) preferentially affects the events occur in about 30%, of patients; these include mitral valve and can cause embolic complications. venous and arterial thrombosis, miscarriage, stillbirth, livedo

All patients with SLE should be regularly evaluated for Pulmonary lnvolvement kidney involvement through assessment of serum creatinine Pulmonary involvement is common in SLE, with most patients and urine for protein and microscopic evaluation. Active kid- presenting with pleuritis (45"1, 6O'X,). Pleural effusions occur ney disease should be suspected when there is active urine in approximately half of these patients and are typically exu sediment or proteinuria greater than 500 mgl24 h (or a spot dative; fluid analysis may reveal lymphocytic pleocytosis and urine protein to creatine ratio >500 mg/g). Elevated or rising mildly depressed glucose levels. anti-double stranded DNA antibody titers or complement Parenchymal lung involvement occurs in less than 10'1, of consumption are commonly associated with active kidney patients with SLE. A nonspecific interstitial pneumonia pat- disease. tern is most common, and evaluation centers on assessing SLE Kidney biopsy defines both the histologic subtype and the activity and excluding other causes of diffuse parenchymal activity/chronicity of disease, which are important for thera lung disease. Two rare but potentially life threatening compli peutic decisions. Indications fbr kidney biopsy include an cations of SLE lung disease are acute lupus pneumonitis (pre- increase in serum creatinine level, unexplained decrease in senting as fever, cough, dyspnea, hypoxemia, pleuritic chest glomerular filtration rate, or proteinuria greater than pain, and infiltrates) and diffuse alveolar hemorrhage (pre- 5OO mgl24 h (or a spot urine protein-to-creatinine ratio senting with dyspnea, hypoxemia, diffuse alveolar infiltrates, >500 mg/g), especially in the presence of hematuria or an a dropping hematocrit, and a high Dr.co). Both carry a high active urine sediment. mortality rate (>50'X,). Early recognition, rapid evaluation (CT See MKSAP 19 Nephrologz fbr information on the classes and/or bronchoscopy with bronchoalveolar lavage or biopsy), and treatment of lupus nephritis. and aggressive respiratory support combined with high dose glucocorticoids and immunosuppression are required. With Neuropsychiatric lnvolvement new pulmonary infiltrates, differentiation between these dis Neuropsychiatric systemic lupus erythematosus (NPSLE) may orders and infection can be difficult. and antibiotics and involve the central and/or peripheral nervous systems. NPSLE immunosuppressive therapy are often administered simulta prevalence is high (75%), but most of the common manifesta neously until the diagnosis is clear. tions (headache, mild cognitive dysfunction, and mood disor Shrinking lung syndrome is a rare but characteristic syn der) are nonspecific. Peripheral neuropathy occurs in 10"/n to drome consisting of pleuritic chest pain and dyspnea, with 14% ofpatients. Severe acute presentations, including seizures progressive decrease in lung volumes. The cause is uncertain, and psychosis, are uncommon (<5'1,) but require aggressive but pleuropulmonary disease and/or diaphragmatic dysfunc symptomatic as well as disease speciflc treatment. tion may contribute. Immunosuppression may reverse the Patients suspected of having serious central NPSLE, process in some patients. such as meningitis, stroke, and psychosis, should undergo central nervous system imaging (CT, MRI, or PET) and cere- brospinal fluid analysis as appropriate. ln some patients Hematologic lnvolvement with severe disease, measurement of cerebrospinal fluid for In patients with SLE, normocytic, normochromic anemia of NPSLE associated autoantibodies (antineuronal, anti inflammation is common; autoimmune hemolytic anemia N methyl r) aspartate receptor, antiribosomal P, and others) occurs in approximately 10u1, of cases and correlates with SLE may be useful. For patients suspected of having peripheral activity. Lymphopenia/leukopenia is also common but usually neuropathies, electromyography and nerve conduction mild. Thrombocytopenia occurs in 30'1, to 50% of cases, and studies should be performed. Neuropsychologic testing may approximately 10'2, of patients develop severe thrombocytope help define and distinguish organic versus functional cogni nia (<50,000/pL [50 x 10e/L]) in isolation or in conjunction tive changes. with hemolytic anemia. Cytopenia in SLE may be caused by immune and non- Cardiovascular lnvolvement immune destructive mechanisms (including microangiopa- Asymptomatic pericarditis is the most frequent cardiac mani- thy), medications, and kidney and liver disease. Moderate and festation of acute SLE (40'1,). When symptomatic, features severe or rapidly progressive cytopenia requires prompt evalu- include chest pain, exudative effusion, and, rarely, tamponade ation with serologic studies and/or bone marrow biopsy. An or chronic constriction. Myocarditis occurs in 5'1, to 10% of exact cause of cytopenia may be diflicult to ascertain, and a patients with SLE and usually presents as insidious heart fail trial of medication adjustment in concert with evaluation for ure but can be acute. other causes is often necessary. Valvular abnormalities occurring in SLE include those Antiphospholipid antibodies and lupus anticoagulant are associated with antiphospholipid syndrome (nonspecific present in about 40'2, of patients with SLE and may be associ thickening of the mitral and aortic valve leaflets, vegetations, ated with a false positive result on a rapid plasma reagin test regurgitation, and stenosis). Libman Sacks endocarditis (non fbr syphilis. Most patients are asymptomatic. Thrombotic infectious verrucous vegetations) preferentially affects the events occur in about 30%, of patients; these include mitral valve and can cause embolic complications. venous and arterial thrombosis, miscarriage, stillbirth, livedo 45

Systemic Lupus Erythematosus reticularis, and cardiac valve thickening/vegetations. The risk of death among older patients with SLE, even those whose for thrombosis is highest in the presence of triple positivity fbr lupus has become quiescent. A history of high SLE disease lupus anticoagulant, anti pr-glycoprotein, and anticardi activity (especially nephritis) and prednisone dosages greater olipin antibodies. Patients with SLE are at increased risk for than 10 mg/d are independent risk factors for coronary artery thrombotic events even in the absence of antiphospholipid disease. Patients with SLE are also at increased risk for antibodies. See MKSAP 19 Hematologz for more information. ischemic stroke.

reticularis, and cardiac valve thickening/vegetations. The risk of death among older patients with SLE, even those whose for thrombosis is highest in the presence of triple positivity fbr lupus has become quiescent. A history of high SLE disease lupus anticoagulant, anti pr-glycoprotein, and anticardi activity (especially nephritis) and prednisone dosages greater olipin antibodies. Patients with SLE are at increased risk for than 10 mg/d are independent risk factors for coronary artery thrombotic events even in the absence of antiphospholipid disease. Patients with SLE are also at increased risk for antibodies. See MKSAP 19 Hematologz for more information. ischemic stroke. XEY POIT{TS Gastrointestinal lnvolvement o Patients with systemic lupus erythematosus are at Gastrointestinal involvement is a common (+oy,) and under increased risk for malignancy; immunosuppressive use recognized SLE manifestation. Serositis presents as abdominal contributes to this increased risk. pain, is usually associated with active disease, and improves with treatment. Mesenteric vasculitis, inflammation of the . Patients with systemic lupus erythematosus have a 2- to small and large bowel, pancreatitis, protein losing enteropa- 10 fold increased prevalence of coronary artery disease; thy, and diffuse peritonitis are uncommon but may be severe high SLE disease activity and prednisone dosages and associated with cutaneous vasculitis. greater than 10 mg/d are independent risk factors for Noninfectious hepatitis can occur and is associated with coronary artery disease. the presence of antiribosomal P antibodies. Patients with SLE who have Raynaud phenomenon and anti U1 ribonucleoprotein antibodies are at increased risk fbr esopha Diagnosis geal disease and reflux. General Considerations Medications used to treat SLE (NSAIDs, prednisone, The diagnosis of SLE should be considered in patients, espe mycophenolate, azathioprine) also frequently affect the gas- cially young women, with any individual manifestation of SLE trointestinal system and may cause esophagitis, gastritis, pan or with symptoms affecting multiple organ systems. The most creatitis, and other manifestations. common presenting clinical features that differentiate patients XEY PO Il{IS with SLE from those with other mimicking conditions include . The facial eruption of acute cutaneous lupus erythema- malar rash, photosensitivity, inflammatory arthritis, weight tosus (malar or butterfly rash) is characterized by ery loss, and fever, along with such laboratory features as positiv thema/edema over the chin, cheeks, and bridge of the ity lor ANA, low complement levels, and presence of lupus nose, sparing the nasolabial folds. specific antibodies. Patients with subjective reports of fatigue, r Many patients with systemic lupus erythematosus have myalgia, and/or arthralgia but lacking objective flndings most likely have an alternative diagnosis and should not be evalu arthralgia, and a much smaller group exhibits arthritis. ated for SLE. o A11 patients with systemic lupus erythematosus should Several classification criteria for SLE have been used; be regular$ evaluated for kidney involvement through although intended for recruitment of homogenous SLE popu- assessment of serum creatinine and urine for protein lations for research sfudies, they can also be used to suggest a and microscopic evaluation. clinical diagnosis ofSLE. A 2019 update ofthese criteria from . The most common manifestations of neuropsychiatric the European League Against Rheumatism/American College systemic lupus erythematosus are headache, mild cog- of Rheumatologr includes the requirement for a positive ANA nitive dysfunction, and mood disorder. result at least once, with the addition of clinical and/or immu- nologic criteria totaling at least 10 points on a weighted scale Comorbidities (Figure 33). These criteria compare favorably to prior pub Patients with SLE have a higher overall risk for malignancies Iished criteria, with a sensitivity of about 96% and specificity (particularly hematologic); the risk for non Hodgkin lym ofabout 93%. phoma is at least two to three times higher than in the general population. Malignancy risk in SLE is tied to the use of immu Laboratory Studies nosuppressive agents. Higher cumulative cyclophosphamide Initial evaluation for SLE includes routine laboratory test- doses are associated with increased risk for solid organ tumors, ing to establish organ specific involvement, including com and azathioprine use is associated with an increased risk for plete blood count, chemistry panel, and urinalysis with myeloproliferative syndromes. Cervical cancer is also increased microscopy. in patients with SLE, especially those receiving immunosup ANA should be obtained to screen for nuclear directed pressive therapies. Hydroxychloroquine use does not appear to autoantibodies. The most appropriate method for testing increase malignancy risk and may be protective. ANA is the indirect immunofluorescence assay, which is Patients with SLE have a 2- to 10 fold increased preva highly sensitive (>9s'l.) for SLE but not specific. ANA tests lence of coronary artery disease. It is the most common cause should be interpreted in the context of the probability of

XEY POIT{TS Gastrointestinal lnvolvement o Patients with systemic lupus erythematosus are at Gastrointestinal involvement is a common (+oy,) and under increased risk for malignancy; immunosuppressive use recognized SLE manifestation. Serositis presents as abdominal contributes to this increased risk. pain, is usually associated with active disease, and improves with treatment. Mesenteric vasculitis, inflammation of the . Patients with systemic lupus erythematosus have a 2- to small and large bowel, pancreatitis, protein losing enteropa- 10 fold increased prevalence of coronary artery disease; thy, and diffuse peritonitis are uncommon but may be severe high SLE disease activity and prednisone dosages and associated with cutaneous vasculitis. greater than 10 mg/d are independent risk factors for Noninfectious hepatitis can occur and is associated with coronary artery disease. the presence of antiribosomal P antibodies. Patients with SLE who have Raynaud phenomenon and anti U1 ribonucleoprotein antibodies are at increased risk fbr esopha Diagnosis geal disease and reflux. General Considerations Medications used to treat SLE (NSAIDs, prednisone, The diagnosis of SLE should be considered in patients, espe mycophenolate, azathioprine) also frequently affect the gas- cially young women, with any individual manifestation of SLE trointestinal system and may cause esophagitis, gastritis, pan or with symptoms affecting multiple organ systems. The most creatitis, and other manifestations. common presenting clinical features that differentiate patients XEY PO Il{IS with SLE from those with other mimicking conditions include . The facial eruption of acute cutaneous lupus erythema- malar rash, photosensitivity, inflammatory arthritis, weight tosus (malar or butterfly rash) is characterized by ery loss, and fever, along with such laboratory features as positiv thema/edema over the chin, cheeks, and bridge of the ity lor ANA, low complement levels, and presence of lupus nose, sparing the nasolabial folds. specific antibodies. Patients with subjective reports of fatigue, r Many patients with systemic lupus erythematosus have myalgia, and/or arthralgia but lacking objective flndings most likely have an alternative diagnosis and should not be evalu arthralgia, and a much smaller group exhibits arthritis. ated for SLE. o A11 patients with systemic lupus erythematosus should Several classification criteria for SLE have been used; be regular$ evaluated for kidney involvement through although intended for recruitment of homogenous SLE popu- assessment of serum creatinine and urine for protein lations for research sfudies, they can also be used to suggest a and microscopic evaluation. clinical diagnosis ofSLE. A 2019 update ofthese criteria from . The most common manifestations of neuropsychiatric the European League Against Rheumatism/American College systemic lupus erythematosus are headache, mild cog- of Rheumatologr includes the requirement for a positive ANA nitive dysfunction, and mood disorder. result at least once, with the addition of clinical and/or immu- nologic criteria totaling at least 10 points on a weighted scale Comorbidities (Figure 33). These criteria compare favorably to prior pub Patients with SLE have a higher overall risk for malignancies Iished criteria, with a sensitivity of about 96% and specificity (particularly hematologic); the risk for non Hodgkin lym ofabout 93%. phoma is at least two to three times higher than in the general population. Malignancy risk in SLE is tied to the use of immu Laboratory Studies nosuppressive agents. Higher cumulative cyclophosphamide Initial evaluation for SLE includes routine laboratory test- doses are associated with increased risk for solid organ tumors, ing to establish organ specific involvement, including com and azathioprine use is associated with an increased risk for plete blood count, chemistry panel, and urinalysis with myeloproliferative syndromes. Cervical cancer is also increased microscopy. in patients with SLE, especially those receiving immunosup ANA should be obtained to screen for nuclear directed pressive therapies. Hydroxychloroquine use does not appear to autoantibodies. The most appropriate method for testing increase malignancy risk and may be protective. ANA is the indirect immunofluorescence assay, which is Patients with SLE have a 2- to 10 fold increased preva highly sensitive (>9s'l.) for SLE but not specific. ANA tests lence of coronary artery disease. It is the most common cause should be interpreted in the context of the probability of 46

Systemic Lupus Erythematosus Emry Grttetton Antinuclear antibody at a titer >1:80 on Hep-2 cells or equivalent positive test result lf absent do not classify as SLE lf present apply additive criteria Addldvr Ct{trria Do not count a criterion if there is a mora likely explanation than SLE, Occurrenca of a criterion on at least one occasion is sufficient SLE classification requires at least one clinical criterion and >10 points. Criteria need not occur simultaneously. Wrthin each domain, only the highest weighted criterion is counted toward the total score. (llnlcd Domrlnr end Crlterlr Wclglrt lmmunologlc Domdnr rnd Critorle Wdgh0 Gonrtltrtlonrl Fever (temparature >38.3 'C) 2 Anticardiolipin antibodi€s or Anti-pr-glycoprotein I antibodies or Lupus anticoagulant 2 H.m.tologlc Gmphmrntprctdm teukopenia (<4000/yL [4.0 x 1 0'lL]) 3 Low C3 or low C4 3 Thrombocytopenia (<1 00,000/pL [1 00 x 1 0'lL]) 4 Low Crl and low C4 4 Autoimmune hemolysis (with positive 4 direct antiglobulin test result) Nouroprydrlrtrlc SlErpeclfic endbodlor Delirium 2 Anti-dsDNA antibody or Psychosis (delusions and hallucinations in Anti6mith antibody 6 absence of delirium) 3 Seizure (primary generalized or focal seizure) 5

Nouroprydrlrtrlc SlErpeclfic endbodlor Delirium 2 Anti-dsDNA antibody or Psychosis (delusions and hallucinations in Anti6mith antibody 6 absence of delirium) 3 Seizure (primary generalized or focal seizure) 5 tlucocutrneout (obcorvcd by dlnlcien) Nonscarring alopecia 2 Oral ulcers 2 Subacute cutaneous or discoid lupus 4 Acute cutaneous lupus 6 !hrcrel Pleural or pericandial effusion 5 Acute pericarditis 6 Murculorkclctrl Joint involvement (synovitis in >2 joints or tendemess of >2 joints with >30 minutes of moming stiffness) 6 Ronel Proteinuria >0,5 g/24 h (or equivalent rpot urine protein-to-creatinine ratio) 4 Renal biopsy showing class ll or V lupus nephritis 8 Renal biopsy showing class lll or lV lupus nephritis 10 is fulfilled' Classifu as systemic lupus erythematosus with a score of 10 or more if entry criterion DNA; Hep-2 = human epithelial 2; 5LE = systemic lupus erythematosus' f I G U R E 3 3 . Classification criteria for systemic luPus erythematosus' dsDNA = dou ble*tranded 2019;78;I15i-1159. PMID: 3l383717 doi:10.1136/annrheumdis 20l8 214819 47

Systemic Lupus Erythematosus disease because ANA may be present in patients with other and objective abnormalities that cannot be categorized or autoimmune diseases as well as in healthy individuals. Low diagnosed as a specific connective tissue disease (see Mixed titer ANA (<1,80) is considered negative; even ANA at a more Connective Tissue Disease and Undifferentiated Connective positive titer in the absence ol specific features of SLE may be Tissue Disease). noninformative. Certain medications can cause drug induced lupus ery lf the ANA result is positive and the clinical context sup thematosus (DILE), which mimics SLE (Table 2o). The syn portive, SlE-specific autoantibodies (anti-double stranded drome is usually milder; malaise, fever, arthritis, and rash are DNA, anti Smith, anti Ul ribonucleoprotein, anti Ro/SSA, associated with transient positivity for ANA and antihistone and anti LalSSB), as well as tests for other autoimmune antibodies. Symptoms usually resolve after discontinuation of diseases under consideration. should be obtained to further the offending agent. Kidney and central nervous system dis characterize the disease (Table 19). ease are uncommon. Patients with SLE are at no more risk for Disease activity markers, including complements C3 DILE than the general population, and medications associated and C4, should be assessed initially and regularly thereaf with DILE are not contraindicated in patients with SLE. ter. Complement levels are typically reduced during SLE f,EY POIilTt activity, reflecting immune complex formation and com plement consumption. Rising titers of anti-double- . Patients with systemic lupus ery.thematosus typically stranded DNA antibody levels may be concordant with SLE initially present with skin and joint manifestations; kidney disease activity. Other SLE autoantibodies, includ- many also have fever or weight loss. ing ANA, do not reflect disease activity and need not be . Initial evaluation for systemic lupus erythematosus repeated. Erythrocyte sedimentation rate and C reactive includes antinuclear antibody testing as well as routine protein are variably associated with disease activity; laboratory testing to establish organ-specific involvement, some patients with SLE have little to no elevation in including complete blood count, chemistry panel, and C reactive protein during SLE flares, which may help dis urinalysis with microscopy. tinguish flares from infection once the individual patient's o Ifresults ofantinuclear antibody testing are positive pattern of responsiveness is established. and the clinical context is supportive, autoantibodies specific to systemic lupus erythematosus (anti-double- Differential Diagnosis stranded DNA, anti-Smith, anti-Ul-ribonucleoprotein, The differential diagnosis of SLE includes multisystem dis- anti-Ro/SSA, and anti-LaiSSB) should be obtained to eases, acute and chronic infections, medication effect, malig- further characterize the disease. nancies (particularly hematologic), and neurologic diseases (e.g., multiple sclerosis). Multisystem autoimmune diseases (ANCA associated vasculitis, rheumatoid arthritis, adult-onset Still disease, dermatomyositis, Sjogren syndrome, and mixed Management connective tissue disease) have overlapping features but may SLE most often follows a relapsing remitting pattem (ZO'7,) be distinguished through a careful assessment oftheir unique with periods of inactive disease, although some patients may manifestations. have a monophasic or persistently active pattern. The most SLE should also be distinguished from undifferentiated commonly used instrument for monitoring disease activity is connective tissue disease, which presents with milder slmptoms the SLE Disease Activity Index (SLEDAI), which incorporates

disease because ANA may be present in patients with other and objective abnormalities that cannot be categorized or autoimmune diseases as well as in healthy individuals. Low diagnosed as a specific connective tissue disease (see Mixed titer ANA (<1,80) is considered negative; even ANA at a more Connective Tissue Disease and Undifferentiated Connective positive titer in the absence ol specific features of SLE may be Tissue Disease). noninformative. Certain medications can cause drug induced lupus ery lf the ANA result is positive and the clinical context sup thematosus (DILE), which mimics SLE (Table 2o). The syn portive, SlE-specific autoantibodies (anti-double stranded drome is usually milder; malaise, fever, arthritis, and rash are DNA, anti Smith, anti Ul ribonucleoprotein, anti Ro/SSA, associated with transient positivity for ANA and antihistone and anti LalSSB), as well as tests for other autoimmune antibodies. Symptoms usually resolve after discontinuation of diseases under consideration. should be obtained to further the offending agent. Kidney and central nervous system dis characterize the disease (Table 19). ease are uncommon. Patients with SLE are at no more risk for Disease activity markers, including complements C3 DILE than the general population, and medications associated and C4, should be assessed initially and regularly thereaf with DILE are not contraindicated in patients with SLE. ter. Complement levels are typically reduced during SLE f,EY POIilTt activity, reflecting immune complex formation and com plement consumption. Rising titers of anti-double- . Patients with systemic lupus ery.thematosus typically stranded DNA antibody levels may be concordant with SLE initially present with skin and joint manifestations; kidney disease activity. Other SLE autoantibodies, includ- many also have fever or weight loss. ing ANA, do not reflect disease activity and need not be . Initial evaluation for systemic lupus erythematosus repeated. Erythrocyte sedimentation rate and C reactive includes antinuclear antibody testing as well as routine protein are variably associated with disease activity; laboratory testing to establish organ-specific involvement, some patients with SLE have little to no elevation in including complete blood count, chemistry panel, and C reactive protein during SLE flares, which may help dis urinalysis with microscopy. tinguish flares from infection once the individual patient's o Ifresults ofantinuclear antibody testing are positive pattern of responsiveness is established. and the clinical context is supportive, autoantibodies specific to systemic lupus erythematosus (anti-double- Differential Diagnosis stranded DNA, anti-Smith, anti-Ul-ribonucleoprotein, The differential diagnosis of SLE includes multisystem dis- anti-Ro/SSA, and anti-LaiSSB) should be obtained to eases, acute and chronic infections, medication effect, malig- further characterize the disease. nancies (particularly hematologic), and neurologic diseases (e.g., multiple sclerosis). Multisystem autoimmune diseases (ANCA associated vasculitis, rheumatoid arthritis, adult-onset Still disease, dermatomyositis, Sjogren syndrome, and mixed Management connective tissue disease) have overlapping features but may SLE most often follows a relapsing remitting pattem (ZO'7,) be distinguished through a careful assessment oftheir unique with periods of inactive disease, although some patients may manifestations. have a monophasic or persistently active pattern. The most SLE should also be distinguished from undifferentiated commonly used instrument for monitoring disease activity is connective tissue disease, which presents with milder slmptoms the SLE Disease Activity Index (SLEDAI), which incorporates TABLE 1*. Common Autoantibodies in Systemic Lupus Erythematosus Autoantibody Frequenry in SLE Comments Antinuclear >95"/o Useful as an initial screening test; assesses multiple antigens simultaneously Anti-double-stranded DNA 50"/"-60"/" Found in more severe disease, especially kidney disease; antibody levels commonly {ollow disease activity and are useful to monitor Anti-Ro/SSA 30% Associated with photosensitive rashes, discoid lupus erythematosus, and neonatal lupus erythematosus; also common when secondary Sjogren syndrome is present Anti-U I -ribonucleoprotein 35% as.sgTrled with Raynaud phenomenon and esophageal dysmotility; also seen in MCTD : Anti-Smith 30% Specific for SLE; often associated with more severe disease Anti LalSSB 20% Common in Sjogren syndrome; less common in SLE and neonatal lupus erythematosus Antiribosomal P 150/" Associated with CNS lupus and lupus hepatitis CNS = central nervous system; MCTD = mixed connective tissue disease; SLE = systemic lupus e rlthematosus.

TABLE 1*. Common Autoantibodies in Systemic Lupus Erythematosus Autoantibody Frequenry in SLE Comments Antinuclear >95"/o Useful as an initial screening test; assesses multiple antigens simultaneously Anti-double-stranded DNA 50"/"-60"/" Found in more severe disease, especially kidney disease; antibody levels commonly {ollow disease activity and are useful to monitor Anti-Ro/SSA 30% Associated with photosensitive rashes, discoid lupus erythematosus, and neonatal lupus erythematosus; also common when secondary Sjogren syndrome is present Anti-U I -ribonucleoprotein 35% as.sgTrled with Raynaud phenomenon and esophageal dysmotility; also seen in MCTD : Anti-Smith 30% Specific for SLE; often associated with more severe disease Anti LalSSB 20% Common in Sjogren syndrome; less common in SLE and neonatal lupus erythematosus Antiribosomal P 150/" Associated with CNS lupus and lupus hepatitis CNS = central nervous system; MCTD = mixed connective tissue disease; SLE = systemic lupus e rlthematosus. 48

Systemic Lupus Erythematosus TABLE 20. Medications Commonly Associated With Drug-lnduced Lupus Erythematosus Medication Antibodies Detected Comments Procainamide ANA(75%); antihistone 207o develop DILE; fever; arthritis; serositis Hyd ralazine ANA(20%); antihistone 5%-B% develop DILE; fever; arthritis; rare vasculitis and kidney disease Minocycline ANA; ANCA; anti-dsDNA rare Arthritis; vasculitis; autoimmune hepatitis Antithyroid drugs ANA; ANCA; antihistone Vasculitic rash; rare pulmonary and kidney disease Statins ANA; antihistone; anti-dsDNA SLE, SCLE, dermatomyositis, and polymyositis all reported Calcium channel blockers ANA; anti-Ro/SSA; antihistone rare SCLE Thiazide diuretics ANA; anti-Ro/SSA; antihistone rare SCLE ACE inhibitors ANA; anti-Ro/SSA; antihistone rare SCLE TNF inhibitors ANA (23%-57%); chromatin and anti DILE most common with in{liximab, uncommon for dsDNA common; antihistone rare etanercept; SLE, SCLE, DLE all reported ANA = antinuclear antibodies; DILE = drug induced lupus erghematosus; DLE = discoid lupus erythematosus; dsDNA = double stranded DNA; SCLE = subacute cutaneous lupus erythematosus; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor.

TNF inhibitors ANA (23%-57%); chromatin and anti DILE most common with in{liximab, uncommon for dsDNA common; antihistone rare etanercept; SLE, SCLE, DLE all reported ANA = antinuclear antibodies; DILE = drug induced lupus erghematosus; DLE = discoid lupus erythematosus; dsDNA = double stranded DNA; SCLE = subacute cutaneous lupus erythematosus; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor. both clinical and laboratory measures. Clinical remission or (especially skin and joints) and in combination with other low disease activity are typical goals of therapy. agents in severe disease. Pharmacologic therapy is almost always required; the Glucocorticoids are also used in most patients with SLE, choice of agents should reflect disease activity and specific particularly in acute disease. The glucocorticoid dose should be organ involvement. Management requires frequent disease determined by the level of disease activity and organ systems assessment and adjustment of treatment to reflect changing threatened. For severe disease actMty (including profound cyto- conditions (Table 21). penia, class III/IV nephritis, and NPSLE), high-dose glucocorti Hydroxychloroquine is a mainstay of treatment in SLE coids are recommended. For life- or organ-threatening disease because it reduces disease-associated damage, prevents dis (such as rapidly progressive glomerulonephritis or seizures), ease flares, and improves kidney and overall survival. In addi high dose intravenous glucocorticoids are given, typically fol tion, hydroxychloroquine may reduce the risk for thrombosis, lowed by daily oral glucocorticoids. After disease stability is liver disease, and myocardial infarction; improve lipid pro- achieved, glucocorticoids are tapered to the lowest effective dos files; and improve outcomes in high-risk pregnancies. Almost age, preferably to no more than 7.5 mg/d within 4 to 6 months. all patients with SLE without contraindications should receive Literature supports limiting exposure to glucocorticoids, espe hydroxychloroquine. With very rare exceptions the dosage cially at high doses, because ofassociated risk for organ damage, should be limited to 5 mg/kg/d or less, and patients should infection, and premature mortality Glucocorticoids should be receive annual monitoring by an ophthalmologist after 5 years discontinued entirely when possible. of treatment to reduce the risk for retinal toxicity. For moderate or severe disease, immunosuppressive ther- Hydroxychloroquine can be used alone for mild disease apy should be initiated concurrently with glucocorticoids to

both clinical and laboratory measures. Clinical remission or (especially skin and joints) and in combination with other low disease activity are typical goals of therapy. agents in severe disease. Pharmacologic therapy is almost always required; the Glucocorticoids are also used in most patients with SLE, choice of agents should reflect disease activity and specific particularly in acute disease. The glucocorticoid dose should be organ involvement. Management requires frequent disease determined by the level of disease activity and organ systems assessment and adjustment of treatment to reflect changing threatened. For severe disease actMty (including profound cyto- conditions (Table 21). penia, class III/IV nephritis, and NPSLE), high-dose glucocorti Hydroxychloroquine is a mainstay of treatment in SLE coids are recommended. For life- or organ-threatening disease because it reduces disease-associated damage, prevents dis (such as rapidly progressive glomerulonephritis or seizures), ease flares, and improves kidney and overall survival. In addi high dose intravenous glucocorticoids are given, typically fol tion, hydroxychloroquine may reduce the risk for thrombosis, lowed by daily oral glucocorticoids. After disease stability is liver disease, and myocardial infarction; improve lipid pro- achieved, glucocorticoids are tapered to the lowest effective dos files; and improve outcomes in high-risk pregnancies. Almost age, preferably to no more than 7.5 mg/d within 4 to 6 months. all patients with SLE without contraindications should receive Literature supports limiting exposure to glucocorticoids, espe hydroxychloroquine. With very rare exceptions the dosage cially at high doses, because ofassociated risk for organ damage, should be limited to 5 mg/kg/d or less, and patients should infection, and premature mortality Glucocorticoids should be receive annual monitoring by an ophthalmologist after 5 years discontinued entirely when possible. of treatment to reduce the risk for retinal toxicity. For moderate or severe disease, immunosuppressive ther- Hydroxychloroquine can be used alone for mild disease apy should be initiated concurrently with glucocorticoids to TABLE 21 . Medications Commonly Used to Treat Systemic Lupus Erythematosus Medication Common Uses in SLE lmportant Adverse Effects NSAIDs Arthritis; pain; fever Hypertension; Gl bleeding; AKI Prednisone Used for all manifestations in varying doses Hypertension; glucose intolerance; weight gain; i nfection; osteonecrosis Hydroxychloroquine Used in almost all patients without contraindications; Gl intolerance; rash; blurry vision; retinopathy; especially useful{or skin involvement and to prevent vacuolar myopathy disease flares Mycophenolate mofetil Moderate to severe disease; as effective as Bone marrow suppression; elevation of liver cyclophosphamide for remission induction for nephritis enzymes; infection Azathioprine Moderate to severe disease Bone marrow suppression; elevation of liver enzymes; hematologic malignancy Cyclophosphamide Severe organ- or life-threatening disease Bone marrow suppression; hemorrhagic cystitis; i nfection ; ma g na ncy; i nferti ity Ii I

TABLE 21 . Medications Commonly Used to Treat Systemic Lupus Erythematosus Medication Common Uses in SLE lmportant Adverse Effects NSAIDs Arthritis; pain; fever Hypertension; Gl bleeding; AKI Prednisone Used for all manifestations in varying doses Hypertension; glucose intolerance; weight gain; i nfection; osteonecrosis Hydroxychloroquine Used in almost all patients without contraindications; Gl intolerance; rash; blurry vision; retinopathy; especially useful{or skin involvement and to prevent vacuolar myopathy disease flares Mycophenolate mofetil Moderate to severe disease; as effective as Bone marrow suppression; elevation of liver cyclophosphamide for remission induction for nephritis enzymes; infection Azathioprine Moderate to severe disease Bone marrow suppression; elevation of liver enzymes; hematologic malignancy Cyclophosphamide Severe organ- or life-threatening disease Bone marrow suppression; hemorrhagic cystitis; i nfection ; ma g na ncy; i nferti ity Ii I Belimumab Add-on therapy for moderate to severe disease lnfusion reactions; infections AKI = acute kidney injury; Gl = gastrointestinal; SLE = systemic lupus erythematosus. 49

Systemic Lupus Erythematosus achieve and maintain disease control and to allow tapering of Pregnancy and Childbirth lssues glucocorticoids. The choice of medication should be deter- SLE is associated with a five to eightfold increase in miscar- mined by the organs involved and disease severity. Intravenous riage, stillbirth, premature delivery and intrauterine growth cyclophosphamide is used as induction therapy for severe or retardation. Outcomes are worse in patients with active dis refractory disease (e.g., severe active nephritis, acute central ease, nephritis, or anti-Ro/SSA and/or antiphospholipid anti- nervous system lupus, diffuse alveolar hemorrhage, or myo- bodies. The best time to consider pregnancy is when SLE is carditis), followed by maintenance therapy with mycopheno quiescent, and conception should be planned after at least late mofetil or azathioprine. Mycophenolate mofetil is the 6 months ofadequate disease control. preferred oral agent for lupus nephritis and is as effective as Proteinuria may increase during pregnancy in patients cyclophosphamide for induction therapy. The biologic agent with SLE, making the distinction betlveen SLE and pre- belimumab is FDA approved for patients with incomplete eclampsia a challenge. Increases in anti-double stranded response to conventional treatments and is useful for skin/ joint involvement and moderate/severe disease. Experience DNA antibody titers, decreasing complement levels, or the development of active urine sediment suggests SLE as the suggests a possible benefit as add on therapy for more severe cause. In contrast. serum urate levels are increased in organ involvement. preeclampsia but not during SLE flares. Less commonly used medications include quinacrine, Fetuses of women who have anti-Ro/SSA or anti LalSSB methotrexate, leflunomide, calcineurin inhibitors, and antibodies are at risk for neonatal lupus ery.thematosus, which rituximab. Other agents under investigation include pro is characterized by rash and congenital heart block. Although teasome inhibitors, Janus kinase inhibitors, interleukin 12 the risk for congenital heart block in the offspring ofan anti and interleukin-23 inhibitors, and other B cell-acting Ro/SSA positive woman is only 2'7,, this condition is associ agents. ated with significant fetal and neonatal morbidity and Adjunctive agents may be used for specific clinical fea mortality. After a woman bears a child with neonatal lupus tures. NSAIDs can be used to treat arthritis and pleuropericar erythematosus, the risk for congenital heart block is ditis but are not disease modi[zing and may adversely affect substantially increased (20%) in subsequent pregnancies. kidney function and blood pressure. Statins and antihyper- Hydroxychloroquine may reduce the overall risk. Women with tensive agents are often used to reduce cardiovascular risks. SLE who have concurrent antiphospholipid syndrome are at ACE inhibitors should be considered in patients with pro- increased risk lor miscarriage. teinuria. Adequate vitamin D intake is important in patients Management of medications during SLE pregnancy is with SLE. Bone health should be monitored, with treatment complicated. Hydroxychloroquine and low dose glucocorti- for appropriate patients, especially those receiving glucocor coids can be started during or continued throughout the preg ticoids. Sun avoidance and regular use of sunscreen that nancy. Higher dose glucocorticoids can be used to treat blocks both UV-A and UV B should be recommended for all patients with SLE. flare ups or end-organ involvement. The preferred immuno suppressive agent for SLE during pregnancy is azathioprine, See Principles of Therapeutics for information on SLE but this drug should be used only if necessary. Belimumab, medication toxicities, monitoring parameters, and more. See methotrexate, mycophenolate mofetil, and cyclophosphamide MKSAP 19 Nephrologr for details on the treatment of lupus should be avoided because of risks for teratogenic effects. nephritis. Cyclophosphamide is associated with age and dose dependent XTY POIf,TS infertility. See Principles of Therapeutics for information on HVC o Almost all patients with systemic lupus erythematosus medications and pregnancy. without contraindications should receive hydroxychlo- XEY POIilIS roquine because it can reduce disease-associated dam- age, prevent disease flares, and improve kidney and . Systemic lupus erythematosus is associated with a five- overall survival. to eightfold increase in miscarriage, stillbirth, premature o Glucocorticoids are used in most patients with systemic delivery and intrauterine growth retardation. lupus erythematosus, particularly in acute disease; after o The best time to consider pregnancy is when systemic disease stability is achieved, glucocorticoids should be lupus erythematosus is quiescent, and conception tapered to the lowest effective dose, ideally to discontin- should be planned only after at least 6 months of ade- uation. quate disease control. . For moderate or severe systemic lupus erythematosus, o Fetuses of women who have anti-Ro/SSA or anti-La/SSB immunosuppressive therapy should be initiated antibodies are at risk for neonatal lupus erlrthematosus (rash and congenital heart block). 'l concurrently with glucocorticoids to achieve and maintain disease control and to allow tapering of . Hydroxychloroquine and low-dose glucocorticoids can glucocorticoids. be started during or continued throughout preg-nancy.

achieve and maintain disease control and to allow tapering of Pregnancy and Childbirth lssues glucocorticoids. The choice of medication should be deter- SLE is associated with a five to eightfold increase in miscar- mined by the organs involved and disease severity. Intravenous riage, stillbirth, premature delivery and intrauterine growth cyclophosphamide is used as induction therapy for severe or retardation. Outcomes are worse in patients with active dis refractory disease (e.g., severe active nephritis, acute central ease, nephritis, or anti-Ro/SSA and/or antiphospholipid anti- nervous system lupus, diffuse alveolar hemorrhage, or myo- bodies. The best time to consider pregnancy is when SLE is carditis), followed by maintenance therapy with mycopheno quiescent, and conception should be planned after at least late mofetil or azathioprine. Mycophenolate mofetil is the 6 months ofadequate disease control. preferred oral agent for lupus nephritis and is as effective as Proteinuria may increase during pregnancy in patients cyclophosphamide for induction therapy. The biologic agent with SLE, making the distinction betlveen SLE and pre- belimumab is FDA approved for patients with incomplete eclampsia a challenge. Increases in anti-double stranded response to conventional treatments and is useful for skin/ joint involvement and moderate/severe disease. Experience DNA antibody titers, decreasing complement levels, or the development of active urine sediment suggests SLE as the suggests a possible benefit as add on therapy for more severe cause. In contrast. serum urate levels are increased in organ involvement. preeclampsia but not during SLE flares. Less commonly used medications include quinacrine, Fetuses of women who have anti-Ro/SSA or anti LalSSB methotrexate, leflunomide, calcineurin inhibitors, and antibodies are at risk for neonatal lupus ery.thematosus, which rituximab. Other agents under investigation include pro is characterized by rash and congenital heart block. Although teasome inhibitors, Janus kinase inhibitors, interleukin 12 the risk for congenital heart block in the offspring ofan anti and interleukin-23 inhibitors, and other B cell-acting Ro/SSA positive woman is only 2'7,, this condition is associ agents. ated with significant fetal and neonatal morbidity and Adjunctive agents may be used for specific clinical fea mortality. After a woman bears a child with neonatal lupus tures. NSAIDs can be used to treat arthritis and pleuropericar erythematosus, the risk for congenital heart block is ditis but are not disease modi[zing and may adversely affect substantially increased (20%) in subsequent pregnancies. kidney function and blood pressure. Statins and antihyper- Hydroxychloroquine may reduce the overall risk. Women with tensive agents are often used to reduce cardiovascular risks. SLE who have concurrent antiphospholipid syndrome are at ACE inhibitors should be considered in patients with pro- increased risk lor miscarriage. teinuria. Adequate vitamin D intake is important in patients Management of medications during SLE pregnancy is with SLE. Bone health should be monitored, with treatment complicated. Hydroxychloroquine and low dose glucocorti- for appropriate patients, especially those receiving glucocor coids can be started during or continued throughout the preg ticoids. Sun avoidance and regular use of sunscreen that nancy. Higher dose glucocorticoids can be used to treat blocks both UV-A and UV B should be recommended for all patients with SLE. flare ups or end-organ involvement. The preferred immuno suppressive agent for SLE during pregnancy is azathioprine, See Principles of Therapeutics for information on SLE but this drug should be used only if necessary. Belimumab, medication toxicities, monitoring parameters, and more. See methotrexate, mycophenolate mofetil, and cyclophosphamide MKSAP 19 Nephrologr for details on the treatment of lupus should be avoided because of risks for teratogenic effects. nephritis. Cyclophosphamide is associated with age and dose dependent XTY POIf,TS infertility. See Principles of Therapeutics for information on HVC o Almost all patients with systemic lupus erythematosus medications and pregnancy. without contraindications should receive hydroxychlo- XEY POIilIS roquine because it can reduce disease-associated dam- age, prevent disease flares, and improve kidney and . Systemic lupus erythematosus is associated with a five- overall survival. to eightfold increase in miscarriage, stillbirth, premature o Glucocorticoids are used in most patients with systemic delivery and intrauterine growth retardation. lupus erythematosus, particularly in acute disease; after o The best time to consider pregnancy is when systemic disease stability is achieved, glucocorticoids should be lupus erythematosus is quiescent, and conception tapered to the lowest effective dose, ideally to discontin- should be planned only after at least 6 months of ade- uation. quate disease control. . For moderate or severe systemic lupus erythematosus, o Fetuses of women who have anti-Ro/SSA or anti-La/SSB immunosuppressive therapy should be initiated antibodies are at risk for neonatal lupus erlrthematosus (rash and congenital heart block). 'l concurrently with glucocorticoids to achieve and maintain disease control and to allow tapering of . Hydroxychloroquine and low-dose glucocorticoids can glucocorticoids. be started during or continued throughout preg-nancy. 50

Sjiigren Syndrome Prognosis TABLE 22. Extraglandular Clinical Manifestations of Sjcigren Syndrome The prognosis in SLE has improved significantly. The 5 year survival rate is 90u1,, although mortality remains high com Site/Organ Manifestation/Frequency pared to that in age-matched controls. Early mortali[z is usu General Fatigue (70%), fever (6%) ally related to SLE disease and infections, and late mortality is S kin Dry skin (xerosis), cutaneous vasculitis: related to cardiovascular disease. Factors adversely affecting 10o/"-1 67" ; survival include myocarditis, nephritis, low socioeconomic Joint Arthralgia/arthritis: 36% status, male sex, and age older than 50 years at diagnosis. Lung lnterstitial pneumonitis: 5%-9% I(EY POIilI Kidney lnterstitial nephritis, type 1 (hypokalemic distal) renal tubular acidosis, . Factors adversely affecting survival in systemic lupus glomeru loneph rilis: 57o- 60/" erythematosus include myocarditis, nephritis, low soci- Neurologic CNS: demyelinating disease, myelopathy, oeconomic status, male sex, and age older than 50 years cranial nerve neuropathy at diagnosis. Peripheral nervous system: small-fiber neuropathy, mononeuritis multiplex, peripheral neuropathy 8o/"-27"/ofor CNS and peripheral nervous

Prognosis TABLE 22. Extraglandular Clinical Manifestations of Sjcigren Syndrome The prognosis in SLE has improved significantly. The 5 year survival rate is 90u1,, although mortality remains high com Site/Organ Manifestation/Frequency pared to that in age-matched controls. Early mortali[z is usu General Fatigue (70%), fever (6%) ally related to SLE disease and infections, and late mortality is S kin Dry skin (xerosis), cutaneous vasculitis: related to cardiovascular disease. Factors adversely affecting 10o/"-1 67" ; survival include myocarditis, nephritis, low socioeconomic Joint Arthralgia/arthritis: 36% status, male sex, and age older than 50 years at diagnosis. Lung lnterstitial pneumonitis: 5%-9% I(EY POIilI Kidney lnterstitial nephritis, type 1 (hypokalemic distal) renal tubular acidosis, . Factors adversely affecting survival in systemic lupus glomeru loneph rilis: 57o- 60/" erythematosus include myocarditis, nephritis, low soci- Neurologic CNS: demyelinating disease, myelopathy, oeconomic status, male sex, and age older than 50 years cranial nerve neuropathy at diagnosis. Peripheral nervous system: small-fiber neuropathy, mononeuritis multiplex, peripheral neuropathy 8o/"-27"/ofor CNS and peripheral nervous Sjtigren Syndrome Gastrointestina I system

Prognosis TABLE 22. Extraglandular Clinical Manifestations of Sjcigren Syndrome The prognosis in SLE has improved significantly. The 5 year survival rate is 90u1,, although mortality remains high com Site/Organ Manifestation/Frequency pared to that in age-matched controls. Early mortali[z is usu General Fatigue (70%), fever (6%) ally related to SLE disease and infections, and late mortality is S kin Dry skin (xerosis), cutaneous vasculitis: related to cardiovascular disease. Factors adversely affecting 10o/"-1 67" ; survival include myocarditis, nephritis, low socioeconomic Joint Arthralgia/arthritis: 36% status, male sex, and age older than 50 years at diagnosis. Lung lnterstitial pneumonitis: 5%-9% I(EY POIilI Kidney lnterstitial nephritis, type 1 (hypokalemic distal) renal tubular acidosis, . Factors adversely affecting survival in systemic lupus glomeru loneph rilis: 57o- 60/" erythematosus include myocarditis, nephritis, low soci- Neurologic CNS: demyelinating disease, myelopathy, oeconomic status, male sex, and age older than 50 years cranial nerve neuropathy at diagnosis. Peripheral nervous system: small-fiber neuropathy, mononeuritis multiplex, peripheral neuropathy 8o/"-27"/ofor CNS and peripheral nervous Sjtigren Syndrome Gastrointestina I system Autoimmune hepatitis, primary biliary cirrhosis: 3"/o-207" Epidemiology and Hematologic Lym p homa, cytope ni a : 27o Pathophysiology Other Systemic vasculitis (7%), cryoglobulinemia Sjogren syndrome is a systemic autoimmune exocrinopathy (4o/"- 1 2o/"), Rayna ud phe nomenon ( 1 6%),

Autoimmune hepatitis, primary biliary cirrhosis: 3"/o-207" Epidemiology and Hematologic Lym p homa, cytope ni a : 27o Pathophysiology Other Systemic vasculitis (7%), cryoglobulinemia Sjogren syndrome is a systemic autoimmune exocrinopathy (4o/"- 1 2o/"), Rayna ud phe nomenon ( 1 6%), primarily affecting salivary and lacrimal glands. The condition thyroid d isease (1 0"/"- 1 5"/") is female predominant, with a female-to-male ratio between 6 CNS = central nervous system- and 9 to 1. Sjogren syndrome most commonly presents in the fifth and sixth decades of life, but patients of any age may be affected; a pediatric variant is also recognized. Primary SjOgren include fatigue and Raynaud phenomenon. Both peripheral syndrome occurs in isolation; secondary Sjogren syndrome and central nervous system involvement may be seen, although develops with other rheumatologic diseases, most commonly the former is more common. The typical peripheral nervous rheumatoid arthritis and systemic Iupus erythematosus. system manifestation is axonal polyneuropathy. Central nerv Whereas the primary form is uncommon (ranging from 0.5 ous system involvement often presents as demyelinating dis to 5 patients/l0O0), secondary Sjdgren syndrome is often ease, such as optic neuritis, transverse myelitis, or a multiple observed (10%-30%) among populations with predisposing sclerosis-like presentation. Cutaneous, pulmonary and kid rheumatologic conditions. Sjdgren syndrome is thought to ney disease are relatively rare. Nonspecific laboratory findings result from activation of mucosal epithelial cells by unknown include hypocomplementemia, hypergammaglobulinemia, stimuli. This, in turn, leads to tonic activation of the innate and leukopenia, and anemia of inflammation. adaptive immune systems, including extensive influx of lym Patients with Sjogren syndrome are at increased risk for I phocytes into exocrine glands. The resulting epithelial and non Hodgkin lymphoma compared with the general popula obliterative damage impairs the ability to produce or deliver tion. Estimates suggest as much as a 44 fold increased risk fbr secretions. mucosal associated lymphoid tissue lymphoma; this increase presumably results from an elevated risk for lymphomatous transformation due to chronic activation of tissue lympho- Cli nica I Manifestations cytes. Clinical features conferring a higher risk include lym The most common presentation of Sjdgren syndrome is sicca, phadenopathy, recurrent parotid gland swelling, monoclonal I consisting of ocular and oral dryness. Patients report gritty gammopathy, depressed C4 complement, and decreased rheu matoid factor if titer is elevated at baseline. About 5'7, of .

primarily affecting salivary and lacrimal glands. The condition thyroid d isease (1 0"/"- 1 5"/") is female predominant, with a female-to-male ratio between 6 CNS = central nervous system- and 9 to 1. Sjogren syndrome most commonly presents in the fifth and sixth decades of life, but patients of any age may be affected; a pediatric variant is also recognized. Primary SjOgren include fatigue and Raynaud phenomenon. Both peripheral syndrome occurs in isolation; secondary Sjogren syndrome and central nervous system involvement may be seen, although develops with other rheumatologic diseases, most commonly the former is more common. The typical peripheral nervous rheumatoid arthritis and systemic Iupus erythematosus. system manifestation is axonal polyneuropathy. Central nerv Whereas the primary form is uncommon (ranging from 0.5 ous system involvement often presents as demyelinating dis to 5 patients/l0O0), secondary Sjdgren syndrome is often ease, such as optic neuritis, transverse myelitis, or a multiple observed (10%-30%) among populations with predisposing sclerosis-like presentation. Cutaneous, pulmonary and kid rheumatologic conditions. Sjdgren syndrome is thought to ney disease are relatively rare. Nonspecific laboratory findings result from activation of mucosal epithelial cells by unknown include hypocomplementemia, hypergammaglobulinemia, stimuli. This, in turn, leads to tonic activation of the innate and leukopenia, and anemia of inflammation. adaptive immune systems, including extensive influx of lym Patients with Sjogren syndrome are at increased risk for I phocytes into exocrine glands. The resulting epithelial and non Hodgkin lymphoma compared with the general popula obliterative damage impairs the ability to produce or deliver tion. Estimates suggest as much as a 44 fold increased risk fbr secretions. mucosal associated lymphoid tissue lymphoma; this increase presumably results from an elevated risk for lymphomatous transformation due to chronic activation of tissue lympho- Cli nica I Manifestations cytes. Clinical features conferring a higher risk include lym The most common presentation of Sjdgren syndrome is sicca, phadenopathy, recurrent parotid gland swelling, monoclonal I consisting of ocular and oral dryness. Patients report gritty gammopathy, depressed C4 complement, and decreased rheu matoid factor if titer is elevated at baseline. About 5'7, of . eyes or a foreign body sensation. Oral dryness can cause diffi i culty eating unmoistened food and increases the risk for den patients with Sjdgren syndrome develop lymphoma over time, tal caries. Symmetric parotid and lacrimal swelling can occur. usually within the first decade after diagnosis. Other exocrine glands can be involved, leading to skin and vaginal dryness. Pancreatic involvement has been reported. Diagnosis I

eyes or a foreign body sensation. Oral dryness can cause diffi i culty eating unmoistened food and increases the risk for den patients with Sjdgren syndrome develop lymphoma over time, tal caries. Symmetric parotid and lacrimal swelling can occur. usually within the first decade after diagnosis. Other exocrine glands can be involved, leading to skin and vaginal dryness. Pancreatic involvement has been reported. Diagnosis I Extraglandular manilestations may occur in some patients (Table 22). Arthralgia and fibromyalgia are common, An evaluation for Sjogren syndrome is typically triggered but nonerosive arthritis in the absence of rheumatoid arthritis when the patient reports symptoms of ocular or oral dryness. is uncommon. Other common extraglandular manifestations It requires objective confirmation of exocrinopathy along with 51