InternalMed_Harrison

InternalMed_Harrison. ThediagnosisofSLEisbasedoncharacteristicclinicalfeaturesandautoantibodies. Current criteria for classification are listed in Table 378-3, and an algorithm for diagnosis and initial therapy is shown in Fig. 378-2. The criteria are intended for confirming the diagnosis of SLE in patients included in studies; the author uses them in individual patients for estimating the probability that a disease is SLE. Any combination of four or more criteria, with at least one in the clinical and one in the immunologic category, well documented at any time during an individual’s history, makes it likely that the patient has SLE. (Specificity and sensitivity are ~93% and ~92%, respectively.) In many patients, criteria accrue over time. Antinuclear antibodies (ANA) are positive in >98% of patients during the course of disease; repeated negative tests by immunofluorescent methods suggest that the diagnosis is not SLE, unless other autoantibodies are present (Fig. 378-2). High-titer IgG antibodies to


InternalMed_Harrison

InternalMed_Harrison. the course of disease; repeated negative tests by immunofluorescent methods suggest that the diagnosis is not SLE, unless other autoantibodies are present (Fig. 378-2). High-titer IgG antibodies to double-stranded DNA and antibodies to the Sm antigen are both specific for SLE and, therefore, favor the diagnosis in the presence of compatible clinical manifestations. The


InternalMed_Harrison

InternalMed_Harrison. Class I: Minimal Mesangial Lupus Nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence. Class II: Mesangial Proliferative Lupus Nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits. A few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron microscopy, but not by light microscopy. Class III: Focal Lupus Nephritis Active or inactive focal, segmental or global endo-or extracapillary glomerulonephritis involving ≤50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations. Class III (A): Active lesions—focal proliferative lupus nephritis Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing lupus nephritis Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing lupus nephritis


InternalMed_Harrison

InternalMed_Harrison. Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing lupus nephritis Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing lupus nephritis Class IV: Diffuse Lupus Nephritis Active or inactive diffuse, segmental or global endo-or extracapillary glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than one-half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation. Class IV-S (A): Active lesions—diffuse segmental proliferative lupus nephritis


InternalMed_Harrison

InternalMed_Harrison. Class IV-S (A): Active lesions—diffuse segmental proliferative lupus nephritis Class IV-G (A): Active lesions—diffuse global proliferative lupus nephritis Class IV-S (A/C): Active and chronic lesions—diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C): Active and chronic lesions—diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C): Chronic inactive lesions with scars—diffuse segmental sclerosing lupus nephritis Class IV-G (C): Chronic inactive lesions with scars—diffuse global sclerosing lupus nephritis Class V: Membranous Lupus Nephritis Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations. Class V lupus nephritis may occur in combination with class III or IV, in which case both will be diagnosed. Class V lupus nephritis may show advanced sclerosis.


InternalMed_Harrison

InternalMed_Harrison. Class VI: Advanced Sclerotic Lupus Nephritis ≥90% of glomeruli globally sclerosed without residual activity. Note: Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, and severity of arteriosclerosis or other vascular lesions. Source: JJ Weening et al: Kidney Int 65:521, 2004. Reprinted by permission from Macmillan Publishers Ltd., Copyright 2004. presence in an individual of multiple autoantibodies without clinical symptoms should not be considered diagnostic for SLE, although such persons are at increased risk. When a diagnosis of SLE is made, it is important to establish the severity and potential reversibility of the illness and to estimate the possible consequences of various therapeutic interventions. In the following paragraphs, descriptions of some disease manifestations begin with relatively mild problems and progress to those more life-threatening.


InternalMed_Harrison

InternalMed_Harrison. At its onset, SLE may involve one or several organ systems; over time, additional manifestations may occur (Tables 378-3 and 378-4). Most of the autoantibodies characteristic of each person are present at the time clinical manifestations appear (Tables 378-1 and 378-3). Severity aRenal biopsy read as systemic lupus qualifies for classification as SLE even if none of the other above features are present. Interpretation: Presence of any 4 criteria (must have at least 1 in each category) qualifies patient to be classified as having SLE with 93% specificity and 92% sensitivity. Abbreviations: ANA, antinuclear antibody; Cr, creatinine; LE, lupus erythematosus; Prot, protein. Source: M Petri et al: Arthritis Rheum 64:2677, 2012. Because these criteria are new, currently ongoing clinical studies use prior American College of Rheumatology Criteria; see EM Tan et al: Arthritis Rheum 25:1271, 1982; update MC Hochberg: Arthritis Rheum 40:1725, 1997.


InternalMed_Harrison

InternalMed_Harrison. of SLE varies from mild and intermittent to severe and fulminant. Approximately 85% of patients have either continuing active disease (while being treated) or one or more flares of active disease annually. Permanent complete remissions (absence of symptoms with no treatment) are rare. Systemic symptoms, particularly fatigue and myalgias/ arthralgias, arepresentmostofthetime.Severesystemic illnessrequiring glucocorticoid therapy can occur with fever, prostration, weight loss, and anemia with or without other organ-targeted manifestations.


InternalMed_Harrison

InternalMed_Harrison. Most people with SLE have intermittent polyarthritis, varying from mild to disabling, characterized by soft tissue swelling and tenderness in joints and/or tendons, most commonly in hands, wrists, and knees. Joint deformities (hands and feet) develop in only 10%. Erosions on joint x-rays are rare but can be identified by ultrasound in almost half of patients. Some individuals have rheumatoid-like arthritis with erosions and fulfill criteria for both RA and SLE (“rhupus”); they may be coded as having both diseases. If pain persists in a single joint, such as knee, shoulder, or hip, a diagnosis of ischemic necrosis of bone should be considered, particularly if there are no other manifestations of active SLE because its prevalence is increased in SLE, especially in patients treated with systemic glucocorticoids. Myositis with clinical muscle weakness, elevated creatine kinase levels, positive magnetic resonance imaging (MRI)scan,andmusclenecrosis and inflammation on biopsy can occur,


InternalMed_Harrison

InternalMed_Harrison. glucocorticoids. Myositis with clinical muscle weakness, elevated creatine kinase levels, positive magnetic resonance imaging (MRI)scan,andmusclenecrosis and inflammation on biopsy can occur, although most patients have myalgias without frank myositis. Glucocorticoid therapies (commonly) and antimalarial therapies (rarely) can cause muscle weakness; these adverse effects must be distinguished from active inflammatory disease.


InternalMed_Harrison

InternalMed_Harrison. Lupus dermatitis can be classified as acute, subacute, or chronic, and there are many different types of lesions encompassed within these groups. Discoid lupus erythematosus (DLE) is the most common Diagnosis: Symptom complex suggestive of SLE Order laboratory tests: ANA, CBC, platelets, urinalysis


InternalMed_Harrison

InternalMed_Harrison. Diagnosis: Symptom complex suggestive of SLE Order laboratory tests: ANA, CBC, platelets, urinalysis All tests normal symptoms subside All tests normal symptoms persist ANA positive Not SLE Not SLE Treatment Repeat ANA, add anti-dsDNA, anti-Ro All negative Some positive Definite SLE (˜4 criteria, Table 378-3) Possible SLE (<4 criteria, Table 378-3) Not lifeor organ-threatening Lifeor organ-threatening Quality of life: Acceptable Quality of life: Not acceptable High-dose glucocorticoids, usually with addition of second agent Conservative manage-ment (Table 378-5) Conservative treatment plus low-dose glucocorticoids Consider belimumab Mycophenolate mofetil (or myfortic acid) Cyclophosphamide Low or high dose Do not exceed 6 months of Rx After response, d/c cyclophosphamide; maintain with mycophenolate or azathioprine No response Response Taper dose of all agents, especially glucocorticoids Belimumab, Rituximab, calcineurin inhibitors, or experimental therapies


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 378-2 Algorithm for diagnosis and initial therapy of systemic lupus erythematosus (SLE). For guidelines on management of lupus and lupus nephritis, see BH Hahn et al: Arthritis Care Res (Hoboken) 64:797, 2012; GK Bertsias et al: Ann Rheum Dis 71:1771, 2012; and G Bertsias et al: Ann Rheum Dis 67:195, 2008. For details on mycophenolate and cyclophosphamide induction and maintenance therapies, see L Henderson et al: Cochrane Database Syst Rev 12:CD002922, 2012; Z Touma et al: J Rheumatol 38:69, 2011; EM Ginzler et al: Arthritis Rheum 62:211, 2010; FA Houssiau et al: Ann Rheum Dis 69:61, 2010; and MA Dooley et al: N Engl J Med 365:1886, 2011. For belimumab in treatment, see BH Hahn: N Eng J Med 368:1528, 2013. For rituximab, see L Lightstone: Lupus 22:390, 2013; and BH Rovin et al: Arthritis Rheum 64:1215, 2012. ANA, antinuclear antibodies; CBC, complete blood count.


InternalMed_Harrison

InternalMed_Harrison. extensor surfaces of the arms. Worsening of this rash often accompanies flare of systemic disease. Subacute cutaneous lupus erythematosus (SCLE) consists of scaly red patches similar topsoriasis,orcircularflatred-rimmedlesions. Patients with these manifestations are exquisitely photosensitive; most have antibodies to Ro (SS-A). Other SLE rashes include recurring urticaria, lichen planus-like dermatitis, bullae, and panniculitis (“lupus profundus”). Rashes can be minor or severe; they may be the major disease manifestation. Small ulcerations on the oral or nasal mucosa are common in SLE; the lesions resemble aphthous ulcers.


InternalMed_Harrison

InternalMed_Harrison. Nephritis is usually the most serious manifestation of SLE, particularly because nephritis and infection are the leading causes of mortality in the first decade of disease. Because nephritis is asymptomatic in most lupus patients, urinalysis should be ordered in any person suspected of having SLE. The classification of lupus nephritis is primarily histologic (see “Pathology,” above, and Table 378-2). Renal biopsy is recommended for every SLE patient with any clinical evidence of nephritis; results are used to plan current andnear-futuretherapies.Patients withdangerous proliferative forms of glomerular damage (ISN III and IV) usually have microscopic hematuria and proteinuria (>500 mg per 24 h); approximately one-half develop nephrotic syndrome, and most develop hypertension. If diffuse proliferative glomerulonephritis (DPGN) is inadequately treated, virtually all patients develop ESRD within 2 years of diagnosis. Therefore, aggressive


InternalMed_Harrison

InternalMed_Harrison. and most develop hypertension. If diffuse proliferative glomerulonephritis (DPGN) is inadequately treated, virtually all patients develop ESRD within 2 years of diagnosis. Therefore, aggressive immunosuppressionisindicated(usuallysystemicglucocorticoids plus a cytotoxic drug), unless damage is irreversible (Fig. 378-2, Table 378-5). African Americans are more likely to develop ESRD than are whites, even with the most current therapies. Overall in the United States, ~20% ofindividualswithlupusDPGNdieordevelop ESRD within 10 years of diagnosis. Such individuals require aggressive control of SLE and of the complications of renal disease and of therapy. Approximately 20% of SLE patients with proteinuria (usually nephrotic) have membranous glomerular changes without proliferative changes on renal biopsy. Their outcome is better than for those with DPGN, but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or IV proliferative


InternalMed_Harrison

InternalMed_Harrison. biopsy. Their outcome is better than for those with DPGN, but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or IV proliferative disease. Lupus nephritis tends to be an ongoing disease, with flares requiring re-treatment chronic dermatitis in lupus; lesions are roughly circular with slightly or increased treatment over many years. For most people with lupus raised, scaly hyperpigmented erythematous rims and depigmented, nephritis, accelerated atherosclerosis becomes important after several atrophic centers in which all dermal appendages are permanently years of disease; attention must be given to control of systemic inflamdestroyed. Lesions can be disfiguring, particularly on the face and mation, blood pressure, hyperlipidemia, and hyperglycemia. scalp. Treatment consists primarily of topical or locally injected glucocorticoids and systemic antimalarials. Only 5% of people with NErVOUS SYSTEM MaNIFESTaTIONS DLE have


InternalMed_Harrison

InternalMed_Harrison. and hyperglycemia. scalp. Treatment consists primarily of topical or locally injected glucocorticoids and systemic antimalarials. Only 5% of people with NErVOUS SYSTEM MaNIFESTaTIONS DLE have SLE (although half have positive ANA); however, among There are many central nervous system (CNS) and peripheral nerindividuals with SLE, as many as 20% have DLE. The most common vous system manifestations of SLE; in some patients, these are the acute SLE rash is a photosensitive, slightly raised erythema, occasion-major cause of morbidity and mortality. It is useful to approach ally scaly, on the face (particularly the cheeks and nose—the “butter-this diagnostically by asking first whether the symptoms result from fly” rash), ears, chin, V region of the neck and chest, upper back, and SLE or another condition (such as infection in immunosuppressed


InternalMed_Harrison

InternalMed_Harrison. Manifestation Prevalence, % aNumbers indicate percentage of patients who have the manifestation at some time during the course of illness. Abbreviations: ARDS, acute respiratory distress syndrome; TIA, transient ischemic attack.


InternalMed_Harrison

InternalMed_Harrison. individuals or side effects of therapies). If symptoms are related to 2129 SLE, it should be determined whether they are caused by a diffuse process (requiring immunosuppression) or vascular occlusive disease (requiring anticoagulation). The most common manifestation of diffuse CNS lupus is cognitive dysfunction, including difficulties with memory and reasoning. Headaches are also common. When excruciating, they often indicate SLE flare; when milder, they are difficult to distinguish from migraine or tension headaches. Seizures of any type may be caused by lupus; treatment often requires both antiseizure and immunosuppressive therapies. Psychosis can be the dominant manifestation of SLE; it must be distinguished from glucocorticoid-induced psychosis. The latter usually occurs in the first weeks of glucocorticoid therapy, at daily doses of ≥40 mg of prednisone or equivalent; psychosis resolves over several days after glucocorticoids are decreased or stopped. Myelopathy is not rare and


InternalMed_Harrison

InternalMed_Harrison. weeks of glucocorticoid therapy, at daily doses of ≥40 mg of prednisone or equivalent; psychosis resolves over several days after glucocorticoids are decreased or stopped. Myelopathy is not rare and is often disabling; rapid initiation ofimmunosuppressivetherapystartingwithhigh-doseglucocorticoids is standard of care.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of transient ischemic attacks, strokes, and myocardial infarctions is increased in patients with SLE. These vascular events are increased in, but not exclusive to, SLE patients with antibodies to phospholipids (antiphospholipid antibodies), which are associated with hypercoagulability and acute thrombotic events (Chap. 379). Chronic SLE with or without antiphospholipid antibodies is associated withacceleratedatherosclerosis.Ischemiainthebraincanbecausedby focal occlusion (either noninflammatory or associated with vasculitis) or by embolization from carotid artery plaque or from fibrinous vegetations of Libman-Sacks endocarditis. Appropriate tests for antiphospholipid antibodies (see below) and for sources of emboli should be ordered in such patients to estimate the need for, intensity of, and duration of anti-inflammatory and/or anticoagulant therapies. In SLE, myocardial infarctions are primarily manifestations of accelerated atherosclerosis. The increased risk for


InternalMed_Harrison

InternalMed_Harrison. for, intensity of, and duration of anti-inflammatory and/or anticoagulant therapies. In SLE, myocardial infarctions are primarily manifestations of accelerated atherosclerosis. The increased risk for vascular events is three-to tenfold overall, and is highest in women <49 years old. Characteristics associated with increased risk for atherosclerosis include older age, hypertension, dyslipidemia, dysfunctional proinflammatory high-density lipoproteins, repeated high scores for disease activity, high cumulative or daily doses of glucocorticoids, and high levels of homocysteine. When it is most likely that an event results from clotting, long-term anticoagulation is the therapy of choice. Two processes can occur at once—vasculitis plus bland vascular occlusions—in which case it is appropriate to treat with anticoagulation plus immunosuppression. Statin therapies reduce levels of low-density lipoproteins (LDL) in SLE patients; reduction of cardiac events by statins has been shown in SLE


InternalMed_Harrison

InternalMed_Harrison. to treat with anticoagulation plus immunosuppression. Statin therapies reduce levels of low-density lipoproteins (LDL) in SLE patients; reduction of cardiac events by statins has been shown in SLE patients with renal transplants but not in other SLE cohorts to date.


InternalMed_Harrison

InternalMed_Harrison. ThemostcommonpulmonarymanifestationofSLEispleuritiswithor without pleural effusion. This manifestation, when mild, may respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs); when more severe, patients require a brief course of glucocorticoid therapy. Pulmonary infiltrates also occur as a manifestation of active SLE and are difficult to distinguish from infection on imaging studies. Life-threatening pulmonary manifestations include interstitial inflammation leading to fibrosis, shrinking lung syndrome, and intraalveolar hemorrhage; all of these probably require early aggressive immunosuppressive therapy as well as supportive care.


InternalMed_Harrison

InternalMed_Harrison. Pericarditis is the most frequent cardiac manifestation; it usually responds to anti-inflammatory therapy and infrequently leads to tamponade.Moreseriouscardiacmanifestationsare myocarditis andfibrinous endocarditis of Libman-Sacks. The endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valves, or to embolic events. It has not been proven that glucocorticoid or other immunosuppressive therapies lead to improvement of lupus myocarditis or endocarditis, but it is usual practice to administer a trial of high-dose steroids along with appropriate supportive therapy for NSAIDs, salicylates (Ecotrina and St. Joseph’s aspirina approved by FDA for use in SLE) Methotrexate (for dermatitis, arthritis) Glucocorticoids, orala (several specific brands are approved by FDA for use in SLE) Methylprednisolone sodium succinate, IVa (FDA approved for lupus nephritis) Rituximab (for patients resistant to above therapies)


InternalMed_Harrison

InternalMed_Harrison. Methylprednisolone sodium succinate, IVa (FDA approved for lupus nephritis) Rituximab (for patients resistant to above therapies) Doses toward upper limit of recommended range usually required Mid potency for face; mid to high potency for other areas 10–25 mg once a week, PO or SC, with folic acid; decrease dose if CrCl <60 mL/min Prednisone, prednisolone: 0.5–1 mg/ kg per day for severe SLE 0.07–0.3 mg/kg per day or qod for milder disease For severe disease, 1 g IV qd × 3 days Low dose (for whites of northern European backgrounds): 500 mg every 2 weeks for 6 doses, then begin maintenance with MMF or AZA. High dose: 7–25 mg/kg q month × 6; consider mesna administration with dose 1.5–3 mg/kg per day; decrease dose for CrCl <25 mL/min MMF: 2–3 g/d PO for induction therapy, 1–2 g/d for maintenance therapy; max 1 g bid if CrCl <25 mL/min


InternalMed_Harrison

InternalMed_Harrison. MMF: 2–3 g/d PO for induction therapy, 1–2 g/d for maintenance therapy; max 1 g bid if CrCl <25 mL/min MPA: 360–1080 mg bid; caution if CrCl <25 mL/min 2–3 mg/kg per day PO for induction; 1–2 mg/kg per day for maintenance; decrease frequency of dose if CrCl <50 mL/min 10 mg/kg IV wks 0, 2, and 4, then monthly aIndicates medication is approved for use in SLE by the U.S. Food and Drug Administration. A2R/ACE inhibitors, glucocorticoids, fluconazole, methotrexate, thiazides Acitretin, leflunomide, NSAIDs and salicylates, penicillins, probenecid, sulfonamides, trimethoprim A2R/ACE antagonists, antiarrhythmics class III, cyclosporine, NSAIDs and salicylates, phenothiazines, phenytoins, quinolones, rifampin, risperidone, thiazides, sulfonylureas, warfarin Allopurinol, bone marrow suppressants, colony-stimulating factors, doxorubicin, rituximab, succinylcholine, zidovudine


InternalMed_Harrison

InternalMed_Harrison. Allopurinol, bone marrow suppressants, colony-stimulating factors, doxorubicin, rituximab, succinylcholine, zidovudine Acyclovir, antacids, azathioprine, bile acid-binding resins, ganciclovir, iron, salts, probenecid, oral contraceptives ACE inhibitors, allopurinol, bone marrow suppressants, interferons, mycophenolate mofetil, rituximab, warfarin, zidovudine IVIg NSAIDs: Higher incidence of aseptic meningitis, elevated liver enzymes, decreased renal function, vasculitis of skin; entire class, especially COX-2specific inhibitors, may increase risk for myocardial infarction Salicylates: ototoxicity, tinnitus Both: GI events and symptoms, allergic reactions, dermatitis, dizziness, acute renal failure, edema, hypertension Atrophy of skin, contact dermatitis, folliculitis, hypopigmentation, infection


InternalMed_Harrison

InternalMed_Harrison. Both: GI events and symptoms, allergic reactions, dermatitis, dizziness, acute renal failure, edema, hypertension Atrophy of skin, contact dermatitis, folliculitis, hypopigmentation, infection Retinal damage, agranulocytosis, aplastic anemia, ataxia, cardiomyopathy, dizziness, myopathy, ototoxicity, peripheral neuropathy, pigmentation of skin, seizures, thrombocytopenia. Quinacrine usually causes diffuse yellow skin coloration. Acne, menstrual irregularities, high serum levels of testosterone Anemia, bone marrow suppression, leukopenia, thrombocytopenia, hepatotoxicity, nephrotoxicity, infections, neurotoxicity, pulmonary fibrosis, pneumonitis, severe dermatitis, seizures. Infection, VZV infection, hypertension, hyperglycemia, hypokalemia, acne, allergic reactions, anxiety, aseptic necrosis of bone, cushingoid changes, CHF, fragile skin, insomnia, menstrual irregularities, mood swings, osteoporosis, psychosis


InternalMed_Harrison

InternalMed_Harrison. Infection, VZV infection, bone marrow suppression, leukopenia, anemia, thrombocytopenia, hemorrhagic cystitis (less with IV), carcinoma of the bladder, alopecia, nausea, diarrhea, malaise, malignancy, ovarian and testicular failure. Ovarian failure is probably not a problem with low dose. Infection, leukopenia, anemia, thrombocytopenia, lymphoma, lymphoproliferative disorders, malignancy, alopecia, cough, diarrhea, fever, GI symptoms, headache, hypertension, hypercholesterolemia, hypokalemia, insomnia, peripheral edema, elevated liver enzymes, tremor, rash Infection, VZV infection, bone marrow suppression, leukopenia, anemia, thrombocytopenia, pancreatitis, hepatotoxicity, malignancy, alopecia, fever, flulike illness, GI symptoms Infusion reactions, allergy, infections probable Infection (including PML), infusion reactions, headache, arrhythmias, allergic responses bIndicates the medication has been used with glucocorticoids in the trials showing efficacy.


InternalMed_Harrison

InternalMed_Harrison. Infection (including PML), infusion reactions, headache, arrhythmias, allergic responses bIndicates the medication has been used with glucocorticoids in the trials showing efficacy. Abbreviations: A2R, angiotensin II receptor; ACE, angiotensin-converting enzyme; CHF, congestive heart failure; CrCl, creatinine clearance; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; IVIg, intravenous immunoglobulin; NSAIDs, nonsteroidal anti-inflammatory drugs; PML, progressive multifocal leukoencephalopathy; SLE, systemic lupus erythematosus; SPF, sun protection factor; VZV, varicella-zoster virus. heartfailure,arrhythmia,orembolicevents.Asdiscussedabove,patients with SLE are at increased risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from immune attack, chronic inflammation, and/or chronic oxidative damage to arteries.


InternalMed_Harrison

InternalMed_Harrison. The most frequent hematologic manifestation of SLE is anemia, usually normochromic normocytic, reflecting chronic illness. Hemolysis can be rapid in onset and severe, requiring high-dose glucocorticoid therapy, which is effective in most patients. Leukopenia is also common and almost always consists of lymphopenia, not granulocytopenia; lymphopenia rarely predisposes to infections and by itself usually does not requiretherapy.Thrombocytopenia maybe a recurring prob-lem.If platelet counts are >40,000/μL and abnormal bleeding is absent, therapy may not be required. High-dose glucocorticoid therapy (e.g., 1 mg/kg per day of prednisone or equivalent) is usually effective for the first few episodes of severe thrombocytopenia. Recurring or prolonged hemolytic anemia or thrombocytopenia, or disease requiring an unacceptably high dose of daily glucocorticoids, should be treated with an additional strategy (see “Management of Systemic Lupus Erythematosus” below).


InternalMed_Harrison

InternalMed_Harrison. Nausea, sometimes with vomiting, and diarrhea can be manifestations of an SLE flare, as can diffuse abdominal pain probably caused by autoimmune peritonitis and/or intestinal vasculitis. Increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are common when SLE is active. These manifestations usually improve promptly during systemic glucocorticoid therapy. Vasculitis involving the intestine may be life-threatening; perforations, ischemia, bleeding, and sepsis are frequent complications. Aggressive immunosuppressive therapy with high-doseglucocorticoidsis recommendedfor short-term control;evidenceofrecurrenceis anindicationforadditionaltherapies.


InternalMed_Harrison

InternalMed_Harrison. Siccasyndrome(Sjögren’ssyndrome; Chap. 383)andnonspecificconjunctivitis are common in SLE and rarely threaten vision. In contrast, retinal vasculitis and optic neuritis are serious manifestations: blindness can develop over days to weeks. Aggressive immunosuppression is recommended, although there arenocontrolledtrialstoprove effectiveness. Complications of systemic and intraorbital glucocorticoid therapy include cataracts (common) and glaucoma. Laboratory tests serve (1) to establish or rule out the diagnosis; (2) to followthe courseof disease,particularly to suggest that a flare is occurring or organ damage is developing; and (3) to identify adverse effects of therapies.


InternalMed_Harrison

InternalMed_Harrison. Diagnostically, the most important autoantibodies to detect are ANA because the test is positive in >95% of patients, usually at the onset of symptoms. A few patients develop ANA within 1 year of symptom onset; repeated testing may thus be useful. ANA tests using immunofluorescent methods are more reliable than enzyme-linked immunosorbent assays (ELISAs) and/or bead assays, which have less specificity. ANA-negative lupus exists but is rare in adults and is usually associated with other autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to double-stranded DNA (dsDNA) (but not to single-stranded DNA) are specific for SLE. ELISA and immunofluorescent reactions of sera with the dsDNA in the flagellate Crithidia luciliae have ~60% sensitivity for SLE; identification of high-avidity anti-dsDNA in the Farr assay is not as sensitive but may correlate better with risk for nephritis. Titers of anti-dsDNA vary over time. In some patients, increases in quantities of anti-dsDNA herald


InternalMed_Harrison

InternalMed_Harrison. anti-dsDNA in the Farr assay is not as sensitive but may correlate better with risk for nephritis. Titers of anti-dsDNA vary over time. In some patients, increases in quantities of anti-dsDNA herald a flare, particularly of nephritis or vasculitis, especially when associated with declining levels of C3 or C4 complement. Antibodies to Sm are also specific for SLE and assist in diagnosis; anti-Sm antibodies do not usually correlate with disease activity or clinical manifestations.


InternalMed_Harrison

InternalMed_Harrison. Antiphospholipid antibodies are not specific for SLE, but their pres-2131 ence fulfills one classification criterion, and they identify patients at increased risk for venous or arterial clotting, thrombocytopenia, and fetal loss. There are three widely accepted tests that measure different antibodies (anticardiolipin, anti-β2-glycoprotein, and the lupus anticoagulant). ELISA is used for anticardiolipin and anti-β2-glycoprotein (both internationally standardized with good reproducibility); a sensitive phospholipid-based activated prothrombin time such as the dilute Russell venom viper test is used to identify the lupus anticoagulant. The higher the titers of IgG anticardiolipin (>40 IU is considered high), and the greater the number of different antiphospholipid antibodies that are detected, the greater is the risk for a clinical episode of clotting. Quantities of antiphospholipid antibodies may vary markedly over time; repeated testing is justified if clinical manifestations of the


InternalMed_Harrison

InternalMed_Harrison. the greater is the risk for a clinical episode of clotting. Quantities of antiphospholipid antibodies may vary markedly over time; repeated testing is justified if clinical manifestations of the antiphospholipid syndrome (APS) appear (Chap. 379). To classify a patient as having APS, with or without SLE, by international criteria requires the presence of one or more clotting episodes and/or repeated fetal losses plus at least two positive tests for antiphospholipid anti bodies, at least 12 weeks apart; however, many patients with APS do not meet these stringent criteria, which are intended for inclusion of patients into studies.


InternalMed_Harrison

InternalMed_Harrison. An additional autoantibody test with predictive value (not used for diagnosis) detects anti-Ro/SS-A, which indicates increased risk for neonatallupus,siccasyndrome,andSCLE.Womenwithchild-bearing potential and SLE should be screened for antiphospholipid antibodies and anti-Ro, because both antibodies have the potential to cause fetal harm. Screening testsforcomplete blood count,platelet count,and urinalysis may detect abnormalities that contribute to the diagnosis and influence management decisions.


InternalMed_Harrison

InternalMed_Harrison. It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include urinalysis for hematuria and proteinuria, hemoglobin levels, platelet counts, and serum levels of creatinine or albumin. There is great interest in identification of additional markers of disease activity. Candidates include levels of anti-DNA and anti-C1q antibodies, several components of complement (C3 is most widely available), activated complement products (including those that bind to the C4d receptor on erythrocytes), IFN-inducible gene expression in peripheral blood cells, serum levels of BLyS (B lymphocyte stimulator, also called BAFF), and urinary levels of TNF-like weak inducer of apoptosis (TWEAK), neutrophil gelatinase-associated lipocalin (NGAL), or monocyte chemotactic protein1(MCP-1).Noneisuniformlyagreeduponasareliableindicator of flare or of response to therapeutic interventions. It is likely that a panelof multiple proteins willbe


InternalMed_Harrison

InternalMed_Harrison. or monocyte chemotactic protein1(MCP-1).Noneisuniformlyagreeduponasareliableindicator of flare or of response to therapeutic interventions. It is likely that a panelof multiple proteins willbe developed topredictbothimpending flare and response to recently instituted therapies. For now, the physician should determine for each patient whether certain laboratory test changes predict flare. If so, altering therapy in response to these changes may be advisable (30 mg of prednisone daily for 2 weeks has been shown to prevent flares in patients with rising anti-DNA plus falling complement). In addition, given the increased prevalence of atherosclerosis in SLE, it is advisable to follow the recommendations of the National Cholesterol Education Program for testing and treatment, including scoring of SLE as an independent risk factor, similar to diabetes mellitus.


InternalMed_Harrison

InternalMed_Harrison. There is no cure for SLE, and complete sustained remissions are rare. Therefore, the physician should plan to induce remissions of acute flares and then maintain improvements with strategies that suppress symptoms to an acceptable level and prevent organ damage. Usually patients will endure some adverse effects of medications. Therapeutic choices depend on (1) whether disease manifestations are life-threatening or likelytocause organ damage,justifyingaggressive therapies;(2)whether 2132 manifestations are potentially reversible; and (3) the best approaches to preventingcomplicationsofdiseaseanditstreatments.Therapies,doses, and adverse effects are listed in Table 378-5.


InternalMed_Harrison

InternalMed_Harrison. Among patients with fatigue, pain, and autoantibodies indicative of SLE, but without major organ involvement, management can be directed to suppression of symptoms. Analgesics and antimalarials are mainstays. NSAIDs are useful analgesics/anti-inflammatories, particularly for arthritis/arthralgias. However, two major issues indicate caution in using NSAIDs. First, SLE patients compared with the general populationareatincreasedriskforNSAID-inducedasepticmeningitis, elevated serum transaminases, hypertension, and renal dysfunction. Second, all NSAIDs, particularly those that inhibit cyclooxygenase-2 specifically,mayincreaseriskformyocardialinfarction.Acetaminophen to control pain may be a good strategy, but NSAIDs are more effective in some patients. The relative hazards of NSAIDs compared with low-dose glucocorticoid therapy have not been established. Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often reduce dermatitis, arthritis, and fatigue. A randomized,


InternalMed_Harrison

InternalMed_Harrison. compared with low-dose glucocorticoid therapy have not been established. Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often reduce dermatitis, arthritis, and fatigue. A randomized, placebo-controlled, prospective trial has shown that withdrawal of hydroxychloroquine results inincreasednumbersofdiseaseflares;hydroxychloroquinealsoreduces accrual of tissue damage, including renal damage, over time. Because of potential retinal toxicity, patients receiving antimalarials should undergo ophthalmologic examinations annually. A placebo-controlled prospective trial suggests that administration of dehydroepiandrosterone may reduce disease activity. If quality of life is inadequate despite these conservative measures, treatment with low doses of systemic glucocorticoids may be necessary. The clinician may also considertreatmentwithbelimumab(anti-BLyS)inthesepatients,although published clinical trials enrolled patients who had failed to respond to conservative therapies. Lupus


InternalMed_Harrison

InternalMed_Harrison. The clinician may also considertreatmentwithbelimumab(anti-BLyS)inthesepatients,although published clinical trials enrolled patients who had failed to respond to conservative therapies. Lupus dermatitis should be managed with topical sunscreens, antimalarials, topical glucocorticoids, and/or tacrolimus, and if severe or unresponsive, systemic glucocorticoids with or without mycophenolate mofetil.


InternalMed_Harrison

InternalMed_Harrison. LIFE-THrEaTENING SLE: PrOLIFEraTIVE FOrMS OF LUPUS NEPHrITIS


InternalMed_Harrison

InternalMed_Harrison. Guidelines for management of lupus nephritis have been published recently by the American College of Rheumatology and the European LeagueAgainstRheumatism(encompassedandreferencedinFig. 378-2 andTable378-5).Themainstayoftreatmentforanyinflammatorylifethreatening or organ-threatening manifestations of SLE is systemic glucocorticoids(0.5–1mg/kgperdayPOor500–1000mgofmethylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent). Evidence that glucocorticoid therapy is life-saving comes from retrospective studies from the predialysis era; survival was significantly better in people with DPGN treated with high-dose daily glucocorticoids (40–60 mg of prednisone daily for 4–6 months) versus lower doses. Currently, high doses are recommended for much shorter periods; recent trials of interventions for severe SLE use 4–6 weeks of 0.5–1 mg/kg per day of prednisone or equivalent. Thereafter, doses are tapered as rapidly as the clinical


InternalMed_Harrison

InternalMed_Harrison. for much shorter periods; recent trials of interventions for severe SLE use 4–6 weeks of 0.5–1 mg/kg per day of prednisone or equivalent. Thereafter, doses are tapered as rapidly as the clinical situation permits, usually to a maintenance dose ranging from 5 to 10 mg of prednisone or equivalent per day. Most patients with an episode of severe SLE require many years of maintenance therapy with low-dose glucocorticoids, which can be increased to prevent or treat disease flares. Frequent attempts to gradually reduce the glucocorticoid requirement are recommended because virtually everyone develops important adverse effects (Table 378-5). High-quality clinical studies regarding initiating therapy for severe, active SLE with IV pulses of high-dose glucocorticoids are not available. Most recent clinical trials in lupus nephritis have initiated therapy with high-dose IV glucocorticoid pulses (500–1000 mg daily for 3–5 days). This approach must be tempered by safety considerations, such as


InternalMed_Harrison

InternalMed_Harrison. clinical trials in lupus nephritis have initiated therapy with high-dose IV glucocorticoid pulses (500–1000 mg daily for 3–5 days). This approach must be tempered by safety considerations, such as the presence of conditions adversely affected by glucocorticoids (e.g., infection, hyperglycemia, hypertension, osteoporosis).


InternalMed_Harrison

InternalMed_Harrison. Cytotoxic/immunosuppressive agents added to glucocorticoids are recommended to treat serious SLE. Almost all prospective controlled trials in SLE involvingcytotoxicagentshavebeen conducted incombinationwithglucocorticoidsinpatientswithlupusnephritis.Therefore, the following recommendations apply to treatment of nephritis. Either cyclophosphamide (an alkylating agent) or mycophenolate mofetil (a relatively lymphocyte-specific inhibitor of inosine monophosphatase andthereforeofpurine synthesis)isan acceptablechoiceforinduction of improvement in severely ill patients; azathioprine (a purine analogue and cycle-specific antimetabolite) may be effective but is slower to influence response and associated with more flares. In patients whose renal biopsies show ISN grade III or IV disease, early treatment with combinations of glucocorticoids and cyclophosphamide reduces progression to ESRD and death. Shorter-term studies with glucocorticoids plus mycophenolate mofetil (prospective randomized


InternalMed_Harrison

InternalMed_Harrison. treatment with combinations of glucocorticoids and cyclophosphamide reduces progression to ESRD and death. Shorter-term studies with glucocorticoids plus mycophenolate mofetil (prospective randomized trials of 6 months, follow-up studies of 36 months) show that this regimen is similar to cyclophosphamide in achieving improvement. Comparisons are complicated by effects of race, since higher proportions of African Americans (and other non-Asian, nonwhite races) respond to mycophenolate than to cyclophosphamide, whereas similar proportions of whitesandAsiansrespondtoeachdrug.Regardingtoxicity,diarrheais more common with mycophenolate mofetil; amenorrhea, leukopenia, and nausea are more common with cyclophosphamide. Importantly, rates of severe infections and death are similar in meta-analyses. Two different regimens of IV cyclophosphamide are available. For white patients with northern European backgrounds, low doses of cyclophosphamide (500 mg every 2 weeks for six total doses, followed


InternalMed_Harrison

InternalMed_Harrison. Two different regimens of IV cyclophosphamide are available. For white patients with northern European backgrounds, low doses of cyclophosphamide (500 mg every 2 weeks for six total doses, followed by azathioprine or mycophenolate maintenance) are as effective as standard high doses, with less toxicity. Ten-year follow-up has shown no differences between the high-dose and low-dose groups (death or ESRD in 9–20% of patients in each group). The majority of the European patients were white; it is not clear whether the data apply to U.S. populations. High-dose cyclophosphamide (500–1000 mg/m2 body surface area given monthly IV for 6 months, followed by azathioprine or mycophenolate maintenance) is an acceptable approach for patients with severe nephritis (e.g., multiple cellular crescents and/or fibrinoid necrosis on renal biopsy, or rapidly progressive glomerulonephritis). Cyclophosphamide and mycophenolate responses begin 3–16 weeks after treatment is initiated, whereas glucocorticoid


InternalMed_Harrison

InternalMed_Harrison. fibrinoid necrosis on renal biopsy, or rapidly progressive glomerulonephritis). Cyclophosphamide and mycophenolate responses begin 3–16 weeks after treatment is initiated, whereas glucocorticoid responses may begin within 24 h.


InternalMed_Harrison

InternalMed_Harrison. For maintenance therapy, mycophenolate and azathioprine probably are similar in efficacy and toxicity; both are safer than cyclophosphamide. In a recently published multicenter study, mycophenolate was superior to azathioprine in maintaining renal function and survival in patients who responded to induction therapy with either cyclophosphamide or mycophenolate. The incidence of ovarian failure, a common effect of high-dose cyclophosphamide therapy (but probably not of low-dose therapy), can be reduced by treatment with a gonadotropin-releasing hormone agonist (e.g., leuprolide 3.75 mg intramuscularly) prior to each monthly cyclophosphamide dose. Patients with high serum creatinine levels (e.g., ≥265 μmol/L [≥3.0 mg/dL]) many months in duration and high chronicity scores on renal biopsy are not likely to respond to any of these therapies. In general, it may be better to induce improvement in an African-American or Hispanic patient with proliferative glomerulonephritis with


InternalMed_Harrison

InternalMed_Harrison. biopsy are not likely to respond to any of these therapies. In general, it may be better to induce improvement in an African-American or Hispanic patient with proliferative glomerulonephritis with mycophenolate mofetil (2–3 g daily) rather than cyclophosphamide, with the option to switch if no evidence of response is detectable after 3–6 months of treatment. For whites and Asians, induction with either mycophenolate mofetil or cyclophosphamide is acceptable. Cyclophosphamide may be discontinued when it is clear that a patient is improving. The number of SLE flares is reduced by maintenance therapy with mycophenolate mofetil (1.5–2 g daily) or azathioprine (1–2.5 mg/kg per day). Both cyclophosphamide and mycophenolate mofetil are potentially teratogenic; patients should be off either medication for at least 3 months before attempting to conceive. Azathioprine can be used if necessary to control active SLE in patients who are pregnant. If azathioprine is used either for induction or


InternalMed_Harrison

InternalMed_Harrison. for at least 3 months before attempting to conceive. Azathioprine can be used if necessary to control active SLE in patients who are pregnant. If azathioprine is used either for induction or maintenance therapy, patients may be prescreened for homozygous deficiency of the TMPT enzyme (which is required to metabolize the 6-mercaptopurine product of azathioprine) because they are at higher risk for bone marrow suppression.


InternalMed_Harrison

InternalMed_Harrison. Good improvement occurs in ~80% of lupus nephritis patients receiving either cyclophosphamide or mycophenolate at 1–2 years of follow-up. However, in some studies, at least 50% of these individuals have flares of nephritis over the next 5 years, and re-treatment is required; such individuals are more likely to progress to ESRD. Long-term outcome of lupus nephritis to most interventions is better in whites than in African Americans. Methotrexate (a folinic acid antagonist) may have a role in the treatment of arthritis and dermatitis but probably not in nephritis or other life-threatening disease. Small controlled trials (in Asia) of leflunomide, a relatively lymphocyte-specific pyrimidine antagonist licensed for use in rheumatoid arthritis, have suggested it can suppress disease activity in some SLE patients. Cyclosporine and tacrolimus, which inhibit production of IL-2 and T lymphocyte functions, have not been studied in prospective controlled trials in SLE in the United States;


InternalMed_Harrison

InternalMed_Harrison. in some SLE patients. Cyclosporine and tacrolimus, which inhibit production of IL-2 and T lymphocyte functions, have not been studied in prospective controlled trials in SLE in the United States; several studies in Asia have shown they are effective in lupus nephritis. Because they have potential nephrotoxicity but little bone marrow toxicity, the author uses them for periods of a few months in patients with steroid-resistant cytopenias of SLE or in steroid-resistant patients who have developed bone marrow suppression from standard cytotoxic agents.


InternalMed_Harrison

InternalMed_Harrison. Use of biologics directed against B cells for active SLE is under intense study. Use of anti-CD20 (rituximab), particularly in patients with SLE who are resistant to the more standard combination therapies discussed above, is controversial. Several open trials have shown efficacy in a majority of such patients, both for nephritis and for extrarenal lupus. However, recent prospective placebo-controlled randomized trials, one in renal and one in nonrenal SLE, did not show a difference between anti-CD20 and placebo when added to standard combination therapies. In contrast, recent trials of standard therapy plus belimumab (anti-BLyS, which binds soluble BLyS/BAFF, which is required for maturation of naïve and transitional B cells to plasma cellsandmemory Bcells) showed improvement in51%ofSLEpatients compared to 36% of those on placebo; these differences were statistically significant. The U.S. Food and Drug Administration (FDA) has approved belimumab for treatment of seropositive patients


InternalMed_Harrison

InternalMed_Harrison. compared to 36% of those on placebo; these differences were statistically significant. The U.S. Food and Drug Administration (FDA) has approved belimumab for treatment of seropositive patients with SLE who have failed standard treatments. The belimumab trial did not includepatientswithactivenephritisorCNSdisease.Posthocanalyses have shown that the SLE patient most likely to respond to belimumab has fairly robust clinical activity (a Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score of ≥10), positive anti-DNA, and low serum complement. SLEDAI is a widely used measure of SLE diseaseactivity;scores>3reflectclinicallyactivedisease.Atthistime,it is useful to add belimumab to the therapeutic armamentarium in SLE, and it is clear that some patients benefit. However, its role in management of lupus nephritis is not yet known.


InternalMed_Harrison

InternalMed_Harrison. SPECIaL CONDITIONS IN SLE THaT MaY rEQUIrE aDDITIONaL Or DIFFErENT THEraPIES Crescentic Lupus Nephritis The presence of cellular or fibrotic crescents in glomeruli with proliferative glomerulonephritis indicates a worse prognosis than in patients without this feature. There are no large prospective multinational controlled trials showing efficacy of cyclophosphamide, mycophenolate, cyclosporine, or tacrolimus in such cases. Most authorities currently recommend that high-dose cyclophosphamide is the induction therapy of choice, in addition to high-dose glucocorticoids. One prospective trial from China showed superiority of mycophenolate to cyclophosphamide.


InternalMed_Harrison

InternalMed_Harrison. Membranous Lupus Nephritis Most SLE patients with membranous (INS-V) nephritis also have proliferativechanges and should be treated for proliferative disease. However, some have pure membranous changes. Treatment for this group is less well defined. Some authorities do not recommend immunosuppression unless proteinuria is in the nephrotic range (although treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers is recommended). In those patients, recent prospective controlled trials suggest that alternate-day glucocorticoids plus cyclophosphamide or mycophenolate mofetil or cyclosporine are all effective in the majority of patients in reducing proteinuria. It is more controversial whether they 2133 preserve renal function over the long term.


InternalMed_Harrison

InternalMed_Harrison. Pregnancy and Lupus Fertility rates for men and women with SLE are probably normal. However, rate of fetal loss is increased (approximately two-to threefold) in women with SLE. Fetal demise is higher in mothers with high disease activity, antiphospholipid antibodies, and/or active nephritis. Suppression of disease activity can be achieved by administration of systemic glucocorticoids. A placental enzyme, 11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone. Glucocorticoids are listed by the FDA as pregnancy category A (no evidence of teratogenicity in human studies); cyclosporine, tacrolimus, and rituximab are listed as category C (may be teratogenic in animals but no good evidence in humans); azathioprine, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide are category D (there is evidence of teratogenicity in humans, but benefits might


InternalMed_Harrison

InternalMed_Harrison. but no good evidence in humans); azathioprine, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide are category D (there is evidence of teratogenicity in humans, but benefits might outweigh risks in certain situations); and methotrexate is category X (risks outweigh benefits).


InternalMed_Harrison

InternalMed_Harrison. Therefore, active SLE in pregnant women should be controlled with hydroxychloroquine and, if necessary, prednisone/prednisolone at the lowest effective doses for the shortest time required. Azathioprine may be added if these treatments do not suppress disease activity. Adverse effects of prenatal glucocorticoid exposure (primarily betamethasone) on offspring may include low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome. It is likely that each of these glucocorticoids and immunosuppressive medications gets into breast milk, at least in low levels; patients should consider not breastfeeding if they need therapy for SLE. In SLE patients with antiphospholipid antibodies (on at least two occasions) and prior fetal losses, treatment with heparin (usually low-molecular-weight) plus low-dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births; however, a recent


InternalMed_Harrison

InternalMed_Harrison. treatment with heparin (usually low-molecular-weight) plus low-dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births; however, a recent prospectivetrialshowednodifferencesinfetaloutcomesinwomentakingaspirincomparedtothosetakingaspirinpluslow-molecular-weight heparin.Anadditionalpotential problemfor the fetusis the presenceof antibodies to Ro, sometimes associated with neonatal lupus consisting of rash and congenital heart block with or without cardiomyopathy. The cardiac manifestations can be life-threatening; therefore the presence of anti-Ro requires vigilant monitoring of fetal heart rates with prompt intervention (delivery if possible) if distress occurs. Recent evidence shows that hydroxychloroquine treatment of an anti-Ro-positive mother whose infant develops congenital heart block significantly reduces the chance that subsequent fetuses will develop heart block. There is some evidence that dexamethasone treatment of


InternalMed_Harrison

InternalMed_Harrison. mother whose infant develops congenital heart block significantly reduces the chance that subsequent fetuses will develop heart block. There is some evidence that dexamethasone treatment of a mother in whom first-or second-degree heart block is detected in utero may sometimes prevent progression of heart block. Women with SLE usuallytolerate pregnancy without disease flares. However, a small proportion develops severe flares requiring aggressive glucocorticoid therapy or early delivery. Poor maternal outcomes are highest in women with active nephritisor irreversibleorgandamagein kidneys, brain,orheart.


InternalMed_Harrison

InternalMed_Harrison. Lupus and antiphospholipid Syndrome (aPS) Patients with SLE who have venous or arterial clotting and/or repeated fetal losses and at least two positive tests for antiphospholipid antibodies have APS and should be managed with long-term anticoagulation (Chap. 379). A target international normalized ratio (INR) of 2.0–2.5 is recommended for patients with one episode of venous clotting; an INR of 3.0–3.5 is recommended for patients with recurring clots or arterial clotting, particularly in the CNS. Recommendations are based on both retrospective and prospective studies of posttreatment clotting events and adverse effects from anticoagulation.


InternalMed_Harrison

InternalMed_Harrison. Microvascular Thrombotic Crisis (Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome) This syndrome of hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys, brain, and other tissues carries a high mortality rate and occurs most commonly in young individuals with lupus nephritis. The most useful laboratory tests are identification of schistocytes on peripheral blood smears, elevated serum levels of lactate dehydrogenase, and antibodies to 2134 ADAMS13. Plasma exchange or extensive plasmapheresis is usually life-saving; most authorities recommend concomitant glucocorticoid therapy; there is no evidence that cytotoxic drugs are effective.


InternalMed_Harrison

InternalMed_Harrison. Lupus Dermatitis Patients with any form of lupus dermatitis should minimize exposure to ultraviolet light, using appropriate clothing and sunscreens with a sun protection factor of at least 30. Topical glucocorticoids and antimalarials (such as hydroxychloroquine) are effective in reducing lesion severity in most patients and are relatively safe. Systemictreatmentwithretinoicacidisausefulstrategyinpatientswith inadequate improvement on topical glucocorticoids and antimalarials; adverse effects are potentially severe (particularly fetal abnormalities), and there are stringent reporting requirements for its use in the United States. Extensive, pruritic, bullous, or ulcerating dermatitides usually improve promptly after institution of systemic glucocorticoids; tapering may be accompanied by flare of lesions, thus necessitating use of a second medication such as hydroxychloroquine, retinoids, or cytotoxic medications such as methotrexate, azathioprine, or mycophenolate mofetil. In


InternalMed_Harrison

InternalMed_Harrison. by flare of lesions, thus necessitating use of a second medication such as hydroxychloroquine, retinoids, or cytotoxic medications such as methotrexate, azathioprine, or mycophenolate mofetil. In therapy-resistant lupus dermatitis there are reports of success with topical tacrolimus (caution must be exerted because of the possible increased risk for malignancies) or with systemic dapsone or thalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the supplier).


InternalMed_Harrison

InternalMed_Harrison. Prevention of complications of SLE and its therapy include providing appropriatevaccinations(theadministrationofinfluenzaandpneumococcal vaccines has been studied in patients with SLE; flare rates are similar to those receiving placebo) and suppressing recurrent urinary tract infections. Vaccination with attenuated live viruses is generally discouragedin patients who are immunosuppressed.Strategiesto prevent osteoporosis should be initiated in most patients likely to require long-term glucocorticoid therapy and/or with other predisposing factors. Postmenopausal women can be protected from steroid-induced osteoporosis with either bisphosphonates or denosumab. Safety of long-term use of these strategies in premenopausal women is not well established. Control of hypertension and appropriate prevention strategies for atherosclerosis, including monitoring and treatment of dyslipidemias, management of hyperglycemia, and management of obesity, are recommended.


InternalMed_Harrison

InternalMed_Harrison. Studies of highly targeted experimental therapies for SLE are in progress. They include targeting (1) activated B lymphocytes with anti-CD22 or TACI-Ig, (2) inhibition of IFN-α, (3) inhibition of B/T cell second signal coactivation with CTLA-Ig, (4) inhibition of innate immune activation via TLR7 or TLR7 and 9, (5) induction of regulatory T cells with peptides from immunoglobulins or autoantigens; (6) suppression of T cells, B cells, and monocyte/macrophages with laquinimod; and (7) inhibition of lymphocyte activation by blockade of Jak/Stat. A few studies have used vigorous untargeted immunosuppression with high-dose cyclophosphamide plus anti-T cell strategies, with rescue by transplantation of autologous hematopoietic stem cells forthetreatmentofsevereandrefractory SLE. OneU.S.report showed an estimated mortality rate over 5 years of 15% and sustained remission in 50%. It is hoped that in the next edition of this text, we will be able to recommend more effective and less toxic


InternalMed_Harrison

InternalMed_Harrison. showed an estimated mortality rate over 5 years of 15% and sustained remission in 50%. It is hoped that in the next edition of this text, we will be able to recommend more effective and less toxic approaches to treatment of SLE based on some of these strategies.


InternalMed_Harrison

InternalMed_Harrison. PaTIENT OUTCOMES, PrOGNOSIS, aND SUrVIVaL


InternalMed_Harrison

InternalMed_Harrison. Survival in patients with SLE in the United States, Canada, Europe, and China is approximately 95% at 5 years, 90% at 10 years, and 78% at 20 years. In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis than whites, whereas Africans in Africa and Hispanic Americans with a Puerto Rican origin do not. The relative importance of gene mixtures and environmental differences accounting for ethnic differences is not known. Poor prognosis (~50% mortality in 10 years) in most series is associated with (at the time of diagnosis) high serum creatinine levels (>124 μmol/L [>1.4 mg/dL]), hypertension, nephrotic syndrome (24-h urine protein excretion >2.6 g), anemia (hemoglobin <124 g/L [<12.4 g/dL]), hypoalbuminemia, hypocomplementemia, antiphospholipid antibodies, male sex, ethnicity (African American, Hispanic with mestizo heritage), and low socioeconomic status. Data regarding outcomes in SLE patients with renal transplants show mixed


InternalMed_Harrison

InternalMed_Harrison. antibodies, male sex, ethnicity (African American, Hispanic with mestizo heritage), and low socioeconomic status. Data regarding outcomes in SLE patients with renal transplants show mixed results: some series show a twofold increase in graft rejection compared to patients with other causes of ESRD, whereas others show no differences. Overall patient survival is comparable (85% at 2 years). Lupus nephritis occurs in approximately 10% of transplanted kidneys. Disability in patients with SLE is common due primarily to chronic fatigue, arthritis, and pain, as well as renal disease. As many as 25% of patients may experience remissions, sometimes for a few years, but these are rarely permanent. The leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.


InternalMed_Harrison

InternalMed_Harrison. This is a syndrome of positive ANA associated with symptoms such as fever, malaise, arthritis or intense arthralgias/myalgias, serositis, and/ or rash. The syndrome appears during therapy with certain medications and biologic agents, is predominant in whites, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated with anti-dsDNA, is commonly associated with antibodies to histones, and usually resolves over several weeks after discontinuation of the offending medication. The list of substances that can induce lupus-like disease is long. Among the most frequent are the antiarrhythmics procainamide, disopyramide, and propafenone; the anti-hypertensive hydralazine; several angiotensin-converting enzyme inhibitors and beta blockers; the antithyroid propylthiouracil; the antipsychotics chlorpromazine and lithium; the anticonvulsants carbamazepine and phenytoin; the antibiotics isoniazid, minocycline, and nitrofurantoin (Macrodantin); the antirheumatic


InternalMed_Harrison

InternalMed_Harrison. the antipsychotics chlorpromazine and lithium; the anticonvulsants carbamazepine and phenytoin; the antibiotics isoniazid, minocycline, and nitrofurantoin (Macrodantin); the antirheumatic sulfasalazine; the diuretic hydrochlorothiazide; the antihyperlipidemics lovastatin and simvastatin; and IFNs and TNF inhibitors. ANA usually appears before symptoms; however, many of the medications mentioned above induce ANA in patients who never develop symptoms of drug-induced lupus. It is appropriate to test for ANA at the first hint of relevant symptoms and to use test results to help decide whether to withdraw the suspect agent.


InternalMed_Harrison

InternalMed_Harrison. 379 Haralampos M. Moutsopoulos, Panayiotis G. Vlachoyiannopoulos


InternalMed_Harrison

InternalMed_Harrison. Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity. The major autoantibodies detected in the patient’s sera are directed against phospholipid (PL)binding plasma proteins, mainly against a 43-kDa plasma apolipoproteinknownasβ2glycoproteinI(β2GPI)andprothrombin.Theplasma concentrationofβ2GPI is 50–200 μg/mL. β2GPI consists of326 amino acids arranged in five domains (I through V). Domain V forms a positively charged patch, suitable to interact with negatively charged PL. In plasma, β2GPI has a circular conformation with domain V binding to andconcealingthe Bcellepitopes lying on domainI. Another groupof antibodies termed lupus anticoagulant (LA) elongate clotting times in vitro; this elongation is not corrected by adding normal plasma to the detection system (Table 379-1). Patients with APS often possess antibodies recognizing Treponema pallidum PL/cholesterol complexes,


InternalMed_Harrison

InternalMed_Harrison. this elongation is not corrected by adding normal plasma to the detection system (Table 379-1). Patients with APS often possess antibodies recognizing Treponema pallidum PL/cholesterol complexes, which are detected as biologic false-positive serologic tests for syphilis


InternalMed_Harrison

InternalMed_Harrison. Lupus anticoagulant Activated partial thromboplastin time (aPTT) Antibodies recognize β2GPI or prothrombin (PT) and elongate aPTT, implying that they (LA) interfere with the generation of thrombin by prothrombin. Prolongation of the clotting Kaolin clotting time (KCT) times is an in vitro phenomenon, and LA induces thromboses in vivo. Abbreviations: APL, antiphospholipid syndrome; β2GPI, β2 glycoprotein I; PL, phospholipid. (BFP-STS) and Venereal Disease Research Laboratory (VDRL) tests. APS may occur alone (primary) or in association with any other autoimmune disease (secondary). Catastrophic APS (CAPS) is defined as a rapidly progressive thromboembolic disease involving simultaneously three or more organs, organ systems, or tissues leading to corresponding functional defects.


InternalMed_Harrison

InternalMed_Harrison. Anti-PL (aPL)-binding plasma protein antibodies occur in 1–5% of the general population. Their prevalence increases with age; however, it is questionable whether they induce thrombotic events in elderly individuals. One-third of patients with systemic lupus erythematosus (SLE) (Chap. 378) possess these antibodies, whereas their prevalence in other autoimmune connective tissue disorders, such as systemic sclerosis (scleroderma), Sjögren’s syndrome, dermatomyositis, rheumatoid arthritis, and early undifferentiated connective tissue disease, ranges from 6 to 15%. One-third of aPL-positive individuals experience thrombotic events or pregnancy morbidity.


InternalMed_Harrison

InternalMed_Harrison. The trigger for the induction of antibodies to PL-binding proteins is not known. However infections, oxidative stress, major physical stresses such as surgery, and discontinuation of anticoagulant treatment may induce the exacerbation of the disease. Experimental data have shown that these phenomena are induced via (1) conformational changes of β2GPI either complexed with microbial antigens or dimerization through interaction with endothelial cell surface receptor annexin 2/TLR4, the platelet receptors apolipoprotein E receptor 2′ (apoER2′) and/or GPIb/IX/V receptor, and/or the chemokine platelet factor 4 (PF4); or (2) impaired defensive mechanisms such as reduced generation of endothelial nitric oxide synthase. Adherence of β2GPI to apoER2′, GPIb/IX/V receptor, and/or PF4 induces activation of endothelial cells, platelets, and monocytes. This process activates downstream pathways such as p38 mitogen-activated protein (p38 MAP) kinase and nuclear factor (NF)-κB, leading to the


InternalMed_Harrison

InternalMed_Harrison. activation of endothelial cells, platelets, and monocytes. This process activates downstream pathways such as p38 mitogen-activated protein (p38 MAP) kinase and nuclear factor (NF)-κB, leading to the following events: secretion of proinflammatory cytokines, such as interleukin (IL) 1, IL-6, and IL-8; the expression of adhesion molecules; inhibition of cell-surface plasminogen activation; and expression of tissue factor. The above events change the phenotype of these cells to a prothrombotic form. In addition, anti-β2GPI antibodies induce fetal injury in mice through complement activation, as shown by the evidence that C4-deficient mice were protected from fetal injury.


InternalMed_Harrison

InternalMed_Harrison. Clinical manifestations represent mainly a direct or indirect expression of venous or arterial thrombosis and/or pregnancy morbidity (Table 379-2). Clinical features associated with venous thrombosis are superficial and deep vein thrombosis, cerebral venous thrombosis, signs and symptoms of intracranial hypertension, retinal vein thrombosis, pulmonary emboli, pulmonary arterial hypertension, and Budd-Chiari syndrome. Livedo reticularis consists of a mottled reticular vascular pattern that appears as a lace-like, purplish discoloration of the skin. It is probably caused by swelling of the venules owing to obstruction of capillaries by thrombi. This clinical manifestation correlates with vascular lesions such as those in the central nervous system as well as aseptic bone necrosis. Arterial thrombosis is manifested as migraines, cognitive dysfunction, transient ischemic attacks, stroke, myocardial infarction, arterial thrombosis of upper and lower thrombosis Leg ulcers and/or digital


InternalMed_Harrison

InternalMed_Harrison. thrombosis is manifested as migraines, cognitive dysfunction, transient ischemic attacks, stroke, myocardial infarction, arterial thrombosis of upper and lower thrombosis Leg ulcers and/or digital gangrene 9 Arterial thrombosis in the extremities 7 Retinal artery thrombosis/amaurosis fugax 7 Ischemia of visceral organs or avascular necrosis of bone 6 Multi-infarct dementia 3


InternalMed_Harrison

InternalMed_Harrison. Neurologic Manifestations of Uncertain Etiology Migraine 20 Epilepsy 7 Chorea 1 Cerebellar ataxia 1 Transverse myelopathy 0.5 Renal Manifestations Due to Various Reasons (Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia) 3 39 Arthritis 27 Obstetric Manifestations (Referred to the Number of Pregnancies) Preeclampsia 10 Eclampsia


InternalMed_Harrison

InternalMed_Harrison. Fetal Manifestations (Referred to the Number of Pregnancies) 2136 extremities, ischemic leg ulcers, digital gangrene, avascular necrosis of bone, retinal artery occlusion leading to painless transient vision loss, renal artery stenosis, and glomerular lesions, as well as infarcts of spleen, pancreas, and adrenals. Libman-Sacks endocarditis consists of very small vegetations, histologically characterized by organized platelet-fibrin microthrombi surrounded by growing fibroblasts and macrophages. Glomerular lesions are manifested with hypertension, mildly elevated serum creatinine levels, proteinuria, and mild hematuria. Histologically, these lesions are characterized in an acute phase by thrombotic microangiopathy involving glomerularcapillaries, and in a chronic phasewith fibrousintima hyperplasia, fibrous and/or fibrocellular occlusions of arterioles, and focal cortical atrophy (Table 379-2). PrematureatherosclerosishasbeenrecognizedasararefeatureofAPS. Coombs-positive hemolytic


InternalMed_Harrison

InternalMed_Harrison. hyperplasia, fibrous and/or fibrocellular occlusions of arterioles, and focal cortical atrophy (Table 379-2). PrematureatherosclerosishasbeenrecognizedasararefeatureofAPS. Coombs-positive hemolytic anemia and thrombocytopenia are laboratory findings associated with APS. Discontinuation of therapy, major surgery, infection, and trauma may trigger CAPS.


InternalMed_Harrison

InternalMed_Harrison. ThediagnosisofAPSshouldbeseriouslyconsideredincasesofthrombosis, cerebral vascular accidents in individuals younger than 55 years of age, or pregnancy morbidity in the presence of livedo reticularis or thrombocytopenia. In these cases, aPL antibodies should be measured. The presence of at least one clinical and one laboratory criterion ensures the diagnosis even in the presence of other causes of thrombophilia. Clinical criteria include: (1) vascular thrombosis defined as one ormoreclinicalepisodesofarterial,venous,orsmallvesselthrombosis in any tissue or organ; and (2) pregnancy morbidity, defined as (a) one or more unexplained deaths of a morphologically normal fetus at or beyond the tenth week of gestation; (b) one or more premature births of a morphologically normal neonate before the thirty-fourth week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency; or (c) three or more unexplained consecutive spontaneous abortions before the tenth week of


InternalMed_Harrison

InternalMed_Harrison. the thirty-fourth week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency; or (c) three or more unexplained consecutive spontaneous abortions before the tenth week of gestation. Laboratory criteria include (1) LA, (2) anticardiolipin (aCL), and/or (3) anti-β2GPI antibodies, at intermediate or high titers on two occasions, 12 weeks apart.


InternalMed_Harrison

InternalMed_Harrison. Differential diagnosis is based on the exclusion of other inherited or acquiredcausesofthrombophilia (Chap. 141),Coombs-positivehemolytic anemia (Chap. 129), and thrombocytopenia (Chap. 140). Livedo reticularis with or without a painful ulceration on the lower extremities also may be a manifestation of disorders affecting (1) the vascular wall, such as polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as myeloproliferative disorders, atherosclerosis, hypercholesterolemia, or other causes of thrombophilia.


InternalMed_Harrison

InternalMed_Harrison. After the first thrombotic event, APS patients should be placed on warfarin for life, aiming to achieve an international normalized ratio (INR) ranging from 2.5 to 3.5, alone or in combination with 80 mg of aspirin daily. Pregnancy morbidity is prevented by a combination of heparin with aspirin 80 mg daily. IV immunoglobulin (IVIg) 400 mg/ kg every day for 5 days may also prevent abortions, whereas glucocorticoids are ineffective. Patients with aPL in the absence of any clinical event who are simultaneously positive for aCL, anti-β2GPI, and LA or have SLE are at risk to develop thrombotic events and can be protected by aspirin 80 mg daily.


InternalMed_Harrison

InternalMed_Harrison. Some patients with APS and patients with CAPS have recurrent thrombotic events despite appropriate anticoagulation. In these cases, IVIg 400 mg/kg every day for 5 days may be of benefit. Patients with CAPS, who are treated in the intensive care unit, are unable to receive warfarin; in this situation, therapeutic doses of low-molecular-weight heparin should be administered. In cases of heparin-induced thrombocytopenia and thrombosis syndrome, inhibitors of phospholipid-bound activated factor X (FXa), such as fondaparinux 7.5 mg SC daily or rivaroxaban 10 mg PO daily, are effective. The above drugs are administered by fixed doses and do not require close monitoring; their safety during the first trimester of pregnancy has not been clearly established. Ankoor Shah, E. William St. Clair


InternalMed_Harrison

InternalMed_Harrison. Ankoor Shah, E. William St. Clair Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities.


InternalMed_Harrison

InternalMed_Harrison. Insights gained by a wealth of basic and clinical research over the past two decades have revolutionized the contemporary paradigms for the diagnosis and management of RA. Serum antibodies to cyclic citrullinated peptides (anti-CCPs) are routinely used along with rheumatoidfactorasabiomarkerofdiagnosticandprognosticsignificance. Advances in imaging modalities have improved our ability to detect jointinflammationanddestructioninRA.ThescienceofRAhastaken a major leap forward with the identification of new disease-related genes and further deciphering of the molecular pathways of disease pathogenesis. The relative importance of these different mechanisms hasbeenhighlighted by the observedbenefitsofthenewclassofhighly targeted biologic and small-molecule therapies. Despite these gains, incomplete understanding of the initiating pathogenic pathways of RA remains a sizable barrier to its cure and prevention.


InternalMed_Harrison

InternalMed_Harrison. The last two decades have witnessed a remarkable improvement in the outcomes of RA. The historic descriptions of crippling arthritis are currently encounteredmuch less frequently.Much of thisprogress can be traced to the expanded therapeutic armamentarium and the adoption of early treatment intervention. The shift in treatment strategy dictates a new mind-set for primary care practitioners—namely, one that demands early referral of patients with inflammatory arthritis to a rheumatologist for prompt diagnosis and initiation of therapy. Only then will patients achieve their best outcomes.


InternalMed_Harrison

InternalMed_Harrison. The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases. The presenting symptoms of RA typically result from inflammation of the joints, tendons, and bursae. Patients often complain of early morning joint stiffness lasting more than 1 h that eases with physical activity. The earliest involved joints are typically the small joints of the hands and feet. The initial pattern of joint involvement may be monoarticular, oligoarticular (≤4 joints), or polyarticular (>5 joints), usually in a symmetric distribution. Some patients with inflammatory arthritis will present with too few affected joints to be classified as having RA— so-calledundifferentiatedinflammatoryarthritis.Thosewithanundifferentiated arthritis who are most likely to be diagnosed later with RA have a higher number of tender and swollen joints, test positive for serum rheumatoid factor (RF) or anti-CCP antibodies, and have higher scores for physical


InternalMed_Harrison

InternalMed_Harrison. most likely to be diagnosed later with RA have a higher number of tender and swollen joints, test positive for serum rheumatoid factor (RF) or anti-CCP antibodies, and have higher scores for physical disability.


InternalMed_Harrison

InternalMed_Harrison. Once the disease process of RA is established, the wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints stand out as the most frequently involved joints (Fig. 380-1). Distal interphalangeal(DIP)jointinvolvementmayoccurinRA,butitusuallyisa manifestation of coexistent osteoarthritis. Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, and “trigger” fingers. Progressive destruction of the joints and soft tissues may lead to chronic, irreversible deformities. Ulnar deviation results from subluxation of the MCP joints, with subluxation of the proximal phalanx to the volar side of the hand. Hyperextension of the PIP joint with flexion of the DIP joint (“swanneck deformity”), flexion of the PIP joint with hyperextension of the DIP joint (“boutonnière deformity”), and subluxation of the first MCP jointwithhyperextensionofthefirstinterphalangeal(IP)joint(“Z-line


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 380-1 Metacarpophalangeal and proximal interphalangeal joint swelling in rheumatoid arthritis. (Courtesy of the American College of Rheumatology Image Bank.) Ocular: Keratoconjunctivitis sicca, episcleritis, scleritis Neurologic: Cervical myelopathy Hematologic: Anemia of


InternalMed_Harrison

InternalMed_Harrison. Ocular: Keratoconjunctivitis sicca, episcleritis, scleritis Neurologic: Cervical myelopathy Hematologic: Anemia of Oral: Xerostomia, periodontitis chronic disease, neutropenia, splenomegaly, Felty’s syndrome, large granular lymphocyte leukemia, lymphoma deformity”) also may result from damage to the tendons, joint capsule, 2137 and other soft tissues in these small joints. Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause subluxation of the distal ulna, resulting in a “piano-key movement” of the ulnar styloid. Although metatarsophalangeal (MTP) joint involvement in the feet is an early feature of disease, chronic inflammation of the ankle and midtarsal regions usually comes later and may lead to pes planovalgus (“flat feet”). Large joints, including the knees and shoulders, are often affected in established disease, although these joints may remain asymptomatic for many years after onset.


InternalMed_Harrison

InternalMed_Harrison. Atlantoaxial involvement of the cervical spine is clinically noteworthy because of its potential to cause compressive myelopathy and neurologic dysfunction. Neurologic manifestations are rarely a presenting sign or symptom of atlantoaxial disease, but they may evolve over time withprogressive instability of C1 on C2.Theprevalenceof atlantoaxial subluxation has been declining in recent years, and occurs now in less than 10% of patients. Unlike the spondyloarthritides (Chap. 384), RA rarely affects the thoracic and lumbar spine. Radiographic abnormali ties of the temporomandibular joint occur commonly in patients with RA, but they are generally not associated with significant symptoms or functional impairment.


InternalMed_Harrison

InternalMed_Harrison. Extraarticular manifestations may develop during the clinical course of RA, even prior to the onset of arthritis (Fig. 380-2). Patients most likely to develop extraarticular disease have a history of smoking, have early onset of significant physical disability, and test positive for serum RF. Subcutaneous nodules, secondary Sjögren’s syndrome, pulmonary nodules, and anemia are among the most frequently observed Pulmonary: Pleural effusions, pulmonary nodules, interstitial lung disease, pulmonary vasculitis, organizing pneumonia Cardiac: Pericarditis, ischemic heart disease, myocarditis, cardiomyopathy, arrhythmia, mitral regurgitation Renal: Membranous nephropathy, secondary GI: Vasculitis amyloidosis Skeletal: Osteoporosis Endocrine: Hypoandrogenism Skin: Rheumatoid nodules, purpura, pyoderma gangrenosum FIGUrE 380-2 Extraarticular manifestations of rheumatoid arthritis.


InternalMed_Harrison

InternalMed_Harrison. Skeletal: Osteoporosis Endocrine: Hypoandrogenism Skin: Rheumatoid nodules, purpura, pyoderma gangrenosum FIGUrE 380-2 Extraarticular manifestations of rheumatoid arthritis. 2138 extraarticular manifestations. Recent studies have shown a decrease in the incidence and severity of at least some extraarticular manifestations, particularly Felty’s syndrome and vasculitis. The most common systemic and extraarticular features of RA are described in more detail in the sections below. These signs and symptoms include weight loss, fever, fatigue, malaise, depression, and in the most severe cases, cachexia; they generally reflect a high degree of inflammation and may even precede the onset of joint symptoms. In general, the presence of a fever of >38.3°C (101°F) at any time during the clinical course should raise suspicion of systemic vasculitis (see below) or infection.


InternalMed_Harrison

InternalMed_Harrison. Subcutaneous nodules occur in 30–40% of patients and more commonly in those with the highest levels of disease activity, the disease-related shared epitope (see below), a positive test for serum RF, and radiographic evidence of joint erosions. When palpated, the nodules aregenerally firm; nontender; andadherent toperiosteum, tendons, or bursae; developing in areas of the skeleton subject to repeated trauma or irritation such as the forearm, sacral prominences, and Achilles tendon. They may also occur in the lungs, pleura, pericardium, and peritoneum.Nodules are typicallybenign,although they canbe associated with infection, ulceration, and gangrene. Secondary Sjögren’s syndrome (Chap. 383) is defined by the presence of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with another connective tissue disease, such as RA. Approximately 10% of patients with RA have secondary Sjögren’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. Pleuritis, the most common pulmonary manifestation of RA, may produce pleuritic chest pain and dyspnea, as well as a pleural friction rub and effusion. Pleural effusions tend to be exudative with increased numbers of monocytes and neutrophils. Interstitial lung disease (ILD) may also occur in patients with RA and is heralded by symptoms of dry cough and progressive shortness of breath. ILD can be associated with cigarette smoking and is generally found in patients with higher disease activity, although it may be diagnosed in up to 3.5% of patients prior to the onset of joint symptoms. Diagnosis is readily made by high-resolution chest computed tomography (CT) scan. Pulmonary function testing shows a restrictive pattern (e.g., reduced total lung capacity) with a reduced diffusing capacity for carbon monoxide (DLCO). The presence of ILD confers a poor prognosis. The prognosis is not quite as poor as that of idiopathic pulmonary fibrosis (e.g., usual interstitial pneumonitis) because ILD


InternalMed_Harrison

InternalMed_Harrison. carbon monoxide (DLCO). The presence of ILD confers a poor prognosis. The prognosis is not quite as poor as that of idiopathic pulmonary fibrosis (e.g., usual interstitial pneumonitis) because ILD secondary to RA responds more favorably than idiopathic ILD to immunosuppressive therapy (Chap. 315). Pulmonary nodules may be solitary or multiple. Caplan’s syndrome is a rare subset of pulmonary nodulosis characterized by the development of nodules and pneumoconiosis following silica exposure. Other less common pulmonary findings include respiratory bronchiolitis and bronchiectasis.


InternalMed_Harrison

InternalMed_Harrison. The most frequent site of cardiac involvement in RA is the pericardium. However, clinical manifestations of pericarditis occur in less than 10% of patients with RA despite the fact that pericardial involvement may be detected in nearly one-half of the these patients by echocardiogram or autopsy studies. Cardiomyopathy, another clinically important manifestation of RA, may result from necrotizing or granulomatous myocarditis, coronary artery disease, or diastolic dysfunction. This involvement too may be subclinical and only identified by echocardiography or cardiac magnetic resonance imaging (MRI). Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid. Mitral regurgitation is the most common valvular abnormality in RA, occurring at a higher frequency than the general population.


InternalMed_Harrison

InternalMed_Harrison. Rheumatoid vasculitis (Chap. 385) typically occurs in patients with long-standing disease, a positive test for serum RF, and hypocomplementemia. The overall incidence has decreased significantly in the last decade to be less than 1% of patients. The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene, livedo reticularis, and in severe cases large, painful lower extremity ulcerations. Vasculitic ulcers, which may be difficult to distinguish from those caused by venous insufficiency, may be treated successfully with immunosuppressive agents (requiring cytotoxic treatment in severe cases) as well as skin grafting. Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in association with systemic rheumatoid vasculitis.


InternalMed_Harrison

InternalMed_Harrison. A normochromic, normocytic anemia often develops in patients with RA and is the most common hematologic abnormality. The degree of anemia parallels the degree of inflammation, correlating with the levels of serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Platelet counts may also be elevated in RA as an acute-phase reactant. Immune-mediated thrombocytopenia is rare in this disease.


InternalMed_Harrison

InternalMed_Harrison. Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly, and nodular RA and is seen in less than 1% of patients, although its incidence appears to be declining in the face of more aggressive treatment of the joint disease. It typically occurs in the late stages of severe RA and is more common in whites than other racial groups. T cell large granular lymphocyte leukemia (T-LGL) may have a similar clinical presentation and often occurs in association with RA. T-LGL is characterized by a chronic, indolent clonal growth of LGL cells, leading to neutropenia and splenomegaly. As opposed to Felty’s syndrome, T-LGL may develop early in the course of RA. Leukopenia apart from these disorders is uncommon and most often due to drug therapy.


InternalMed_Harrison

InternalMed_Harrison. Large cohort studies have shown a two-to fourfold increased risk of lymphoma in RA patients compared with the general population. The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma. The risk of developing lymphoma increases if the patient has high levels of disease activity or Felty’s syndrome. In addition to extraarticular manifestations, several conditions associated with RA contribute to disease morbidity and mortality rates. They are worthy of mention because they affect chronic disease management.


InternalMed_Harrison

InternalMed_Harrison. Cardiovascular Disease The most common cause of death in patients with RA is cardiovascular disease. The incidence of coronary artery disease and carotid atherosclerosis is higher in RA patients than in the general population even when controlling for traditional cardiac risk factors, such as hypertension, obesity, hypercholesterolemia, diabetes, and cigarette smoking. Furthermore, congestive heart failure (including both systolic and diastolic dysfunction) occurs at anapproximately twofold higher rate in RA than in the general population. The presence of elevated serum inflammatory markers appears to confer an increased risk of cardiovascular disease in this population.


InternalMed_Harrison

InternalMed_Harrison. Osteoporosis Osteoporosis is more common in patients with RA than an age-and sex-matched population, with prevalence rates of 20–30%. The inflammatory milieu of the joint probably spills over into the rest of the body and promotes generalized bone loss by activating osteoclasts.Chronicuseofglucocorticoidsanddisability-relatedimmobility also contributes to osteoporosis. Hip fractures are more likely to occur in patients withRA and are significant predictors of increased disability and mortality rate in this disease.


InternalMed_Harrison

InternalMed_Harrison. Hypoandrogenism Men and postmenopausal women with RA have lower mean serum testosterone, luteinizing hormone (LH), and dehydroepiandrosterone (DHEA) levels than control populations. It has thus been hypothesized that hypoandrogenism may play a role in the pathogenesis of RA or arise as a consequence of the chronic inflammatory response. It is also important to realize that patients receiving chronicglucocorticoidtherapymaydevelophypoandrogenismowingto inhibition of LH and follicle-stimulating hormone (FSH) secretion from the pituitary gland. Because low testosterone levels may lead to osteoporosis, men with hypoandrogenism should be considered for androgen replacement therapy.


InternalMed_Harrison

InternalMed_Harrison. RA affects approximately 0.5–1% of the adult population worldwide. There is evidence that the overall incidence of RA has been decreasing in recent decades, whereas the prevalence has remained the same because individuals with RA are living longer. The incidence and prevalence of RA varies based on geographic location, both globally and among certain ethnic groups within a country (Fig. 380-3). For example, the Native American Yakima, Pima, and Chippewa tribes of North America have reported prevalence rates in some studies of nearly 7%. In contrast, many population studies from Africa and Asia show lower prevalence rates for RA in the range of 0.2–0.4%.


InternalMed_Harrison

InternalMed_Harrison. Like many other autoimmune diseases, RA occurs more commonly infemalesthaninmales,witha2–3:1ratio.Interestingly,studiesofRA from some of the Latin American and African countries show an even greater predominance of disease in females compared to males, with ratios of 6–8:1. Given this preponderance of females, various theories have been proposed to explain the possible role of estrogen in disease pathogenesis. Most of the theories center on the role of estrogens in enhancing the immune response. For example, some experimental studies have shown that estrogen can stimulate production of tumor necrosis factor a (TNF-α), a major cytokine in the pathogenesis of RA. It has been recognized for over 30 years that genetic factors contribute to the occurrence of RA as well as to its severity. The likelihood that a first-degree relative of a patient will share the diagnosis of RA is 2–10 times greater than in the general population. European ancestry: HLA-DRB1:


InternalMed_Harrison

InternalMed_Harrison. European ancestry: HLA-DRB1: PTPN22: European STAT4: North American TNFAIP3: North American TRAFI/CF: North American CTLA4: European Asian ancestry: HLA-DRB1: *0401 (East Asian) *0405 *0901 (Japanese, Malaysian, Korean) Other: CD40 There remains, however, some uncertainty in the extent to which 2139 geneticsplaysaroleinthecausativemechanismsofRA.Althoughtwin studies imply that genetic factors may explain up to 60% of the occurrence of RA, the more commonly stated estimate falls in the range of 10–25%. The estimate of genetic influence may vary across studies due to gene–environment interactions.


InternalMed_Harrison

InternalMed_Harrison. The alleles known to confer the greatest risk of RA are located within the major histocompatibility complex (MHC). It has been estimated that one-third of the genetic risk for RA resides within this locus. Most, but probably not all, of this risk is associated with allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule. The disease-associated HLA-DRB1 alleles share an amino acid sequence at positions 70–74 in the third hypervariable regions of the HLA-DR β-chain, termed the shared epitope (SE). Carriership of the SE alleles is associated with production of anti-CCP antibodies and worse disease outcomes. Some of these HLA-DRB1 alleles bestow a high risk of disease (*0401), whereas others confer a more moderate risk (*0101, *0404, *1001, and *0901). Additionally, there is regional variation. In Greece, for example, where RA tends to be milder than in western European countries, RA susceptibility has been associated with the *0101 SE allele. By comparison, the


InternalMed_Harrison

InternalMed_Harrison. there is regional variation. In Greece, for example, where RA tends to be milder than in western European countries, RA susceptibility has been associated with the *0101 SE allele. By comparison, the *0401 or *0404 alleles are found in approximately 50–70% of northern Europeans and are the predominant risk alleles in this group. The most common disease susceptibility SE alleles in Asians, namely the Japanese, Koreans, and Chinese, are *0405 and *0901. Lastly, disease susceptibility of Native American populations such as the Pima and Tlingit Indians, where the prevalence of RA can be as high as 7%, is associated with the SE allele *1042.TheriskofRAconferredbytheseSEallelesislessinAfricanand Hispanic Americans than in individuals of European ancestry.


InternalMed_Harrison

InternalMed_Harrison. Genome-wide association studies (GWAS) have made possible the identification of several non-MHC-related genes that contribute to RA susceptibility. GWAS are based on the detection of single-nucleotide polymorphisms (SNPs), which allow for examination of the genetic architecture of complex diseases such as RA. There are approximately 10 million common SNPs within a human genome consisting of 3 billion base pairs. As a rule, GWAS identify only common variants, namely, those with a frequency of more than 5% in the general population. Overall, several themes have emerged from GWAS in RA. First, the non-MHC loci identified as risk alleles for RA have only a modest US: 0.7-1.3% Brazil: 0.4-1.4% Jamaica: 1.9-2.2% UK: 0.8-1.1% South Africa: 2.5-3.6% Lesotho: 1.7-4.5% Saudi Arabia: 0.1-0.2% Java: 0.1-0.2% Liberia: 2-3% Norway: 0.4% Spain: 0.2-0.8% Greece: 0.3-1% Bulgaria: 0.2-0.6% Iraq: 0.4-1.5% India: 0.1-0.4% Japan: 0.2-0.3% Hong Kong: 0.1-0.5%


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 380-3 Global prevalence rates of rheumatoid arthritis (RA) with genetic associations. Listed are the major genetic alleles associated with RA. Although human leukocyte antigen (HLA)-DRB1 mutations are found globally, some alleles have been associated with RA in only certain ethnic groups.