Antiphospholipid antibodies constitute a diverse family of antibodies that are associated with a hypercoagulable state. Antiphospholipid antibodies may be associated with systemic lupus erythematosus or lupus-like disorders, infections, drugs, or miscellaneous conditions; however, in approximately 50% of cases, clinical features attributable to antiphospholipid antibodies occur in the absence of a defined underlying etiology, in which case the designation primary antiphospholipid antibody syndrome (APS) is used (1). Common manifestations of the APS include venous and arterial thrombosis and recurrent miscarriages (Table 1)
| Venous thrombosis | |
| Deep venous thrombosis, with or without pulmonary embolism | |
| Superficial venous thrombosis | |
| Cerebral | |
| Retinal | |
| Renal | |
| Hepatic | |
| Arterial Thrombosis | |
| Cerebral | |
| Peripheral | |
| Coronary | |
| Renal | |
| Retinal | |
| Other manifestations | |
| Obstetric: pregnancy loss, intrauterine growth retardation | |
| Hematologic: thrombocytopenia, hemolytic anemia | |
| Cutaneous: livedo reticularis, leg ulcers | |
| Cardiac: valvular vegetations, intracardiac thrombus, cardiomyopathy | |
| Neurologic: chorea, transverse myelopathy, complicated migraine, encephalopathy | |
| Pulmonary: pulmonary hypertension, adult respiratory distress syndrome,* alveolar hemorrhage* | |
| Renal: hypertension,* renal failure* | |
| Gastrointestinal: abdominal pain, visceral ischemia/gangrene | |
| Endocrine: adrenal infarction* |
Almost any organ system may be affected in the APS, as detailed in Table 1. The central nervous system may be affected as a result of recurrent ischemia and infarction from in situ arterial thrombosis and/or embolic noninfective endocarditis. Stroke of unclear etiology in patients under 45 year of age may be related to the APS in up to one-third of the cases (2). Renal disease can result from either large vessel thrombosis of renal arteries or veins or microvascular thrombosis with pathologic features similar to those seen in the hemolytic–uremic syndrome (2, 5). Thrombocytopenia is seen in approximately 25% of patients with the APS and is usually of a mild degree. The pathophysiology of the thrombocytopenia is not fully understood but could be related to nonspecific consumption as part of the coagulation process, especially if there is a large clot burden, and to antibodies to specific platelet glycoproteins. Thrombocytopenic patients with the APS remain at risk for thrombosis. Unfortunately, full anticoagulation with heparin or warfarin is considered more risky in patients with platelet counts of less than 50 × 109 per L (1, 6).
The diagnosis of APS is based on clinical features of vascular thrombosis and/or pregnancy morbidity, supported by laboratory evidence of antiphospholipid antibodies (Table 2)
| Clinical criteria | |
| Vascular thrombosis | |
| One or more episodes of arterial, venous, or small vessel thrombosis | |
| Confirm by imaging or histopathology (except for superficial venous thrombosis) | |
| Pathology should show thrombosis without significant inflammation | |
| Pregnancy morbidity | |
| One or more unexplained fetal death at 10 or more weeks of gestation, or | |
| One or more premature birth at 34 or less weeks of gestation because of preeclampsia, eclampsia, or placental insufficiency, or | |
| Three or more unexplained consecutive spontaneous abortions at less than 10 weeks of gestation | |
| Laboratory criteria | |
| Anticardiolipin antibody | |
| IgG or IgM isotype | |
| Medium or high titer | |
| On two occasions 6 weeks or more apart | |
| Lupus anticoagulant | |
| Prolonged phospholipid-dependent coagulation test* | |
| Failure to correct by mixing with normal plasma | |
| Correction with addition of excess phospholipid | |
| Exclusion of other coagulopathies |
The differential diagnosis of vaso-occlusive events in systemic lupus erythematosus patients includes mechanisms other than antiphospholipid antibody-related thrombosis, such as immune complex deposition with complement activation and vasculitis, leukoagglutination induced by complement activation products, a thrombotic microangiopathy simulating thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation (Table 3)
Clinical/Laboratory Feature | APS | CAPS | TTP-like | DIC | Immune Complex |
|---|---|---|---|---|---|
| Fever | − | (No literature) | + | − | + |
| Thrombocytopenia | +/− | +/− | + | + | +/− |
| MAHA | − | −/+ | + | + | − |
| Schistocytes | − | −/+ | + | + | − |
| Direct Coombs' | +/− | +/− | − | − | +/− |
| Complement | N | (No literature) | N | N | Decr-N |
| APL antibodies | High titer | High titer | Rare, low titer | Rare, low titer | Variable |
| PT/PTT | N/N-Incr | N/N-Incr | N/N | Incr/Incr | N/N |
| Fibrinogen/FDP | N/N | N-Decr/N-Incr | N/N-Incr | Decr/Incr | N/N |
Treatment of patients with antiphospholipid antibodies and a new thrombotic event with either full-dose unfractionated heparin or low molecular weight heparin, followed by warfarin therapy, is considered standard (6). Several points bear mentioning. First, the use of low molecular weight heparin in this setting has not been as well studied but may be associated with fewer bleeding complications than unfractionated heparin (6). Second, the presence of a lupus anticoagulant may prevent the clinician from assessing the adequacy of conventional heparinization through routine tests such as the activated partial thromboplastin time if the baseline value is abnormal. Options include using specific heparin assays, antifactor Xa assays, activated partial thromboplastin time reagents that are less sensitive to the lupus anticoagulant, or simply using low molecular weight heparin instead of unfractionated heparin. Third, these patients may be more susceptible to the syndrome of warfarin-induced skin necrosis because of acquired functional deficiencies of protein C and/or protein S (8). To avoid this potential complication, we recommend delaying initiation of warfarin by at least 1 or 2 days after full heparinization, omitting a loading dose of warfarin and letting the patient become therapeutic over approximately 1 week while maintaining full heparinization. Finally, the ideal long-term target international normalized ratio for warfarin therapy is controversial. “High-intensity” therapy, with an international normalized ratio of more than 3.0, is associated with fewer recurrent thromboses but greater incidence of hemorrhagic complications (6). The treatment of thrombotic events in patients with antiphospholipid antibodies and thrombocytopenia is particularly challenging. We recommend immediate treatment with corticosteroids to achieve a platelet count of more than 50 × 109 per L concurrent with anticoagulation. Secondary treatment options include intravenous immunoglobulin and staphylococcal protein A column immunoadsorption (1, 6).
Of special relevance to the critical care setting is the recently described “catastrophic APS,” a particularly fulminant presentation of antiphospholipid antibody-associated disease. As highlighted in a recent comprehensive review of the literature (9), the catastrophic APS presents as multiorgan system failure that evolves over days to weeks. More than one-half of patients had primary APS; the remainder had systemic lupus erythematosus or a lupus-like disorder (9). Venous thrombosis had previously occurred in 36% of cases and arterial thrombosis in 24%. Although no precipitating factor could be identified in 80% of cases, infections, medications, surgical procedures, and anticoagulation withdrawal were believed to trigger the fulminant clinical course in some instances (9). Renal insufficiency occurred in almost 80% of patients, often accompanied by hypertension that was occasionally malignant (9). The lung was the second most commonly affected organ, seen in two-thirds of the patients. The most frequent type of lung injury was adult respiratory distress syndrome, presumably induced by tissue injury/ischemia and sometimes accompanied by diffuse alveolar hemorrhage; pulmonary embolism or interstitial infiltrates were also seen. Other common organ system involvement included neurologic (56%), cardiac (50%), cutaneous (50%), gastrointestinal (38%), hepatic (34%), and adrenal (26%) (Table 1). Adrenal infarction was noteworthy in that only a minority presented with typical clinical manifestations of adrenal insufficiency (9).
Laboratory studies at the time of presentation with catastrophic APS included evidence of the lupus anticoagulant and anticardiolipin antibody in approximately 95% of the cases. Thrombocytopenia was detected in two-thirds of the cases; other coagulation studies suggested pathophysiology overlapping with disseminated intravascular coagulation or thrombotic thrombocytopenia (9). Typically, the disease evolves over days to weeks, a time course that would be unusual for sepsis-related multiorgan system failure. Nonetheless, sepsis must be considered in the differential diagnosis when disease progression is particularly rapid. Other diagnostic considerations include heparin-induced thrombocytopenia, multiple cholesterol emboli, and in a pregnant patient, the “hemolysis, elevated liver enzymes, low platelets” syndrome. The mortality rate of the catastrophic APS is approximately 50%, and autopsy findings have revealed that the fundamental underlying pathologic pattern is one of diffuse microvascular thrombosis with tissue ischemia and resultant end-organ damage (9).
Optimal treatment of the catastrophic APS is uncertain. Given the often fulminant clinical course and high mortality rate, it is not surprising that aggressive multimodality therapy has often been given. Asherson and colleagues' analysis suggested that the combined use of anticoagulation, high doses of corticosteroids, and early plasmapheresis to remove antiphospholipid antibodies rapidly was associated with the best survival rate (70%) (9).
Systemic vasculitis is most often classified on the basis of the size of the affected vessel (small, medium, or large) (10). When fulminant vasculitis necessitates admission to an intensive care unit, the underlying disorder is most often Wegener's granulomatosis or microscopic polyangiitis, small-vessel vasculitides that are associated with the presence of serum antineutrophil cytoplasmic antibody. Life-threatening complications caused by other small-vessel vasculitides (e.g., essential mixed cryoglobulinemia, Churg-Strauss syndrome, Henoch-Schonlein purpura), medium-vessel vasculitides (polyarteritis nodosa, Kawasaki disease), or large-vessel vasculitides (giant cell arteritis, Takayasu's arteritis) are rarely encountered in the intensive care unit.
The two most common life-threatening complications of fulminant vasculitis are acute respiratory failure caused by capillaritis-associated diffuse alveolar hemorrhage and acute renal failure caused by acute necrotizing glomerulonephritis. In addition to supportive therapy, control of the underlying vascular inflammation is imperative. Unfortunately, there are very few data from randomized studies regarding the optimal method of immunosuppression. It is generally agreed that the intensity of treatment should be based in large part on the severity of the underlying illness (10, 11). Therefore, critically ill patients with vasculitis are often initially treated very aggressively. Corticosteroids in high doses are uniformly given, and nearly all centers administer concomitant cyclophosphamide for fulminant presentations of Wegener's granulomatosis and microscopic polyangiitis. Cyclophosphamide can be given as a daily oral dose (usually 2 mg/kg/day) or as intravenous pulse therapy (usually 0.75 gm/m2 every 3 weeks). For life-threatening disease, one can administer daily intravenous cyclophosphamide (3–5 mg/kg/day) for the first several days and then convert to a daily oral regimen (12). A recent prospective randomized study of 47 patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement found that intermittent pulse therapy with cyclophosphamide led to a similar rate of initial response as daily administration, but the former was associated with less toxicity such as leukopenia, lymphopenia, thrombocytopenia, severe infections, and gonadal toxicity (13). Hemorrhagic cystitis was not seen in either group. Similar results were obtained in a randomized study of 50 patients with Wegener's granulomatosis, although in the latter study, intermittent therapy did not maintain remission as long or prevent relapses as well (14). Meticulous attention to preventing opportunistic infections is crucial; prophylactic trimethoprim-sulfamethoxazole is empirically recommended (no formal studies are available) until the corticosteroid dose has been tapered to 20 mg of prednisone every other day or an equivalent dose.
The role of plasmapheresis in addition to corticosteroids and cyclophosphamide in treatment of severe vasculitis is controversial. Although one study suggested a benefit to plasma exchange in vasculitis-related renal failure (15), other studies failed to show any positive impact of plasmapheresis (16, 17). Similarly, the benefit of intravenous immunoglobulin in systemic vasculitis is unknown. A recent study of intravenous immunoglobulin in antineutrophil cytoplasmic antibody-related vasculitis with persistent disease activity demonstrated benefit in reducing overall disease activity, but the effect had waned after 3 months (18).
Given that the vasculitides are uncommon diseases, it has been difficult for any one center to encounter a sufficient number of patients to conduct adequate prospective, randomized trials of therapy. Fortunately, in recent years, a number of centers throughout Europe have formed the European Vasculitis Study Group to assess better the different treatment approaches in a more rigorous fashion (19). A number of trials are currently underway, and one has been completed. This trial compared azathioprine versus cyclophosphamide after an initial 3-month treatment with corticosteroids and cyclophosphamide for generalized vasculitis. This trial demonstrated that maintenance therapy with azathioprine was as effective as cyclophosphamide and was less toxic (19). It also demonstrated a 93% remission rate with cyclophosphamide and prednisone and an 18-month mortality of only 6% (19). Although it is unlikely that many of these patients had fulminant vasculitis requiring intensive care treatment, the very high remission rate would seem to support the use of initially intensive immunosuppression with both cyclophosphamide and prednisone in patients with generalized vasculitis.
Scleroderma (systemic sclerosis) is an autoimmune disease that is associated with progressive fibrosis of the skin and various internal organs. In addition to autoantibody formation, which can be demonstrated in the vast majority of patients, abnormalities of cytokine regulation may contribute to fibroblast growth, differentiation, and migration. Microvascular abnormalities are a prominent feature of early scleroderma, with evidence of endothelial cell disruption and additional components of vasospasm, vascular fibrosis, upregulation of adhesion molecules, disseminated intravascular coagulation, and microangiopathic hemolytic anemia (20).
Scleroderma renal crisis (SRC) represents an acute acceleration of the processes described previously here, whereby the reduced renal blood flow results in a uniformly hyper-reninemic state leading to further angiotensin II–induced renal vasoconstriction (21). Hypertension is almost always present and is often of abrupt onset, but normotensive SRC does occur. Clues to the latter include a rising serum creatinine and the presence of microangiopathic hemolytic anemia. A retrospective study has implicated the use of corticosteroids as a potential trigger of normotensive SRC (21); the mechanism is unknown but may involve stimulation of the renin-angiotensin system or inhibition of prostacyclin synthesis (22).
Prompt, aggressive use of angiotensin-converting enzyme (ACE) inhibitors is associated with improved renal outcomes and survival. A recent prospective observational study reviewed long-term outcomes of SRC (23). Of 807 patients with diffuse scleroderma seen between 1979 and 1996, SRC occurred in 145 (18%), and 100% of those patients received ACE inhibitor therapy at the time of diagnosis of SRC. There were four categories of long-term outcome: no dialysis needed (within 1 year of SRC onset), temporary dialysis, permanent dialysis, and early death (within 6 months of SRC). Prognosis was best in those patients who received ACE inhibitors when their serum creatinine was less than 3 mg/dl. Of those SRC patients requiring temporary dialysis, ranging from 2 to 18 months, all were maintained on ACE inhibition during the period of dialysis. The patients needing no dialysis (38%) or only temporary dialysis (23%) had an overall survival similar to scleroderma patients without SRC (23).
Aggressive blood pressure control is critical to the management of SRC, and patients with diffuse scleroderma should consider home blood pressure monitoring equipment. ACE inhibitor therapy should be the cornerstone of treatment. Unlike the situation in most other causes of acute renal failure, the use of other treatment modalities, such as hemodialysis for hyperkalemia or uremia, should not deter the simultaneous initiation of ACE inhibition. Multidrug antihypertensive regimens can be employed as long as the use of ACE inhibitors is included, but overdiuresis and β-blockade should generally be avoided. Normotensive SRC should also be treated with ACE inhibitors (21).
Corticosteroids should generally be avoided in scleroderma. If they are clearly indicated, such as for objective myositis or alveolitis, blood pressure must be scrupulously followed, and consideration should be given to the early use of a steroid-sparing agent. In such a situation, we recommend the use of prophylactic ACE inhibition, although this has not been prospectively studied.
Rheumatoid arthritis is a progressive illness in the majority of afflicted patients, including a decline in functional capacity and an increased risk of mortality from all causes. Clinicians now routinely add a disease-modifying antirheumatic drug for rheumatoid arthritis disease duration as short as 3 months if the systemic symptoms, joint findings, and functional status are inadequately treated with first-line agents such as nonsteroidal antiinflammatory drugs. Although the overall risk–benefit ratio of disease-modifying antirheumatic drugs such as methotrexate (MTX) and the newer tumor necrosis factor-α (TNF-α)–neutralizing drugs appears to be positive, these agents may on occasion have serious side effects. As the disease-modifying antirheumatic drugs become more widely prescribed, it is important for critical care physicians to be aware of the potentially life-threatening toxicities associated with their use.
MTX is the most commonly prescribed disease-modifying antirheumatic drug in rheumatoid arthritis patients. It is used either as a single initial agent in moderate or severe disease or as an “anchor” drug in combination or add-on therapy that might include hydroxychloroquine, sulfasalazine, cyclosporine, TNF-α inhibitors, or other immunosuppressive agents. Attractive features of MTX include its overall predictability and tolerability, weekly dosing regimen, relative inexpensiveness, and sustained benefit among initial responders. The mechanism of action of MTX in rheumatoid arthritis is not fully understood. The toxicities of MTX may be mediated through antiproliferative effects (stomatitis, cytopenias), cumulative toxicity (hepatic fibrosis), or idiosyncratic/hypersensitivity reactions (pulmonary).
The most common life-threatening type of MTX toxicity is pneumonitis. One multicenter case-control study attempted to define risk factors for MTX-induced lung injury (24). In logistic regression models, the strongest predictors were older age, rheumatoid arthritis pleuropulmonary involvement, previous use of other disease-modifying antirheumatic drugs, and hypoalbuminemia (24). Diabetes mellitus was also strongly associated as a risk, but the number of patients with diabetes was too small to speculate on the mechanism. Although this complication is sometimes quite chronic in onset, most patients with MTX pneumonitis present in a subacute fashion over several weeks; occasionally, the onset may be quite explosive with acute respiratory failure (25). Pulmonary toxicity can occur at any time during MTX therapy, with approximately one-half of the cases developing within 32 weeks of drug initiation. In one case-control study, the mean weekly dose of 12.1 ± 3.6 mg among affected patients was not significantly different from controls (24). The most common presenting symptoms are dyspnea and cough, the latter almost always nonproductive. Fever is present in approximately 75% of cases, and it may be difficult or impossible to reliably differentiate MTX-induced pneumonitis from infection, including opportunistic infection. Chest radiographs are almost always abnormal, revealing interstitial and/or alveolar infiltrates, either diffuse or lower lobe predominant. Bronchoalveolar lavage may be helpful for excluding infection but is otherwise nonspecific. Lymphocytes are often increased in the lavage effluent (26). Lung biopsy typically reveals an interstitial pneumonitis, with lymphocytic infiltration and type II pneumocyte hyperplasia, with or without granuloma formation. In some cases, acute and organizing diffuse alveolar damage can be seen (27). Management of MTX pneumonitis mandates early recognition, including appreciation of the frequently subacute nature of the clinical presentation. Although their benefit is unproven, it is strongly recommended to use corticosteroids if MTX pneumonitis is severe enough to cause established or impending respiratory failure. Overall mortality from MTX pneumonitis is approximately 15% (25). Most authorities recommend against rechallenge, in light of the number of alternative disease-modifying antirheumatic drugs for rheumatoid arthritis.
TNF-α is believed to play a critical role in the pathogenesis of rheumatoid arthritis. This effect is mediated through cellular events within the rheumatoid synovium—contributing to synovial inflammation, cartilage loss, and bone demineralization and erosion—as well as through systemic effects on the acute phase response. Two TNF-α–neutralizing therapies are currently available. Etanercept (Enbrel) is a fusion protein of human soluble TNF-α receptor and immunoglobulin G1 (28). Infliximab (Remicade) is a chimeric (murine/human) monoclonal antibody against TNF-α and is generally administered with MTX or another immunosuppressive agent both for synergism and to reduce the incidence of antichimeric antibody formation (29). Etanercept and infliximab provide symptomatic relief, sometimes dramatic, and can halt disease progression in many patients who are resistant to other therapies.
Inhibition of TNF-α might be expected to increase the risk of infection, and this issue has received significant attention in clinical trials. A recent trial involving 428 patients randomized to receive MTX plus either placebo or infliximab in varying doses, showed an overall rate of infection in 35% of the patients receiving MTX alone versus 44% of the patients receiving MTX plus infliximab (29). For serious infections such as pneumonia, cellulitis, and sepsis, the rates were 8 and 6%, respectively. Among patients receiving both drugs, one died from miliary tuberculosis and another from disseminated coccidioidomycosis. TNF-α may play a role in granuloma formation and the containment of mycobacterial and fungal infections. A recent study found that the incidence of tuberculosis during treatment with infliximab was much higher than for other opportunistic infections and was much higher than background rates of active tuberculosis (30). Furthermore, the patterns of disease were unusual in that 57% of patients had extrapulmonary disease, and 24% had disseminated tuberculosis (30). The authors recommended that all patients be screened for latent tuberculosis before therapy with infliximab, and that those with evidence for latent infection begin prophylactic treatment before initiating infliximab (30).
A decision whether or not to temporarily hold etanercept (administered twice weekly; median half-life = 115 hours) or infliximab (administered every 4–8 weeks; median half-life = 8–9.5 days) before elective surgery must weigh the risks of infection against the discomfort and delayed functional recovery that could be caused by a flare of rheumatoid arthritis. We recommend holding these agents before major surgery, or any surgery that carries a significant risk of postoperative infection.
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