Rheumatologic Diseases in the Intensive Care Unit
Nancy Y.N. Liu
Judith A. Stebulis
Patients with established rheumatologic diseases are rarely admitted to the intensive care unit (ICU) because of their inflammatory joint disease. However, since many of these diseases include systemic involvement, organ system failure and complications of therapy are common reasons for ICU admission. Other musculoskeletal problems frequently encountered in the intensive care setting include (a) patients whose underlying rheumatic diseases may pose certain problems in the planning and execution of certain critical care procedures, such as endotracheal intubation or (b) patients in whom acute rheumatic syndromes develop during their hospitalization.
Acute Rheumatic Diseases in the Intensive Care Setting
Several acute musculoskeletal disorders occur with increasing frequency in selected populations of hospitalized patients, including those in the ICU. The most common is crystal-induced arthritis due to monosodium urate, calcium pyrophosphate dihydrate, basic calcium phosphate (BCP)-hydroxyapatite, or calcium oxalate crystals. Two other acute arthritides include septic arthritis from bacteremia and spontaneous hemarthrosis due to complications from anticoagulation therapy or bleeding diathesis.
Gout
Pathogenesis
Gout is characterized by initial intermittent attacks of mono- or polyarticular arthritis in the setting of prolonged hyperuricemia. Over many years, attacks become more frequent and chronic arthropathy may develop. Acute gout is triggered by precipitation or shedding of monosodium urate crystals in the joint space or nearby soft tissues, provoking an intense inflammatory reaction. Regardless of a primary or secondary etiology of hyperuricemia, marked fluctuations in serum urate levels increase the risk of acute gout.
Although the specific triggering event that initiates an isolated attack may be difficult to define, many factors produce serum urate fluctuations and result in an increased incidence of secondary gout in ICU patients. A reduction in glomerular filtration rate from either intrinsic renal disease or decreased effective arteriolar blood volume will result in reduced filtered load of urate, hyperuricemia, and an increased risk of gout. In addition, a reduction in effective arteriolar blood volume results in enhanced tubular reabsorption of urate. Since organic acids such as lactic acid, β-hydroxybutyric acid, and acetoacetic acid may competitively inhibit the renal tubular secretion of uric acid, conditions in which these acids accumulate will also lead to hyperuricemia. Mechanisms of hyperlacticacidemia in the critically ill patient are multiple.
Drug-induced hyperuricemia is a common cause of gout in both hospitalized and nonhospitalized patients. Diuretic therapy decreases effective arteriolar blood volume and also may directly inhibit renal tubular secretion of uric acid. Although thiazide diuretics are the most commonly implicated cause of hyperuricemia and gout, other diuretics including furosemide, acetazolamide, ethacrynic acid, and diazoxide are also potential culprits. Furosemide and diazoxide may also induce hyperlacticacidemia.
In addition to diuretics, other drugs associated with hyperuricemia include low-dose salicylates (less than 2.0 g per day), pyrazinamide, levodopa, α-methyldopa, and cyclosporine. Because of the uricosuric effect of radiocontrast media, a contrast study might precipitate an attack of acute gout. Finally, a hyperuricemic patient who undergoes any surgical procedure is at risk for postoperative gout.
Clinical Features
Gout is easily identifiable and treatable. Classically, the patient with acute gout complains of sudden onset of an exquisitely painful joint that involves one or more sites in an asymmetric pattern. The attack is sometimes accompanied by low-grade fever, particularly in a polyarticular presentation. The great toe is involved in more than 50% of the initial acute attacks and in 90% of acute attacks at some time in the course of the disease. Other common sites of involvement in order of observed frequency include insteps, ankles, knees, wrists, fingers, and elbows. Periarticular sites of urate deposition in bursae, tendons, and soft tissues may be similarly inflamed during an acute attack. On examination, the involved area is erythematous, swollen, warm, and exquisitely painful on palpation, and sometimes with joint motion. The overlying erythema and edema often extends beyond the joint capsule and can mimic cellulitis or bursitis. The presence of lymphangitis or lymphadenopathy and the absence of pain on joint motion are more consistent with cellulitis. Bursitis can be distinguished from true arthritis since full joint extension is preserved in bursitis, and the region of erythema is not within the borders of the joint compartment. If clinical suspicion of joint infection is low then diagnostic arthrocentesis should be avoided until a therapeutic trial of appropriate antibiotics for cellulitis has been completed. Otherwise, there may be a risk of introducing organisms into a sterile joint. However, if motion is restricted or if radiography suggests an effusion, a diagnostic arthrocentesis should be performed before the institution of any therapy.
The diagnosis of gout is confirmed when aspirated synovial fluid or soft tissue site reveals negatively birefringent monosodium urate crystals within polymorphonuclear neutrophils (PMNs) under polarizing light microscopy. Gouty synovial fluid is inflammatory, with more than 2,000 leukocytes
per μL, occasionally as high as 100,000 per μL, and PMNs predominate in the cell differential. Since gout and septic arthritis have similar clinical features and rarely coexist, aspirated synovial fluid should always be Gram stained for microorganisms and cultured. Elevations in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and peripheral leukocytosis cannot distinguish gout from other inflammatory states. Serum urate may be normal during an acute attack, while an elevated level does not confirm the diagnosis without crystal identification.
per μL, occasionally as high as 100,000 per μL, and PMNs predominate in the cell differential. Since gout and septic arthritis have similar clinical features and rarely coexist, aspirated synovial fluid should always be Gram stained for microorganisms and cultured. Elevations in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and peripheral leukocytosis cannot distinguish gout from other inflammatory states. Serum urate may be normal during an acute attack, while an elevated level does not confirm the diagnosis without crystal identification.
Therapy
Once the diagnosis of acute gout is established, the immediate aim of therapy is to terminate the attack by interruption of the inflammatory response. Long-term management (e.g., prevention of recurrent attacks, sequelae of tophaceous disease or renal stones) need not be considered in the ICU setting. In fact, the initiation or discontinuation of any drugs that alter urate levels (i.e., allopurinol, febuxostat, probenecid, or salicylates) may prolong the acute attack. Asymptomatic hyperuricemia should not be treated.
Corticosteroids
Systemic and intra-articular steroids are effective for the treatment of gout. Intravenous (IV) methylprednisolone (100 to 150 mg IV daily for 1 to 3 days) or intramuscular triamcinolone acetonide (60 to 80 mg daily for 1 to 3 days) is the preferred agent in critically ill patients [1]. Oral prednisone may also be effective in doses of 20 to 30 mg twice per day initially and tapered over 7 to 14 days with decrements of 10 mg every two days [1]. Potential complications of steroid treatment include hyperglycemia, fluid retention secondary to mineralocorticoid effects, and hypothalamic-pituitary-adrenal suppression. Intra-articular corticosteroid injections are an excellent choice for acute gouty arthritis if few joints are involved since systemic side effects are avoided. Steroid injections provide rapid resolution of symptoms, usually within 12 to 24 hours, but if infection is suspected, corticosteroid injection should be delayed until culture results are available. Intra-articular corticosteroids are quite effective in small joints if performed by physicians skilled in these injections. Dosing ranges from 10 to 60 mg methylprednisolone or equivalent triamcinolone, depending on the size of the joint involved.
Adrenocorticotropic Hormone
Adrenocorticotropic hormone (ACTH) has been used for more than 40 years for the treatment of gout. Dosing regimens vary, starting at 40 to 80 IU intramuscularly, subcutaneously, or intravenously 1 to 3 times a day until symptoms abate. Adverse effects include mild hyperglycemia and fluid overload. Although the overall safety profile and efficacy of ACTH are excellent, its use is limited by its lack of availability and prohibitive cost. Its anti-inflammatory effects are result of interruptions of microtubule function in multiple cell types but particularly PMNs’ function in chemotaxis, adhesion, phagocytosis, and production of cytokines.
Colchicine
Colchicine is one of the established treatments for gout. Its main mechanism of action involves formation of a reversible complex with the tubulin subunit of microtubules leading to reduced activation and migration of PMNs. Oral colchicine is absorbed in the small intestine and excreted in the bile and urine, reaching a peak serum level in 2 hours. Gastrointestinal side effects, most notably diarrhea, occur in up to 80% of patients, resulting in electrolyte imbalances and fluid losses. In the critically ill patient, oral colchicine may not be feasible and is potentially toxic. Renal and hepatic insufficiencies are risk factors for colchicine related neuromyopathy and bone marrow suppression. In addition, potential drug–drug interactions, including macrolide antibiotics, HMG-CoA reductase inhibitors, fibric acid derivatives, verapamil and diltiazem, and cyclosporine may potentiate colchicine toxicities.
A recent study reports equal efficacy in reducing pain of acute gout with low dose colchicine (1.2 mg orally followed in 1 hour by another 0.6 mg orally) to traditional oral loading of colchicine (1.2 mg orally followed by 0.6 mg every hour for 6 hours) [2]. In addition, the gastrointestinal side effects are significantly reduced with the low dose regimen. Thus, if an ICU patient with an acute onset of gout has normal renal and hepatic function and is able to take oral colchicine, the low dose regimen is a reasonable choice. However, if there is renal insufficiency, dose adjustment is necessary and colchicine is probably best avoided if creatinine clearance is less than 10 mL per minute. A more appropriate use of oral colchicine is the prevention of subsequent attacks once the acute attack is treated. Dosages of 0.6 mg orally once or twice a day have been effective (again dose adjustment is necessary based on GFR) [3]. The most common side effects include nausea, diarrhea, and proximal myopathy with elevated creatinine kinase levels. The risk of myotoxicity correlates with a creatinine clearance of less than 50 mL per minute.
Intravenous colchicine has been used in the past for acute gout. However, due to numerous deaths and inappropriate use of the intravenous route, the United States Food and Drug Administration has recommended the discontinuation of production of intravenous colchicine since 2008 and it is unavailable at this time.
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of acute gout. However, the mechanism of action involves prostaglandin inhibition, which can interfere with gastric mucosal integrity and worsen renal function by reducing renal perfusion in the setting of volume contraction. NSAIDs may also cause other side effects, including decreased coronary flow and mental status changes. Although the cyclooxygenase-2 inhibitor agents offer the possibility of fewer adverse events, their safety profile is based on outpatient experience. Serious adverse effects with these newer agents have been reported. Given the fact that many patients in the ICU have some degree of renal disease and are at risk for gastrointestinal bleeding, NSAIDs are rarely a first-line agent in the treatment of gout in the ICU.
Other Microcrystalline Arthropathies
Although gout is the best-defined and most common crystalline arthropathy, several other crystalline-induced syndromes may mimic gout and cause potential diagnostic confusion. These include calcium pyrophosphate dihydrate (CPPD), BCP-hydroxyapatite, or calcium oxalate crystals.
Pathogenesis
The pathophysiology of these entities appears to be similar to that of gouty arthritis, involving a complex series of biochemical reactions that lead to an inflammatory response within the involved joint or periarticular region. Similar to gout, each of these disorders may be more common in a specific subset of ICU patients.
The acute, self-limited form of CPPD deposition (also known as pseudogout) may be precipitated by surgery of any type and is related to downward fluxes in serum calcium levels that lead to crystal shedding into intra-articular spaces. Attacks commonly occur several days postoperatively and often involve the knee or wrist. Severe medical illnesses, such as ischemic heart disease, cerebral infarction, and thrombophlebitis, may also provoke attacks of CPPD arthritis.
Clinical Features
Clinically, each of the above crystalline arthropathies is indistinguishable from acute gout. The presence of radiographic calcification in hyaline or articular cartilage of the involved joint (i.e., chondrocalcinosis) suggests the diagnosis of pseudogout, but the diagnosis is confirmed by visualizing weakly positively birefringent, rhomboid-shaped CPPD crystals within synovial fluid PMN under polarizing microscopy. Calcium oxalate crystals, likewise, are positively birefringent, but they are pleomorphic, bipyramidal, or rod-like in shape. Smaller BCP-hydroxyapatite crystals, however, are not visible under polarizing microscopy, and a presumptive diagnosis is made given the clinical setting, the exclusion of other diagnoses, and the occasional presence of periarticular, amorphous calcifications on radiographs.
Therapy
Therapeutic options are limited in the ICU patient if NSAIDs are contraindicated. Isolated joints can be aspirated and injected with corticosteroids once infection is excluded. Alternatively, a regimen of tapering corticosteroids similar to acute gout is effective. Pseudogout may also respond dramatically to colchicine in dosing similar to gout. Low dose colchicine is also used to prevent recurrent attacks in patients who have frequent events.
Septic Arthritis
Joint infection is the most critical diagnosis to establish and treat in any ICU patient who develops acute mono- or oligoarthritis. A delay in the diagnosis and treatment of septic arthritis may lead to destruction of articular cartilage and loss of joint function. Furthermore, a diagnosis of septic arthritis may help identify and initiate early treatment of the source of septicemia, such as endocarditis (see Chapter 80).
Pathogenesis
Risk factors for development of septic arthritis include diabetes mellitus, age over 80, skin infections, rheumatoid arthritis (RA), intravenous drug abuse, alcoholism, recent joint surgery, low socioeconomic status, and presence of prosthetic joints [4]. In addition, patients in the ICU often have multiple invasive procedures, indwelling lines, or catheters that are potential portals of infection. Whether or not these predisposing factors exist, acute septic arthritis usually develops from hematogenous seeding from another site of infection. Direct inoculation or local extension from adjacent soft tissue infection or osteomyelitis is less common. Prosthetic joints or damaged joints from rheumatoid or osteoarthritis are particularly susceptible to hematogenous seeding. Once an infection is established within a joint, a complex cascade of physiologic responses occurs that leads to a severe inflammatory reaction with subsequent cartilage degradation and bone destruction. The rapidity and severity of this process depends on the virulence of the organism and the length of time delay before appropriate antibiotics are started.
Clinical Features
Clinically, septic arthritis may be indistinguishable from crystalline arthritis or other inflammatory joint diseases. The presentation is often acute and monoarticular with physical findings of warmth, swelling, tenderness, and erythema within the confines of the joint margins, and markedly limited joint motion. The knee, hip, shoulder, elbow, and ankle are the most common joints involved. Atypical joints such as the sternoclavicular, symphysis pubis, or sacroiliac joints are common sites of infection in younger patients, or those with a history of intravenous drug use. Polyarticular infections may occur in 20% of the cases in reported studies [4], particularly in patients with rheumatoid arthritis. Fever is a variable finding and when present, it may be low grade.
High clinical suspicion remains essential to the diagnosis of septic arthritis. Unless physical examination indicates extra-articular features (e.g., cellulitis), any ICU patient with an acutely swollen, painful joint needs a diagnostic arthrocentesis to exclude infection. In the case of suspected cellulitis, appropriate antibiotics should be administered and arthrocentesis performed only if symptoms or findings do not improve within 48 hours. The diagnosis of septic arthritis is supported by an elevated white blood cell count (WBC), ESR, and CRP, but these studies cannot reliably differentiate infection from other inflammatory processes. Conversely, the absence of fever or normal ESR or CRP cannot exclude septic arthritis. Thus, synovial fluid analysis can confirm septic arthritis and identify organisms on Gram’s stain or in culture. The fluid should be transferred immediately to the laboratory, both anaerobic and aerobic cultures should be ordered routinely, and special requests for fungus or other organisms that require a special growth medium (e.g., Neisseria gonorrhoeae) are ordered if clinically indicated. In addition, synovial fluid analysis for WBC with differential and crystal search may support a diagnosis of infection before microbiology results are available. Although leukocyte counts under 20,000 per μL have been associated with septic arthritis, the WBC generally exceeds 50,000 per μL and on occasion may be as high as 200,000 per μL with a marked PMN predominance. A meta-analysis of various laboratory studies in septic arthritis suggests that the likelihood ratio of septic arthritis increases incrementally with higher synovial leukocyte counts [5]. However, since septic arthritis has been associated with WBC as low as 2,000 per μL to 50,000 per μL, the absolute number cannot differentiate septic arthritis from other inflammatory states such as rheumatoid, psoriatic, or crystalline arthritis.
Although initial radiographs of the infected joint are often normal, baseline x-rays are useful to identify preexisting joint abnormalities and for comparison to identify subsequent changes of septic damage. MRI imaging may be helpful to evaluate joints that are difficult to assess clinically (i.e. spine, sacroiliac, or hip), bone for underlying osteomyelitis, and soft tissue for sinus tracts. Classic late radiographic findings include juxta-articular osteopenia, joint-space narrowing, or subchondral bone loss.
Therapy
Once the diagnosis of septic arthritis is either strongly suspected on clinical grounds or documented by positive Gram’s stain or culture, treatment requires adequate drainage in addition to appropriate antibiotics. N. gonorrhoeae is the most common cause of septic arthritis in patients under the age of 30, but overall, Staphylococcus aureus (S. aureus), including methicillin resistant S. aureus (MRSA), is the most common organism in the immunocompetent patient, followed in frequency by Streptococcal species. Together, these Gram-positive organisms made up 91% of septic arthritis in a prospective study [6]. Gram negative and anaerobic organisms occur less frequently but must be suspected in patients at risk (elderly, immunocompromised, recent hospitalization or surgery, prior antibiotics, and possible urogenital or abdominal infections) [4]. In the critically ill patient with multiple risk factors, broad-spectrum antibiotic coverage against staphylococcus and streptococcus, Gram-negative bacteria, and pseudomonas should be initiated until culture results are available. Fungal or mycobacterial septic arthritis is often subacute or chronic and thus unlikely to be
initially considered but remains the possible cause if symptoms persist. Candida organisms have caused acute arthritis and the Gram stain may be positive before cultures are available. The duration of antibiotic therapy varies according to the clinical situation, but antibiotics should be continued intravenously for at least 2 weeks. Further route and duration of therapy depend on the specific type and sensitivity of identified organism and the patient’s clinical response. However, the length of treatment is usually at least 4 weeks for nongonococcal septic arthritis. Please refer to Chapter 77 for appropriate antibiotic treatment and dosing for presumptive or identified infectious organisms.
initially considered but remains the possible cause if symptoms persist. Candida organisms have caused acute arthritis and the Gram stain may be positive before cultures are available. The duration of antibiotic therapy varies according to the clinical situation, but antibiotics should be continued intravenously for at least 2 weeks. Further route and duration of therapy depend on the specific type and sensitivity of identified organism and the patient’s clinical response. However, the length of treatment is usually at least 4 weeks for nongonococcal septic arthritis. Please refer to Chapter 77 for appropriate antibiotic treatment and dosing for presumptive or identified infectious organisms.
Drainage of the infected joint either with serial percutaneous needle aspirations or surgical intervention is also crucial. Since there are no prospective studies comparing these options, controversy exists regarding the optimal approach. The physical removal of inflammatory cells, cellular debris, lysosomal enzymes, and bacterial byproducts reduce the potential damage to the joint. Prosthetic joints and other native joints such as hip, shoulder, wrist, finger, sacroiliac or sternoclavicular joints require immediate surgical intervention, while native septic knees may respond to serial percutaneous needle aspiration. Arthroscopy or arthrotomy has the advantage of more complete debridement of fibrin, infected synovium, and loculations. However, percutaneous drainage may be the only option in a critically ill patient who is unstable for surgery. Indications for surgical intervention include initial delay in diagnosis, established joint damage from RA or osteoarthritis, failure to sterilize the joint fluid after 3 to 5 days of antibiotics, difficult percutaneous aspirations due to loculations, or infection with Gram-negative bacterium. Thus, the ideal approach is to consult both the orthopedist and rheumatologist at the time of diagnosis to decide on optimal management.
The affected joint should be immobilized in functional position in the first few days. Once antibiotics are given and drainage has been performed, early physical therapy with passive range of motion and graduation to active range of motion will improve outcome [7].
Finally, since septic arthritis usually occurs as a consequence of bacteremia from a distant primary source of infection, investigation for these sites must be pursued. Unless an obvious site of local inoculation is present, cultures from blood, urine, sputum, indwelling lines, and catheters should be obtained before the institution of antibiotics. In addition, imaging studies such as echocardiography, tomography (CT), or gallium scanning might locate the source of infection.
Septic Arthritis in the Prosthetic Joint
Although rates of prosthetic joint infections (PJI) are generally quite low, 0.8% to 1.9% and 0.3% to 1.7% for knees and hips, respectively [8], RA patients have an increased risk of developing infected prosthetic joints. Risk factors are similar for native septic arthritis discussed previously as well as a history of prior infection of prosthetic joint at the same site or revision arthroplasty. Early infection, usually within 3 months of surgery, is usually due to S. aureus or more virulent organisms from direct inoculation at the time of surgery; chronic infections with less aggressive bacterium including coagulase-negative staphylococci occur often months to years after the replacement. Bacteremia with seeding of a prosthetic joint can occur anytime. Causative organisms for PJI are predominantly Gram-positive cocci (65%); aerobic Gram-negative bacilli and anaerobes contribute 10%, while 20% are polymicrobial infections [8].
Clinical features of acute PJI include localized pain, fever (occurring in < 50%), and elevation of ESR, while more chronic infections may present with only pain and loosening of hardware on radiograph. CRP elevation of more than 5 mg per L has a sensitivity of 95% and specificity of 62% in the diagnosis of PJI [9]. Plain radiographs cannot distinguish aseptic periprosthetic loosening from infection. Computed tomography and magnetic imaging may be distorted by ferromagnetic prostheses. The imaging of choice for the diagnosis of PJI is indium-111 labeled WBC in combination with technetium-99m-labeled sulfur colloid bone scan [10]. Synovial fluid studies are as useful in prosthetic joint infections as native joint infections. However, a synovial fluid WBC more than 1,700 cells per μL from the prosthetic knee joint or more than 4,200 cell per μL from the prosthetic hip joint with predominantly PMNs on the differential is enough to suggest infection [8]. If aspiration is not done before surgery, then intraoperative sampling of multiple periprosthetic tissue sites will increase the yield of an organism. Culture of the removed prosthesis may also provide additional microbial information.
Treatment of suspected PJI should initially cover both Gram-negative and Gram-positive organisms with a regimen such as vancomycin and an aminoglycoside until microbiology results and antibiotic sensitivities are available (see Chapter 77). Initial infectious disease consultation will help guide therapy.
Antibiotics alone without surgical intervention, however, are rarely successful. If the patient is a surgical candidate, options include: (1) resection arthroplasty, (2) one or two stage surgery with prosthesis removal and reimplantation, or (3) surgical debridement with retention of prosthesis with or without long-term oral antibiotic suppression. The first option is rarely performed unless the patient has failed previous surgical attempts at eradicating the infection or is likely to have minimal functional improvement after replacement. Chronic PJI requires resection arthroplasty with one or two stage exchanges. The latter usually entails removal of the infected prosthesis, treatment with antibiotics with or without an antibiotic loaded spacer for a period of 6 to 12 weeks, and then subsequent reimplantation. Debridement with retention of the infected prosthesis is an option only if (i) age of the prosthesis is less than 3 months; (ii) symptoms have been present for less than 3 weeks; (iii) absence of sinus tract communicating with joint space; (iv) no radiographic evidence of prosthetic loosening; (v) infection not involving S. aureus, Pseudomonas aeruginosa, enterococcus, fungal or multidrug resistant organisms; and (vi) absence of comorbidities such as diabetes and rheumatoid arthritis [11]. Prolonged oral antibiotics (3 months for hips and 6 months for knees) are recommended in patients treated with debridement with implant retention [8].
Hemarthrosis
In the absence of an underlying inherited disorder of coagulation, hemarthrosis in the intensive care setting is most likely a complication of anticoagulation therapy, most frequently described in patients receiving an oral anticoagulant (sodium warfarin). Since hemarthrosis may occur spontaneously in an anticoagulated patient, a history of trauma is often absent. Clinically, a patient develops a monoarticular, painful, swollen, warm, and tense effusion. A prolongation of coagulation parameters suggests the diagnosis, but diagnostic arthrocentesis is essential to confirm the diagnosis of hemarthrosis and exclude septic arthritis, crystalline disease, or other causes. When performed aseptically and carefully, arthrocentesis is safe and free of significant long-term morbidity. It is unnecessary to reverse the anticoagulant state prior to arthrocentesis.
A precise definition of hemarthrosis has not been established, but the diagnosis is suggested by a synovial fluid hematocrit exceeding 3%. Causes of hemarthrosis other than anticoagulation include trauma (especially with intra-articular fracture), blood dyscrasias, Charcot joint, synovial tumors such as pigmented villonodular synovitis or other primary or metastatic neoplasms, myeloproliferative disease, CPPD
arthropathy, septic arthritis, sickle cell trait or disease, and scurvy.
arthropathy, septic arthritis, sickle cell trait or disease, and scurvy.
Despite the fact that hemophiliac patients with repeated hemarthrosis have significant joint abnormalities, an isolated episode of spontaneous hemarthrosis has a benign prognosis. Treatment of hemarthrosis from hemophilia or other bleeding diathesis is discussed elsewhere (see Chapters 108,109, and 114). Management of spontaneous hemarthrosis from anticoagulation consists of immobilization, analgesia, and if possible, temporarily reducing or correcting clotting parameters with fresh frozen plasma if the patient is not at high risk of thromboembolism. If the patient is at high risk (i.e., prosthetic valve), allowing the INR to drift toward the lower therapeutic range is one option. Arthrocentesis may reduce the pressure of joint distension. Once the hemarthrosis improves, close monitoring of coagulation parameters to values within the therapeutic range minimizes the chance of recurrence.
Aspects of Rheumatic Diseases Complicating Intensive Care Procedures
Difficult endotracheal intubations may be encountered in patients with RA, juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), or systemic sclerosis (SSc). Involvement of the cervical spine, temporal mandibular joints, or oral aperture may limit adequate positioning, visualization, or successful endotracheal intubation with conventional techniques. The use of fiberoptic intubation, laryngoscopy, or blind nasotracheal intubation may suffice in some instances (see Chapter 1), although a tracheostomy may be required for satisfactory tracheal cannulation (see Chapter 15), particularly in emergent situations. Potentially more serious neurological sequelae are anterior atlantoaxial subluxation or a staircase cervical subluxation that involves many cervical vertebrae.
The prevalence of atlantoaxial instability in RA patients is estimated to be anywhere from 23% to 60% depending on the subpopulation studied and is associated with duration and severity of disease [12]. This instability also occurs in certain subgroups of patients with JIA and ankylosing spondylitis. Although the majority of patients with cervical spine involvement are asymptomatic, forced manipulation of the neck (e.g., during intubation, endotracheal suctioning, nasogastric tube placement, bronchoscopy, or endoscopy) may precipitate symptoms and signs of spinal cord compression.
Cervical instability and dislocations most commonly occur at the atlantoaxial (first and second cervical vertebrae) junction due to laxity or erosion of the transverse ligament caused by synovitis. Subsequently, the odontoid (superior peg of the second cervical vertebra) moves more freely and can protrude posteriorly, particularly during neck flexion, and compress the spinal cord, lower medulla, or vertebrobasilar arteries. Fracture or erosive destruction of the odontoid may allow the atlas (first cervical vertebra) to slide posteriorly on the second cervical vertebrae, a process termed posterior atlantoaxial subluxation. Destruction of the lateral atlantoaxial joints and of the bones of the foramen magnum may allow the axis to sublux cephalad, so-called vertical subluxation. Symptoms suggestive of cervical myelopathy include Lhermitte’s sign, neck pain radiating up to the occiput, paresthesias in the hands or feet, loss of arm or leg strength, and urinary incontinence or retention.
Patients at risk are identified with lateral cervical spine radiographs in flexed and extended views. The normal distance between the odontoid process and the arch of the atlantis is less than 4 mm. If this distance is exceeded, care should be taken to avoid sudden or forced neck flexion during any intensive care procedure. A soft cervical collar to maintain the neck in slight extension helps prevent sudden forced flexion and is a reminder to all caregivers that any neck manipulation should proceed with caution. Open-mouth posterior-to-anterior views will exclude odontoid fracture and severe subluxation, but MRI scanning is the best imaging procedure to exclude cord compression.
In patients with ankylosing spondylitis where multilevel cervical fusion exists, large anterior cervical osteophytes can prevent adequate visualization of the larynx or successful endotracheal intubation. Fixed cervical flexion deformities can hinder appropriate neck positioning for intubation. The ankylosed spine is often osteoporotic and brittle. Minor forces in flexing or extending the neck can result in inadvertent fracture. Thus, plain radiograph imaging with lateral views before any procedure can help establish potential barriers to endotracheal intubation and the need for fiberoptic nasotracheal intubation [13].
Patients with JIA (and RA more rarely) may have established micrognathia due to temporomandibular joint disease that restricts lower jaw motion and limits access to the oropharynx. Micrognathia may also cause upper respiratory tract obstruction and sleep apnea, both of which occur more commonly in patients with JIA. In contrast, patients with systemic sclerosis (SSc) may have facial tissue fibrosis and atrophy that reduce the oral aperture and make orotracheal intubation impossible. In these situations, early awareness of the need for nasotracheal intubation will prevent potential complications in routine or emergency endotracheal intubation.
Nearly 50% to 75% of patients with longstanding RA have involvement of the cricoarytenoid joints on CT scans, but only half have symptoms [14]. These synovial joints allow adduction and abduction of the vocal cords. Symptoms of cricoarytenoid involvement include throat pain, sensation of a foreign object in the throat, odynophagia, dysphagia, hoarseness, shortness of breath, and stridor. As a result of acute or chronic inflammation, the vocal cords may become fixed in a position of adduction, resulting in upper airway obstruction and respiratory failure. The diagnosis may be made and distinguished from recurrent laryngeal nerve paralysis, tumor, and thyroiditis by visualizing the vocal cords either by indirect laryngoscopy or fiberoptic nasopharyngoscopy. In the patient with chronically restricted motion of the cricoarytenoid joints, a superimposed insult, like an upper respiratory tract infection or trauma from intubation, may cause sufficient soft tissue swelling to cause laryngospasm or airway obstruction. Treatment of life-threatening airway obstruction includes establishing an airway by cricothyroidotomy or tracheostomy, high-dose systemic corticosteroids, systemic antirheumatic therapy, and topical aerosolized corticosteroids.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disorder that affects synovial joints and extra-articular organ systems. The patient with RA may require admission to the ICU because of airway obstruction due to cricoarytenoid arthritis or atlantoaxial subluxation (discussed previously); septic arthritis; respiratory distress from large pleural effusions or parenchymal lung disease; cardiac dysfunction due to pericardial, myocardial, or endocardial involvement; necrotizing vasculitis; or mononeuritis. The approach to the RA patient in the ICU includes knowledge of the diverse complications of rheumatoid disease and the potential toxicities of RA medications including NSAIDs, corticosteroids, traditional disease modifying agents, and the newer biologic agents.
Pathogenesis
Rheumatoid arthritis is characterized by chronic synovial inflammation with subsequent articular cartilage and bone
destruction in a genetically susceptible host. The initial triggering antigen, whether exogenous or self, has not been identified, but the subsequent CD4 T-cell activation initiates the process of recruitment of other cells to the joint space, including macrophages, neutrophils, and B cells. Fibroblast-like and macrophage-like synovial cells perpetuate synovial inflammation through elaboration of cytokines that have paracrine and autocrine activity. In addition to cytokines, the products of several cell types also induce adhesion molecules and stimulate angiogenesis. Activated synovial cells also release metalloproteinases responsible for degradation of articular cartilage and erosion of bone.
destruction in a genetically susceptible host. The initial triggering antigen, whether exogenous or self, has not been identified, but the subsequent CD4 T-cell activation initiates the process of recruitment of other cells to the joint space, including macrophages, neutrophils, and B cells. Fibroblast-like and macrophage-like synovial cells perpetuate synovial inflammation through elaboration of cytokines that have paracrine and autocrine activity. In addition to cytokines, the products of several cell types also induce adhesion molecules and stimulate angiogenesis. Activated synovial cells also release metalloproteinases responsible for degradation of articular cartilage and erosion of bone.
Joint Infections Complicating Rheumatoid Arthritis
One indication for admission of the RA patient to an ICU is sepsis, particularly involving joints. RA patients are more susceptible to developing septic arthritis, often polyarticular and more severe than in patients without RA. A variety of factors, including immunosuppressive drugs, general debility, immobility, and cutaneous ulcers predispose the rheumatoid patient to developing bacterial infections in other sites, which hematogenously seed inflamed rheumatoid joints. Normal protective mechanisms, PMN leukocyte bacterial killing, PMN chemotaxis, and complement and serum bactericidal activity are all decreased in the rheumatoid joint. Although joint sepsis after arthrocentesis or intra-articular steroid injection is a rare complication, infection has been reported in this context and may be more resistant to treatment.
A delay in diagnosing joint sepsis in RA patients may also contribute to their increased morbidity and mortality. Other factors include: 1) masking of joint pain and inflammation by NSAIDs, corticosteroids, and immunosuppressive agents; 2) generalized debility and malnutrition; and 3) attributing the joint inflammation to RA rather than infection by the patient or physician. Failure to recognize septic arthritis complicating RA may have disastrous effects. When a single or few joints are more inflamed than others in a rheumatoid patient, joint sepsis should be excluded by arthrocentesis, Gram’s stain, and cultures of synovial fluid, blood, and other appropriate sites guided by the patient’s signs and symptoms. Inspection of the skin for a possible portal of bacterial entry and a thorough general examination are of the utmost importance.
The microbiology of septic arthritis complicating RA includes a wide range of organisms, but in approximately 80% of cases, the organism is S. aureus. Streptococcal species are also common pathogens. Gram-negative organisms (Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and others), anaerobes, fungi, mycobacterium, and polymicrobial infection, have all been reported as causes of septic arthritis in the rheumatoid joint.
Management of septic arthritis in a rheumatoid patient is identical to patients without RA. However, the septic rheumatoid joint more frequently fails percutaneous needle aspiration. Early surgical drainage with synovectomy may be the preferred treatment since there is more proliferative synovitis and an increased tendency for loculations to develop in this population.
Pulmonary Involvement in Rheumatoid Arthritis
The respiratory system in the patient with RA can be involved in numerous ways, including upper airway, bronchi, pleura, parenchyma, vasculature, and diaphragmatic muscles. Pulmonary infections are common, particularly in the patient with poor mucociliary clearance, ineffective cough, on immunosuppressive therapy, or with associated Sjögren’s syndrome. Table 193.1 summarizes respiratory tract involvement in RA and other connective tissue disorders. In addition, certain antirheumatic drugs are associated with potential pulmonary toxicities. Angioedema and bronchospasm induced or aggravated by aspirin or other NSAIDs is most common followed by hypersensitivity pneumonitis from methotrexate or sulfasalazine, or interstitial fibrosis from methotrexate.
Pleural Disease
Pleuritis and interstitial disease are the most common pulmonary manifestations of RA, and the former is most common in a subset of male patients who are seropositive and have nodules. Although involvement may be asymptomatic, acute febrile pleurisy or large pleural effusions impairing respiratory function may occur and result in ICU admission. The differential diagnoses of the pleural effusions include malignancy, pulmonary infarction, viral or bacterial infection, tuberculosis, and empyema. Infectious empyema occurs with increased frequency in patients with preexisting rheumatoid pleural effusions and should be suspected in debilitated, anemic, or hypoproteinemic patients who have been treated with corticosteroids and have persistent fever and pleural effusions. In patients on anti–tumor necrosis factor alpha (anti-TNF-α therapies), reactivation of (or new infection with) tuberculosis is of major concern and needs to be excluded with pleural biopsy.
Pleural effusions and sterile empyemas associated with RA are exudative and have characteristic features: elevated lactic dehydrogenase (often > 700 IU per L), total protein (> 4 g per dL), low glucose (< 40 mg per dL), and pH < 7.2. Other characteristics include clear yellow to green-yellow appearance, white blood cell count of 100 to 7,000 cells per μL (predominantly lymphocytes), reduced complement levels, cholesterol crystals, and immune complexes [15]. Chylous effusions may occur if necrotic subpleural nodules rupture into the pleural space.
Once infections including tuberculosis and malignancy are excluded, symptomatic pleural effusions are managed with NSAIDs and thoracentesis. In recurrent pleuritis or sterile empyema, intrapleural corticosteroids, systemic corticosteroids in moderate doses, and additional disease modifying agents are recommended. Rarely, surgical pleurodesis or decortication is required if chronic adhesive fibrothorax develops. There are no prospective trials to evaluate the efficacy of many of these recommendations [15]. High-dose corticosteroid therapy may not be effective and carries an increased risk of an empyema.
Lung Disease
ILD occurs in up to 40% to 60% of patients with RA depending on the subpopulations studied and screening tests used to make the diagnosis. In a prospective European study of newly diagnosed RA patients, the annual incidence was 4 in 1,000 patients but over 20 years, mortality was over 75% in those patients with interstitial lung disease, with the majority of deaths due to ILD [16]. Thus after infection, pulmonary disease is the second most common cause of mortality in RA patients. Pathologically, usual interstitial pneumonia(UIP) is more common than nonspecific interstitial pneumonitis (NSIP). Lymphocytic interstitial pneumonitis (LIP), organizing pneumonia (OP), and acute interstitial pneumonia are less common.
Symptoms include dyspnea on exertion, cough, and chest discomfort. Physical and laboratory findings include dry crackles, diminished diffusion capacity, and restrictive physiology, as well as desaturation with exercise. Chest radiographs may show an interstitial pattern, but high-resolution CT scanning (HRCT) is a more sensitive test in assessing pneumonitis and fibrosis. Bronchoalveolar lavage (BAL) is not particularly helpful except to rule out infection, while thoracoscopy guided lung biopsy provides the best pathologic details. Treatment of ILD due to RA is extremely challenging. Some patients may respond
to corticosteroids alone but the progressive nature of the disease may require treatment with cytotoxic agents although it is unclear which immunosuppressant is most effective [17]. In those patients with ground glass opacities on HRCT scanning, IV cyclophosphamide is being used increasingly, although no large controlled trial exists to support this approach. Case reports on the use of biologic agents are conflicting.
to corticosteroids alone but the progressive nature of the disease may require treatment with cytotoxic agents although it is unclear which immunosuppressant is most effective [17]. In those patients with ground glass opacities on HRCT scanning, IV cyclophosphamide is being used increasingly, although no large controlled trial exists to support this approach. Case reports on the use of biologic agents are conflicting.
Table 193.1 Respiratory Involvement in Connective Tissue Diseases | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other less common manifestations of rheumatoid lung disease may require treatment in the ICU when patients develop respiratory distress. These include bronchiolitis obliterans with organizing pneumonia (BOOP), obliterative bronchiolitis (OB), cryptogenic organizing pneumonia, pulmonary vasculitis, spontaneous pneumothorax, and lung toxicity secondary to antirheumatic therapy. It is particularly important to distinguish BOOP from ILD and OB, and only lung biopsy will provide histological distinction.
Obliterative alveolitis is often characterized by the abrupt onset of dyspnea and a dry cough with inspiratory crackles, sometimes with a mid-inspiratory squeak, a clear chest radiograph or finding of hyperinflation, irreversible airflow obstruction at low volumes on pulmonary function testing, mild-to-moderate arterial hypoxemia with a respiratory alkalosis, and progressive obliteration of small airways (1 to 6 mm in diameter) with constrictive bronchiolitis [18]. The prognosis is generally poor with a fairly rapid rate of progressive airflow obstruction. Despite the lack of adequate therapeutic trials, when patients present with rapidly progressive deterioration, recommendations based on expert opinion include bronchodilators and inhaled and oral corticosteroids (1 to 1.5 mg per kg per day). Macrolides, pulse intravenous cyclophosphamide, or etanercept (with methotrexate) may be considered as second-line therapy [18]. Progression to respiratory failure is common. In contrast, BOOP is more responsive to corticosteroid therapy.
Rarely, chronic vasculitis may involve pulmonary as well as bronchial arterioles and result in pulmonary hypertension and cor pulmonale. Therapy consists of corticosteroids in combination with cytotoxic agents (see Chapter 196).
Although pulmonary manifestations of RA are frequent, they are rarely the primary reason for admission to the ICU. Infectious pneumonia is particularly frequent and the major cause of mortality in rheumatoid patients. Since the advent of TNF-α agents, atypical infections and reactivation of tuberculosis have been of great concern.
Rheumatoid Cardiac Involvement
RA may involve all structures of the heart as a result of granulomatous proliferation or vasculitis. Pericarditis, myocarditis,
endocarditis (valvulitis), coronary arteritis, aortitis, and cardiac conduction abnormalities have all been reported. Cardiac involvement may be the principal reason for intensive care hospitalization, or may complicate the course of the rheumatoid patient hospitalized in the ICU for other medical or surgical problems.
endocarditis (valvulitis), coronary arteritis, aortitis, and cardiac conduction abnormalities have all been reported. Cardiac involvement may be the principal reason for intensive care hospitalization, or may complicate the course of the rheumatoid patient hospitalized in the ICU for other medical or surgical problems.
Pericarditis, the most common of the rheumatoid cardiac manifestations (approximately 50% by autopsy studies) rarely causes impairment of left ventricular function. However, constrictive pericarditis or a large pericardial effusion may rarely cause cardiac tamponade. The pericardial fluid has the same characteristics as pleural fluid (see the section Pulmonary Involvement in Rheumatoid Arthritis). Pericarditis generally responds to the administration of 30 to 40 mg prednisone per day over a several-week period. Corticosteroids alone are less likely to be effective in the setting of cardiac tamponade. Pericardiocentesis should be performed early if tamponade is suspected (see Chapters 7 and 35) or if there is a question of septic or suppurative pericarditis. Aspiration of pericardial fluid may temporarily improve cardiac function, but often the viscosity of the fluid, loculations, and thickness of the pericardium necessitate pericardiectomy. In cases of constrictive pericarditis, pericardiectomy is the only effective therapy.
The myocardium may be affected by granulomatous inflammation and by vasculitis. Cardiac conduction abnormalities, including complete heart block, may develop because of subcutaneous nodules. Arteritis may affect the coronary arteries and the aorta. In patients with active systemic vasculitis, coronary arteritis may be the cause of myocardial infarction. Involvement of the aorta, either by rheumatoid granulomas or inflammation of the aortic vasa vasorum, may result in dilatation of the aortic root and aortic valvular insufficiency.
Rheumatoid arthritis patients die prematurely from cardiovascular events that include (i) ischemic heart disease, often silent; (ii) congestive failure, often in the setting of preserved ejection fraction; and (iii) sudden death. When compared to non-RA patients, these increased cardiovascular complications are not explained by traditional risk factors alone. Other factors, including poor primary or secondary preventive care and comorbid conditions along with the chronic inflammatory or immunologic state contribute to premature cardiac deaths [19]. Thus, in the ICU setting, silent cardiovascular disease with atypical presentations must be considered in the rheumatoid patient.
Rheumatoid Vasculitis
The vasculitis that complicates RA is a panarteritis with mononuclear cell infiltrates in all layers of the involved blood vessels, fibrinoid necrosis in active lesions, and thrombosis associated with intimal proliferation. Rheumatoid vasculitis tends to occur in patients with severe deforming RA, subcutaneous nodules, and high-titer rheumatoid factor, and in patients with Felty’s syndrome. The clinical features of rheumatoid vasculitis are variable and include palpable purpura, cutaneous ulceration including pyoderma gangrenosum, distal arteritis ranging from fingernail-fold infarcts and splinter hemorrhages to digital gangrene, and arteritis of major organs including the bowel, kidneys, heart, lungs, liver, spleen, pancreas, and components of the nervous system in a manner similar to polyarteritis nodosa. Severe necrotizing forms of rheumatoid vasculitis, manifested as digital gangrene, intestinal bleeding or perforation, myocardial or renal infarction, and mononeuritis multiplex, are associated with a poor prognosis and are treated aggressively in a manner similar to that of polyarteritis and Wegener’s granulomatosis (see Chapter 196) with high-dose corticosteroids, cytotoxic agents, and occasionally plasmapheresis.
Neurologic Complications of Rheumatoid Arthritis
All components of the nervous system can be affected by RA. The brain and meninges, spinal cord, peripheral nerves, and muscles may be involved with granulomatous inflammation in the form of rheumatoid nodules or vasculitis; the spinal cord and cranial and peripheral nerves may also be compressed by skeletal and soft tissue structures, and the nervous system may be affected by hyperviscosity syndrome and medications.
Spinal cord compression is one of the most common neurologic complications in patients with RA is discussed in previous section Manifestations that require immediate intervention include the sensation of anterior instability of the head during neck flexion, drop attacks, loss of urinary bladder and anal sphincter control, dysphagia, vertigo, hemiplegia, dysarthria, nystagmus, changes in level of consciousness, and peripheral paresthesias without evidence of a peripheral cause. Although RA patients may have radiographic evidence of cervical subluxation without symptoms, once signs of cord compression become apparent, myelopathy may progress rapidly. For patients with manifestations of spinal cord and brainstem compression, surgical reconstruction of normal alignment and stabilization are treatments of choice. For the nonsurgical candidate, a firm collar can be used in an effort to immobilize the neck and prevent further subluxation.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and immune complex deposition in multiple organ systems. The clinical result of these varied immune abnormalities is a disease with tremendous variation in signs and symptoms that range from arthralgias, rash, and fatigue to life-threatening renal, central nervous system (CNS), cardiac, pulmonary, or hematological manifestations. Diagnosis of SLE is based on the clinical criteria set forth by the American College of Rheumatology [20]. Mortality of SLE patients admitted to the ICU is much higher than the general ICU population (47% vs. 27%) [21]. In the ICU patient with established SLE, it is essential to differentiate problems caused directly by SLE activity from those with secondary causes such as infections, drug-induced lupus, NSAID-induced renal dysfunction, aseptic meningitis, and corticosteroid-induced psychosis. Diseases associated with SLE include avascular necrosis, hypertensive encephalopathy, pseudotumor cerebri, amyloidosis, myasthenia gravis, and thrombotic thrombocytopenic purpura. In ICU patients without a prior history of autoimmune disease, SLE should be considered in the differential diagnosis of patients presenting with acute renal failure, seizures, myocarditis, acute pulmonary deterioration, hemolytic anemia, or thrombocytopenia.
Renal Disease
Renal involvement is the major cause of disease-related mortality in SLE patients. The frequency of renal involvement ranges from 38% to nearly 80% depending on definition, but clinical lupus nephritis (LN) occurs in approximately 50% of the patients. Advances in diagnostic and therapeutic modalities have dramatically improved the survival of lupus patients with renal disease. Glomerulonephritis and progressive renal failure, however, remain major sources of morbidity and mortality. LN constitutes approximately 3% of all end-stage renal failure in
patients on dialysis or requiring transplantation. Recent data from one transplant group with predominantly white patients found no difference in overall 15-year patient survival (80%) and graft survival (69%) in SLE patients compared with controls [22]. Early graft thrombosis occurred more frequently in patients with antiphospholipid antibodies (APAs) and recurrence of LN was around 8% [23].
patients on dialysis or requiring transplantation. Recent data from one transplant group with predominantly white patients found no difference in overall 15-year patient survival (80%) and graft survival (69%) in SLE patients compared with controls [22]. Early graft thrombosis occurred more frequently in patients with antiphospholipid antibodies (APAs) and recurrence of LN was around 8% [23].
Classification of lupus-associated glomerulonephritis (GN) is based on histopathologic, immunofluorescent, and electron microscopic changes according to the 2003 revised classification by the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) classification [24]. The classification includes: Class I: mesangial GN; Class II: mesangial proliferative GN; Class III: focal proliferative GN; Class IV: diffuse proliferative GN with two subclasses, segmental and global; Class V: membranous GN; and Class VI: advanced sclerosing GN. Renal lesions are commonly pleomorphic, vary from one glomerulus to another, and temporally transition from one class to another over time. The tubulointerstitium and vasculature are often involved. Semiquantitative scoring to define activity and chronicity may provide information on prognosis and guidelines for therapeutic options. In particular, the presence of proliferative lesions and chronic lesions are associated with greater mortality.
The clinical manifestations of renal involvement vary from rapidly progressive renal failure with attendant fluid overload, to congestive heart failure or accelerated hypertension, and are common events precipitating an ICU admission. A sudden deterioration in an SLE patient’s renal function warrants careful consideration of other causes of acute renal insufficiency (see Chapter 73) before attributing the deterioration to active SLE. In particular, hypovolemia, drug-induced interstitial nephritis or renal insufficiency, renal vein thrombosis, and contrast-induced acute tubular necrosis must be excluded. Physical examination may reveal evidence of SLE activity in other organ systems. Laboratory studies should include routine tests to assess renal status and fluid balance, and immunologic studies, including double-stranded DNA (dsDNA) antibody, total hemolytic complement, third (C3) and fourth (C4) complement components, and ESR. Active serologies suggest SLE flare, but normal values do not exclude active disease.
Management of LN depends on the patient’s renal histopathology and functional parameters. Thus, a patient with mesangial glomerulonephritis with normal creatinine clearance requires no specific therapy, whereas a patient with increasing azotemia, active urinary sediment, and impaired clearance requires aggressive therapy. It is now established that in patients with severe glomerulonephritis (ISN/RPS class III or IV), the combination of high dose prednisone with monthly intravenous pulse cyclophosphamide (IVCY) for 6 months followed by quarterly infusions for additional 6 months stabilizes renal function and improves survival. This regimen is the standard for comparison in all other LN drug trials [25,26]. In the past few years, several trials in different populations have documented the equivalency of mycophenolate mofetil (MMF) up to 3 g per day to monthly IVCY as induction therapy for class III, IV, or V LN [27]. More recently, a large international trial conducted by the ALMS group (Aspreva Lupus Management Study) confirmed this equivalence of both induction regimens at the end of 24 weeks with a response rate of 56% in each group [28]. However, only 8% from either treatment group reached complete remission. This study also supported the racial and ethnic differences in LN and the response to therapy reported in other studies. Patients of Hispanic and African descent had a much better response to MMF than IVCY (60% vs. 38%), while whites and Asian patients responded equally to either regimen. The risk for gonadal failure was less with MMF but other toxicities such as infections were similar. Given the currently available evidence, it appears that MMF and IVCY are equivalent induction therapies for severe LN. Durability of remission is being assessed in a continuation of the ALMS trial in which responders were randomized to either MMF or azathioprine (AZA) for maintenance therapy [28]. Another recent study demonstrated better efficacy and fewer long-term toxicities in maintenance therapy with AZA or MMF rather than the traditional quarterly IVCY after initial monthly IVCY induction [29].
In an acutely ill ICU patient with LN and/or other organ system involvement, IVCY along with pulse IV methylprednisolone at 500 to 1,000 mg daily for 3 days may be the regimen of choice since many of the studies have not stratified for disease severity. The protocol for administration of IVCY therapy is outlined in Table 193.2. Dose adjustments for renal insufficiency are outlined and subsequent monthly dosing is based on nadir white blood cell counts. Another option for IVCY induction is the low dose regimen from the Euro-Lupus Nephritis Trial, which demonstrated equal efficacy and less gonadal toxicity between low dose IVCY (500 mg every 2 weeks for six doses) and high dose IVCY (500 to 750 mg per M2 with maximum of 1,500 mg, monthly for 6 months, followed by every 3 month infusion until a year) [30]. Both groups then received AZA at 2 mg per kg per day for maintenance. The long-term outcomes measured by death, end-stage renal disease, and doubling of serum creatinine were similar in both groups after 10 years [31].
Table 193.2 Intravenous Cyclophosphamide Therapy (IVCY) | ||
|---|---|---|
|
Membranous GN (Class V), which constitutes 20% of LN, is less aggressive than Class IV GN. While renal survival rate is at 80% at 10 years, it is still associated with significant comorbidities of hyperlipidemia, cardiovascular and thromboembolic diseases [32]. Angiotensin-converting enzyme (ACE) inhibitors have been used successfully to reduce proteinuria. Treatment with corticosteroids, AZA, and cyclosporine has been studied in small series. More recently, the pooled subset of Class V patients from two prospective randomized studies on treatment of GN demonstrated equivalent efficacy and safety profile of MMF and IVCY [33]. Adjunctive renoprotective therapies that include aspirin, statins, ACE inhibitors, or angiotensin receptor blockers should also be instituted.
Advances in biologic therapies for RA and psoriatic arthritis have also stimulated investigations for SLE. Initial open label studies and case reports suggest promising results with the use of rituximab (RTX), an anti-CD20 B-cell depleting monoclonal antibody, for reducing SLE activity. Surprisingly, a randomized trial comparing RTX to placebo with a background of MMF for active proliferative LN revealed no additional benefit, and another study on active nonrenal SLE was also negative [34,35]. Trials of other potential therapies are underway, including a human monoclonal against B-lymphocyte stimulator (BLyS).
Neuropsychiatric Disease
Neuropsychiatric systemic lupus erythematosus (NPSLE), which encompasses involvement of the central, peripheral, and autonomic nervous systems along with psychiatric syndromes, occurs in 25% to 80% of SLE patients depending on the criteria applied or methods used for diagnosis. Although NPSLE was considered a poor prognostic indicator in the older literature, it does not seem to have significant impact on survival rates. Active CNS disease contributed primarily or secondarily to death in only small percentage of patients.
Neuropsychiatric manifestations of SLE can be classified into central versus peripheral nervous system involvement. Due to the limitations of the ACR classification criteria of CNS involvement, an ad hoc neuropsychiatric lupus nomenclature committee of the American College of Rheumatology defined 19 manifestations that included 12 in the CNS and 7 in the peripheral nervous system [36] (Table 193.3). The wide range of prevalence for the more diffuse CNS syndromes (cognitive dysfunction, anxiety, acute confusional states, and psychosis) and headache is due to the definition, criteria, or diagnostic parameters used in reported studies. This proposed nomenclature attempts to define the spectrum of NPSLE but is not a substitute for clinical diagnosis. An individual SLE patient may have multiple neuropsychiatric manifestations and these can develop prior to the formal diagnosis of SLE or during an inactive disease state. Frank psychosis is relatively rare, estimated at 5%. Often, it is difficult to separate active lupus psychosis from other causes such as functional disorders, uremia, illicit drugs, metabolic disturbances, medications, or infections.
Focal central nervous system disease, including seizures that occur in 15% to 35% of SLE patients, can antedate the diagnosis of SLE or develop any time during the disease course. Grand mal seizures are the most common, but essentially all types have been reported. Secondary causes of seizures must be sought since in several prospective studies of SLE patients with neurologic events, a majority of seizures were due to associated infection, uremia, hypertension, and metabolic abnormalities.
Cerebrovascular accidents (5% to 18%) include infarctions secondary to intracranial hemorrhage or arteritis, thrombosis from lupus anticoagulant (LAC) or APA-associated hypercoagulable states, or embolism from Libman-Sacks endocarditis. Movement disorders including chorea, ataxia, and hemiballismus are rare (< 1%) [37]. Transverse myelitis is an unusual but devastating complication of SLE characterized by acute or subacute paraplegia or quadriplegia associated with sensory level deficit and loss of sphincter control. Cerebrospinal fluid (CSF) analysis reveals pleocytosis, low CSF glucose, and high CSF protein. T2-weighted magnetic resonance imaging (MRI) usually demonstrates increased signal intensity and cord edema. Meningitis, usually infectious, may develop in SLE patients. However, aseptic meningitis can be idiopathic or secondary to administration of ibuprofen or AZA.
Table 193.3 Neuropsychiatric Manifestations of Systemic Lupus Erythematosus | ||
|---|---|---|
|
Peripheral nervous system syndromes include cranial neuropathies (4% to 49%) such as facial palsies and ocular muscle dysfunction. Pure sensory or motor abnormalities based on electromyography/nerve conduction studies (EMG/NCS) occur in up to 47% but plexopathy, Guillain-Barré syndrome, and autonomic neuropathy are rare.
The differentiation of NPSLE from other CNS disorders is difficult and remains a process of elimination. CSF pleocytosis and low glucose require exclusion of infections. Electroencephalography generally reveals diffuse brain wave slowing, but focal activity suggests seizures. Serum antiribosomal P antibodies are associated with lupus psychosis. The gold standard for imaging the central nervous system in SLE is conventional MRI with gadolinium. CT scans are less sensitive and should be reserved for patients in whom MRI is contraindicated or for emergent situations to document bleed, infarct, cerebral edema, or masses. Focal lesions in the subcortical white matter
are the most common MRI findings and correlate with ischemic changes. Changes in the gray matter that brighten on T2-weighted imaging suggest more acute events and may improve with therapy. However, it is often difficult to distinguish acute from chronic MRI lesions, and subcortical lesions are found in up to 50% of patients without any neuropsychiatric symptoms. Angiography is invasive and rarely results in an accurate diagnosis of active CNS lupus. Since the sensitivity of MRI in patients with cognitive or affective symptoms is low, additional imaging with single-photon emission computerized tomography (SPECT), which measures functional cerebral blood flow, is attractive. Although sensitivity is high (positive in 86% to 100% of patients with major NPSLE manifestations), specificity is low since nearly half of SLE patients without neuropsychiatric involvement have positive SPECT scans [38]. Magnetic resonance angiography is not sensitive enough to delineate the smaller vessels involved in NPSLE. Newer imaging techniques such as magnetic resonance spectroscopy, magnetic transfer imaging, and perfusion and diffusion weighted imaging are still viewed only as research tools and their roles in assessment of NPSLE remain to be determined.
are the most common MRI findings and correlate with ischemic changes. Changes in the gray matter that brighten on T2-weighted imaging suggest more acute events and may improve with therapy. However, it is often difficult to distinguish acute from chronic MRI lesions, and subcortical lesions are found in up to 50% of patients without any neuropsychiatric symptoms. Angiography is invasive and rarely results in an accurate diagnosis of active CNS lupus. Since the sensitivity of MRI in patients with cognitive or affective symptoms is low, additional imaging with single-photon emission computerized tomography (SPECT), which measures functional cerebral blood flow, is attractive. Although sensitivity is high (positive in 86% to 100% of patients with major NPSLE manifestations), specificity is low since nearly half of SLE patients without neuropsychiatric involvement have positive SPECT scans [38]. Magnetic resonance angiography is not sensitive enough to delineate the smaller vessels involved in NPSLE. Newer imaging techniques such as magnetic resonance spectroscopy, magnetic transfer imaging, and perfusion and diffusion weighted imaging are still viewed only as research tools and their roles in assessment of NPSLE remain to be determined.
Management of SLE patients with neuropsychiatric manifestations should focus on specific neurologic symptoms. Non-SLE causes of CNS disease, including infections, uremia, hypertension, metabolic disturbances, hypoxia, or drug toxicities, must be identified and treated appropriately. If steroid psychosis is suspected, a brief doubling of the steroid dose for 3 days may exclude the possibility of a diffuse CNS syndrome. If no improvement or evidence of active lupus is noted, the steroid dose should be tapered. Seizures are treated with appropriate anticonvulsant medications. Status epilepticus is treated with anticonvulsants and high-dose steroids. Psychotic patients should receive antipsychotic agents. High-dose steroids have been recommended for neuropsychiatric lupus; dosages range from 1.0 to 1.5 mg per kg per day, or its equivalent. In severe cases, pulse IV methylprednisolone in a dose of 1,000 mg per day for 3 days is preferred. As for immunosuppressive agents, few prospective studies of treatment of NPSLE have been performed. A recent Cochrane database review of therapy for neuropsychiatric lupus found only one controlled clinical trial that suggested better outcomes with monthly IVCY than steroids alone [39,40]. Limited case reports of rituximab therapy in NPSLE suggest efficacy but no randomized studies are available. Transverse myelitis has been treated successfully with pulse methylprednisolone, IVCY, and plasmapheresis.
Related posts:
Full access? Get Clinical Tree
