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  Most ICU admissions for rheumatology patients are prompted by infection.

  
  
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  New-onset rheumatic diseases rarely prompt ICU admission in the absence of a revealing prodrome.

  
  
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  In most patients without a previously established collagen vascular disease, suspected vasculitis will be explained by an alternative diagnosis.

  
  
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  Serologic assessment of critically ill patients is a double-edged sword providing both enlightenment and misleading shadows. All serologic testing must be interpreted with a thorough understanding of the patient’s clinical condition.

  
  
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  Inability to assign specific diagnostic labels to patients with severe life-threatening autoimmune or inflammatory disease should not delay therapeutic intervention.

  
  
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  Not all ischemic skin lesions that appear to be vasculitis are. Vasculopathies of various causes should always be part of the differential diagnosis.

  
  
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  Empiric trials with corticosteroids can be a rational approach to patient care when such trials are carried out appropriately and infection and malignancy have been excluded.

  
  
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  Acute organic brain syndrome without focal neurologic deficits or evidence of systemic vasculitis is unlikely to be due to vasculitis.

  
  
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  Fever in patients with systemic autoimmune diseases should be presumed to be infectious if accompanied by chills, leukocytosis with a left shift, or hypotension.

  
  
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  Patients who have been treated with significant doses of corticosteroids within the past year may require empiric replacement therapy during critical illness or surgical procedures until adrenal insufficiency can be excluded.

Approximately 10% to 25% of all rheumatic disease patients visiting the emergency department require hospitalization and up to one-third of these patients will require intensive care.¹ Patients with rheumatic diseases admitted to the medical ICU most often have problems not directly related to their primary illness. Sepsis, massive gastrointestinal bleeding, and myocardial infarcts may arise secondary to treatment. The major direction of care in these circumstances often comes from the intensivist. Circumstances do arise that require the unique insight of the experienced clinical rheumatologist, who at times must direct the management of a disease-specific complication. Just as often the rheumatologist is asked to address a diagnostic dilemma spawned by puzzling clinical and laboratory data. This chapter addresses the more common issues that prompt the rheumatologist and the intensivist to collaborate.

FEVER: IS IT THE LUPUS?

Fever in the patient with lupus presses the clinician for an urgent answer to the question: Is this caused by lupus activity or infection? Fever is a common finding in active systemic lupus erythematosus (SLE) occurring in up to approximately 50%.² It may respond to the usual antipyretics or require corticosteroids. Single-daily-morning dose prednisone may not control late afternoon or evening fevers and may require the use of split-dosing. Leukocytosis and increased bands on peripheral smear are strong presumptive evidence for infection, as is the presence of shaking chills. Complement proteins or components, including C3 and C4, are acute-phase reactants and usually rise with infection. Low levels of complement occur in some but not all patients with active lupus. Using discriminant analysis, Inoue and colleagues³ showed that 95% of 74 febrile episodes could be correctly classified as to the cause of fever when a combination of white blood count (low in SLE, normal to high with infection) and gamma-globulin levels (high with SLE, normal with infection) are used as variables. In the ICU setting, the febrile patient with SLE is probably best considered infected and treated with broad-spectrum antibiotics pending results of cultures.⁴ Infection is most likely to be caused by nonopportunistic organisms, and coverage for gram-positive and gram-negative aerobes represents adequate empirical therapy when no obvious source has been recognized. Systemic infections with Salmonella, endocarditis involving lupus-related valvular lesions, and pneumococcal sepsis in the splenectomized (surgical or autosplenectomy) are among the infections that have special significance for lupus patients.⁴

RENAL FAILURE: IS IT TREATABLE?

In patients with SLE in the ICU, renal insufficiency may be caused by a variety of factors, including drugs, especially nonsteroidal anti-inflammatory drugs (NSAIDs), hypovolemia, sepsis, or previous renal disease.⁵ In some cases, active lupus nephritis is a contributing factor. A careful examination of the urinary sediment is the most critical diagnostic tool. Proteinuria, casts, and dysmorphic red blood cells indicate glomerulonephritis. Lupus patients with active nephritis are often hypertensive. Significant renal lupus (other than membranous disease) is often associated with low complement levels and elevation of anti-DNA antibody. In a patient with a creatinine level above 4.0 mg/dL who has been adequately hydrated, has been divorced from nephrotoxic drugs, and shows evidence of active glomerulonephritis, the question arises: Is more aggressive immunosuppression desirable? The answer to this question depends on the degree of potential disease reversibility. A renal biopsy may help clarify this issue. The presence of significant chronic disease should dampen enthusiasm for aggressive therapy. Review of old records can be enlightening if long-standing loss of renal function is documented. Clinicians have become increasingly aware that immunosuppression in the lupus patient with advanced renal disease may be more hazardous than progression to complete renal failure. Patients with lupus tolerate dialysis in a fashion comparable to other patients, and results of renal transplantation are favorable. Paradoxically, patients with lupus who develop chronic renal failure often enjoy an amelioration of extrarenal symptoms.⁶ A few patients have recovered sufficient renal function to allow withdrawal from dialysis. For all these reasons, the overzealous administration of immunosuppression in patients with lupus and advanced renal disease should be approached with caution.

RESPIRATORY FAILURE AND LUNG INFILTRATES: IS IT LUPUS PNEUMONITIS?

Respiratory failure in the patient with SLE is an ominous development: a paradigm of a compromised host who is on high-dose corticosteroid therapy. The usual opportunistic pulmonary infections need to be urgently excluded by bronchoalveolar lavage, bronchoscopic transbronchial biopsy, or open lung biopsy. If no superimposed infections or embolic etiology can be found and treated, lupus-related respiratory failure remains a diagnosis of exclusion and can be caused by either lupus pneumonitis or diffuse pulmonary hemorrhage. Acute lupus pneumonitis may occur as an initial manifestation of SLE and is characterized by fever, tachypnea and hypoxemia which may be accompanied by cough, pleuritic chest pain, and hemoptysis.⁷ Radiologic findings are highly variable but usually bilateral and at least bibasilar. This diagnosis is not only one of exclusion; it unfortunately still rests solely on clinical suspicion. The other SLE-related cause of respiratory failure is diffuse alveolar pulmonary hemorrhage.⁷ Although invasive Aspergillus or tuberculosis can erode a pulmonary vessel and cause hemorrhage, gross hemoptysis, when present, usually indicates alveolar hemorrhage. Hemoptysis is not usually seen in lupus pneumonitis; unfortunately, this finding is present in <50% of patients with alveolar hemorrhage. Blood or hemosiderin-laden macrophages found during bronchoscopy in a patient without heart failure can be helpful findings but are nonspecific. The presence of thrombocytopenia is not helpful, but bleeding sufficient to cause acute respiratory failure most invariably causes an acute drop in hematocrit. In fact, treatment should not be delayed in order to distinguish between lupus pneumonitis and lupus-associated hemorrhage, because mortality is extremely high in either syndrome and treatment strategies are similar. Pulmonary hypertension, sometimes severe, is frequently present. Cardiac filling pressures, in contrast to B-type natriuretic peptide determinations, can occasionally be helpful discriminators to exclude acute cardiogenic pulmonary edema. Pulmonary artery thrombosis masquerading as massive pulmonary emboli can occur in patients with pulmonary hypertension or thrombotically active anticardiolipin (ACL) antibodies. The mortality of lupus pneumonitis is high, and treatment should be aggressive. Individual preferences will dictate modes of therapy, since no consensus exists on either the etiology of the syndrome or effective treatment. Pulse methyl prednisolone, usually 500 to 1000 mg intravenously given for 3 to 5 days, or bolus cyclophosphamide at 0.5 to 1.0 g/m² has been used. The use of plasmapheresis and plasma-exchange in severe, refractory SLE remains controversial. The use of rituximab in severe, refractory, SLE has been reported as well.

BRAIN DYSFUNCTION: IS IT LUPUS?

A patient with acute, severe neurologic deficits and a history of SLE or a clinical syndrome and laboratory evidence suggestive of systemic vasculitis presents a diagnostic and therapeutic dilemma for the critical care clinician. Involvement of the central nervous system in SLE (NeuroPsychiatric SLE or NPSLE) occurs in approximately 30% to 40% of patients with SLE.⁸ Common presentations of NPSLE include headache, cognitive dysfunction, mood disorders, seizure disorders, and cerebrovascular disease (strokes and transient ischemic attacks are the most common). A common dilemma is to differentiate between steroid-induced mental status/mood changes and those owing to active SLE. Risk factors for the development of NPSLE include other SLE activity or damage, presence of antiphospholipid antibodies and previous or concurrent NPSLE, increasing age, hypertension, hyperlipidemia and other psychiatric distress. The evaluation of a patient with suspected NPSLE starts with a complete history and physical examination with attention to excluding non-SLE-related conditions. Depending on the patient’s symptoms, further evaluation can include complete blood counts, biochemical and serologic tests, examination of the CSF, and MRI of the brain and/or spinal cord. Measurement of serum antiphospholipid antibodies can be clinically very useful, particularly in a patient with focal neurologic symptoms or signs. CSF abnormalities (pleocytosis, protein elevation and low glucose levels) support the diagnosis of NPSLE but are not specific. CSF levels of IL-6, oligoclonal bands, and IgG indices can also be useful in identifying immunologic activity involving the CNS. In general, therapy of active NPSLE starts with addressing general, aggravating factors (eg, hypertension, adverse drug effects, infectious or metabolic complications). Symptomatic therapy targeted to the patient’s CNS problems are considered next, such as anticonvulsants in a seizing patient, antidepressants in depression, antipsychotic medications in a patient with psychosis or antiplatelet/anticoagulation in patients with NSPLE manifestations attributed to antiphospholipid antibodies. Immunomodulatory therapy has been used in aggressive cases of NPSLE and includes corticosteroids, azathioprine, and/or cyclophosphamide. Refractory or severe cases of NPSLE have prompted the use of IVIg, plasma exchange, and rituximab which have been reported in uncontrolled studies.⁸

Four CNS disorders associated with SLE can be puzzling: (1) A small subset of patients with SLE who have taken NSAIDs, especially ibuprofen, will develop a meningitis-like picture that is characterized by fever, severe headache, nuchal rigidity, and cerebrospinal fluid pleocytosis.⁹ In an immunosuppressed patient, these findings prompt consideration of both common and unusual bacterial and fungal etiologies. The syndrome will remit rapidly once the drug is discontinued. (2) Headaches (including migraine) can be frequent in patients with SLE (up to 50% in some studies). High-risk features that would require additional attention and evaluation include explosive onset, severe symptoms, age of onset over 50 years, fever, immunosuppression, presence of antiphospholipid antibodies, the use of anticoagulants, focal neurologic findings, obtundation, meningismus, or other SLE activity.⁸ (3) Rare instances of myelopathy can occur in the context of active SLE, or even as the initial manifestation. The optimal therapy of this disorder is not clear but a retrospective review from 2000 by Kovacs et al suggested that aggressive, early therapy with intravenous methylprednisone followed by cyclophosphamide had the best outcomes. The role of plasmapheresis was not clear. In those patients with antiphospholipid antibodies, a coagulopathic etiology has been postulated; however, it is unclear whether the use of anticoagulation improves the outcome.¹⁰ (4) Posterior reversible, encephalopathy syndrome (PRES) is a syndrome in which patients can present with headache, seizures, changes in vision and changes in mental status who have a characteristic MRI appearance. Imaging shows hyperintensities on T2-weighted scans in the posterior cerebral area. In addition to being seen in patients with active SLE, PRES can be seen in acute hypertension, acute kidney injury, or in those taking immunomodulatory medications. Management of PRES can be challenging. If a medication is implicated, discontinuation of the drug with management of the seizures and hypertension is indicated. If active SLE is implicated, intravenous methylprednisolone and cyclophosphamide have been advocated. The manifestations of PRES have tended to be reversible as reported in the literature but occasionally can lead to permanent deficits or infarction.¹¹

A difficult but critical differentiation must be made in SLE patients with CNS findings, anemia, and thrombocytopenia. The latter findings, while very common in active SLE, coupled with peripheral blood smear evidence of microangiopathy, point instead to thrombotic thrombocytopenic purpura (TTP). TTP is uncommon with an estimated incidence of 4 to 11 cases per million people.¹² The diagnosis requires microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Only 50% patients will have neurological symptoms such as seizures or focal deficits. Although part of the classic pentad, fever is uncommon and should stimulate a search for infection. Increased LDH, indirect bilirubin, and negative Coomb test are consistent with MAHA. ADAMTS13 levels have been associated with the pathophysiology of many cases of TTP; however, results may not be immediately available. Identifying TTP in the ICU setting is further complicated by the fact that critical care patients are usually anemic and thrombocytopenic for other reasons (such as severe sepsis). Ten percent of patients with TTP may have concomitant cancer or sepsis. Once TTP is diagnosed, patients should undergo plasma exchange until platelets are normalized.¹² Case reports suggest that TTP and SLE can co-occur, and the differentiation between the two diseases is vital since the treatment of life-threatening TTP is plasma exchange and not concomitant pulse methylprednisone, alkylating agents, and/or plasmapheresis that many rheumatologists, in spite of unproven benefit, may resort to in the setting of fulminant CNS SLE.

PULMONARY HYPERTENSION

The emergence of effective therapeutic options has given the detection of pulmonary vascular disease a new sense of urgency. The exact prevalence of pulmonary hypertension in scleroderma is unknown but has been estimated to be 8% to 12%.¹³ There are generally two settings in which it is identified. In patients with limited cutaneous systemic sclerosis (previously called CREST syndrome), it occurs classically as an isolated phenomenon in the absence of pulmonary fibrosis. This generally occurs in the second decade of disease or later. Patients who fall into the second major category of scleroderma with diffuse cutaneous involvement may develop pulmonary hypertension as the result of advanced pulmonary fibrosis. In both settings, the vascular disease is characterized by bland endothelial proliferation and vascular occlusion. The vasculopathy of scleroderma is not characterized by an inflammatory infiltrate and is not treated with corticosteroids or immunosuppression. Early symptoms of pulmonary hypertension are exertional breathlessness, but later symptoms could provoke admission to the ICU. These include near-syncope or syncope with exertion, angina, and right heart failure. Scleroderma patients, especially those at greatest risk for pulmonary hypertension, are typically screened yearly or every few years using Doppler echocardiography. Confirmation of diagnosis demands a right heart catheterization, which provides additional important information about pulmonary capillary wedge pressure and cardiac output. The treatment of pulmonary hypertension in the context of scleroderma includes prostanoids (epoprostenol, iloprost, treprostinil), phosphodiesterase-5 inhibitors (sildenafil, tadalafil), endothelin receptor antagonists (bosentan, ambrisentan), and general supportive therapy.¹³ End-stage pulmonary hypertension may require heart-lung transplantation. Other causes of pulmonary hypertension should not be overlooked in scleroderma patients, including recurrent thromboembolic disease.

HYPERTENSIVE RENAL CRISIS

Hypertensive renal crisis in patients with scleroderma has been a major cause of mortality, so rapid recognition is crucial. Scleroderma renal crisis (SRC) typically develops in patients with diffuse cutaneous disease and rarely in patients with limited cutaneous disease.^14,15 Antibodies to RNA Polymerase III have also been associated with the development of SRC.¹⁶ At its onset patients experience a marked increase in blood pressure that may be accompanied by abnormalities of both urinary sediment (erythrocytes and protein) and the peripheral blood smear (fragmented cells and thrombocytopenia). Headache, visual disturbance, congestive heart failure, and cognitive dysfunction may accompany the hypertension. The pathogenesis of hypertensive renal crisis is complex and involves a very high renin state. Although combinations of older antihypertensive agents were occasionally successful, the advent of ACE inhibitors revolutionized the outlook for this problem. Rheumatologists have a low threshold for using these agents in scleroderma patients and typically initiate them at the first diagnosis of hypertension. In the setting of acute hypertensive renal crisis, larger doses of ACE inhibitors should be used. Although captopril and newer ACE inhibitors have been used, some prefer captopril because the dose can be adjusted more flexibly. The evidence supporting the use of angiotensin receptor blockers in place of ACE inhibitors is limited and mixed. They may have a role (along with calcium channel blockers, prostacyclin, and endothelin receptor antagonists) as adjunctive therapy for patients refractory to (or intolerant of) maximum doses of ACE inhibitors.^17,18 Some patients may progress to complete renal failure despite blood pressure control. Continued use of ACE inhibitors and dialysis may be required for months prior to recovery of renal function. Such improvement can continue for up to 2 years. Progressive renal failure can occur in the absence of significant hypertension in as many as 10% of patients with scleroderma renal crisis. Microangiopathic changes may be seen on peripheral smear. Treatment with ACE inhibitors is indicated for this normotensive subset of patients.

DIAGNOSIS IN THE ICU

Very ill patients in the ICU may be weak and have elevations of creatine phosphokinase (CK). Such clinical data prompt speculation about the presence of immune-mediated myositis. The most common presentation of polymyositis is the insidious onset of proximal muscle weakness. The acute development of de novo polymyositis in the ICU is unlikely. Similarly, acute fulminant disease requiring ICU admission with subsequent diagnosis is uncommon. Nonetheless, patients with undiagnosed polymyositis may be discovered in the ICU following admission for another reason (eg, aspiration pneumonia). More likely is the presence of weakness (usually generalized) in combination with a spurious or nonimmune cause of CK elevation. Intramuscular injections and myonecrosis during severe episodes of hypotension are common causes of increased CK levels in critically ill patients. ICU-acquired myopathy can usually be distinguished from polymyositis by clinical history. It is usually characterized by normal or modestly elevated serum CK levels.¹⁹ The skin lesions of dermatomyositis are so highly characteristic as to be diagnostic of dermatomyositis when accompanied by weakness and an elevated CK value. Nearly all patients with active polymyositis will display an elevated CK or aldolase level, although occasional patients will have normal muscle enzymes.²⁰ A unilateral electromyogram (EMG) can provide supportive evidence for the presence of myopathy and identify a biopsy site. Fibrillation potentials suggest active inflammation. A bedside EMG can be done in the ICU, although technical artifact may complicate the interpretation. Magnetic resonance imaging (MRI) may also confirm the presence of inflammatory muscle disease, but is generally impractical for ICU patients. The EMG should be done unilaterally because EMG needle artifact may be confused with muscle inflammation histologically. Because polymyositis/dermatomyositis is a symmetrical disease, the corresponding maximally affected muscle group can be biopsied on the opposite side. Open biopsy can be done at the bedside by an experienced surgeon to ensure proper handling of muscle tissue. Needle biopsies can be done with local anesthesia, have few complications and can be done repetitively to follow the disease course. However, some diseases such as polymyositis or systemic vasculitis have patchy involvement which may limit the yield of a needle biopsy.²¹

RESPIRATORY FAILURE

Patients with polymyositis/dermatomyositis may develop respiratory failure secondary to muscle weakness involving the diaphragm, intercostals, and accessory muscles. If pharyngeal muscles are involved, acute respiratory failure may be precipitated by aspiration pneumonia. Patients with respiratory failure have a poor prognosis.²² Some patients with dermatomyositis and this type of profound weakness harbor an underlying malignancy. Such patients can be refractory to treatment. Steroids are the mainstay of acute management of inflammatory myositis. Prednisone, 1 to 2 mg/kg per day or its approximate intravenous equivalent of methylprednisolone (in single or divided doses) may be given. In the ventilator-dependent patient, a short trial of pulse steroids may be justified up to 1000 mg methylprednisolone intravenously every day for 3 days. Improvement in respiratory muscle strength can be judged by a rise in the maximal inspiratory pressure. Intravenous immunoglobulin (IVIg) is another option for the acute management of the severely ill patient refractory to therapy with corticosteroids.²³ Second-line agents in polymyositis/dermatomyositis (eg, methotrexate, azathioprine, cyclosporine, and rituximab) are most commonly used after corticosteroids. The role of plasmapheresis/leukapheresis is unclear with only limited data available.²³

METHOTREXATE PNEUMONITIS

Oral low-dose methotrexate given intermittently emerged as the major therapeutic innovation in the treatment of rheumatoid arthritis (RA) during the 1980s and it continues to be the gold standard of RA therapy and a frequent adjunct to cytokine-directed therapy. Methotrexate therapy is both highly effective and generally well tolerated. A major, albeit uncommon, toxicity is an acute pneumonitis characterized by dyspnea and nonproductive cough. Fever is a frequent accompaniment. Diffuse alveolar and interstitial infiltrates can be present: either at diagnosis or appearing within days. Opportunistic infections mimicking this syndrome while unusual, need to be excluded. The risk factors for the development of methotrexate-induced lung injury include elderly patients, preexisting lung disease, and previous use of disease-modifying antirheumatic agents.²⁴ Patients can suffer profound hypoxemia. They may appear extremely ill, and deaths have been reported. The mechanism is unclear but is presumed to be a hypersensitivity reaction to the drug. Some patients have been rechallenged without developing the syndrome while others have relapsed. Diagnosis depends on recognition of the clinical scenario developing in a patient taking methotrexate at any dose. Duration of treatment prior to symptoms has been variable. Bronchoscopy with brushings and biopsy shows nonspecific inflammation, and bronchoscopy’s main justification is to rule out an opportunistic infection. Because these are rare, it is not unreasonable to forego bronchoscopy initially. Open-lung biopsy is usually unnecessary. Treatment includes O₂, withdrawal of drug, and the use of corticosteroids. Some have argued that steroids are not critical to recovery. The usual dose is prednisone 1 mg/kg per day or its equivalent in daily or divided doses. Most patients will show signs of recovery within a week.

CERVICAL SPINE SUBLUXATION

Rheumatoid arthritis commonly affects the cervical spine with estimates as high as 80% of patients. Subluxation of vertebrae secondary to ligamentous laxity may occur at single or multiple levels. Anterior atlantoaxial subluxation of C1 on C2 is the most frequent cervical abnormality and is particularly dangerous because of the capacity of the odontoid process (or dens) of C2 to compress the anterior spinal cord with motion. Sudden hyperextension of the neck during intubation could result in quadriplegia. In reality, such occurrences are rare. The explanation may in part include the fact that progressive resorption of the dens often accompanies the most severely unstable necks. Symptomatic patients can be diagnosed with MRI or a myelogram. However, some dramatic subluxations on MRI are not accompanied by neurologic signs or symptoms. Flexion and extension films of the cervical spine may show dynamic instability and subluxation of C1 on C2. There are few data about the specificity or sensitivity of such films to predict a cervical cord catastrophe. Clearly, caution should be exercised in the intubation of patients with rheumatoid arthritis and neck disease; if time allows, nasotracheal or fiberoptically guided endotracheal intubation is preferred. Cervical instability is a problem that attends advanced destructive rheumatoid arthritis. Early aggressive treatment of RA patients with disease-modifying therapy has dramatically reduced the prevalence of this problem.²⁵

Autoinflammatory diseases are rare conditions that have episodic features of inflammation with little or no evidence of systemic autoantibodies or autoreactive T lymphocytes.^26,27 These diseases commonly have episodic fever that can suggest infection or malignancy and include diseases such as adult-onset Still’s disease, systemic-onset juvenile idiopathic arthritis, familial Mediterranean fever, and perhaps Behcet syndrome. Whereas many of the systemic autoimmune diseases we recognize (eg, rheumatoid arthritis, systemic lupus erythematosus) come about due to abnormalities affecting the adaptive immune system, the autoinflammatory diseases appear to arise because of abnormalities in the innate immune system. Interleukin-1 helps “supervise” early immune responses and appears to be central to the development of clinical disease in autoinflammatory syndromes. Recognition of the importance of IL-1 has focused attention on therapeutic value of inhibiting IL-1. Anakinra, the IL-1 receptor antagonist, has gained attention in treating conditions such as familial Mediterranean fever and perhaps adult-onset Still’s disease in addition to potentially being another therapeutic option in Behcet disease.

Mortality rates for patients with systemic rheumatic diseases admitted to the ICU are high.¹ This is perhaps not unexpected when consideration is given to a typical scenario of a chronically ill patient with multiple impaired organs, a disordered immune system, treatment with chronic immunosuppression, and admission to the ICU with infection. Reported ICU mortality rates for patients with rheumatic disease are higher than would be predicted using the Acute Physiology, Age, and Chronic Health Evaluation II (APACHE II) Score or Simplified Acute Physiology Score II (SAPS II).^28,29 Factors associated with poor outcome include higher SAPS II scores, poor health status prior to admission, duration of rheumatic disease, corticosteroids and immunosuppressive drugs, renal failure, coma, and acute respiratory distress syndrome. The overall ICU mortality rate for patients with rheumatic disease ranges from 30% to 60%.¹ Mortality rates are higher for patients admitted because of infection compared to those admitted for exacerbation of rheumatic disease.^28,29 Since infection may cause two-thirds of ICU admissions among patients with rheumatic disease, aggressive intense therapy of the febrile patient with broad-spectrum antibiotic coverage is appropriate.

FEVER OF UNDETERMINED ORIGIN: RHEUMATIC CAUSES

The traditional definition of a fever of undetermined origin (FUO) depicts a patient with a significant fever of 6 weeks or greater duration and no definable cause. In actual practice, depending on the impatience of the attending physician, FUO usually becomes the working diagnosis within 3 to 14 days after a fruitless search for classic causes of pyrexia. The most common causes of FUO are occult infection, drugs, and occasionally, malignancy. After those are excluded, one must consider a limited array of rheumatic diseases that could be present in a febrile patient with protracted fever. Rheumatic disorders may account for approximately 10% of cases of FUO. Because rheumatoid arthritis, scleroderma variants, dermatomyositis, polymyositis, and polymyalgia rheumatica are not usual causes of significant fever, they need not be strongly considered. SLE can present with high fevers, either spiking or relatively constant, and leukopenia, hypoalbuminemia, anemia, and an elevated erythrocyte sedimentation rate (ESR), but few other overt clinical signs of lupus such as rash or serositis, polyarthritis, or active urinary sediment. Most systemic necrotizing vasculitides will be evident after examination of the skin, chest radiograph, and urinary sediment. An extremely high ESR is a nonspecific laboratory clue in FUO, but antibodies to relevant specific antinuclear or streptococcal disorders provide supportive evidence. A most vexing diagnosis to pin down is that of adult Still’s disease. These patients will have relentless spiking fevers, at times a history of FUO in childhood, leukocytosis, elevated levels of ferritin, mild to moderate hepatic enzyme changes, and an occasional truncal rash. Polyarthritis or arthralgias are not a constant feature early in this syndrome. Hepatosplenomegaly and lymphadenopathy are common. Rarely, acute pericarditis with tamponade or myocarditis with respiratory failure may complicate the course of adult Still’s disease.³⁰ In the final analysis, treatment may have to be based on the supposition that the patient has relentless, immunologically driven, noninfectious inflammation that evades specific diagnosis. Blanket suppression of cytokines and white blood cell responses by corticosteroids may be necessary. The steroid dose is tailored to control fever and normalize the acute-phase response. Anakinra and Tocilizumab have also been used for therapy.

ISCHEMIC HEART DISEASE IN THE RHEUMATOLOGY PATIENT

Premature atherosclerosis can be seen in association with systemic autoimmune disease; RA and SLE have been documented well.³¹ Traditional (Framingham) risk factors for cardiovascular disease only partially account for this accelerated atherosclerosis.³² Myocardial infarction makes a major contribution to excessive mortality in SLE. Mortality data suggest a bimodal distribution with many late deaths in SLE secondary to ischemic heart disease. The primary cause of ischemic heart disease in lupus is atherosclerosis. The cause of accelerated atheroma is unclear, but inflammation of the vascular endothelium due to chronic immune complex disease compounded by the effects of corticosteroids is likely to be a major contributing factor. Vasculitis in SLE may affect any organ including the heart although the frequency is not high. Identifying myocardial ischemia caused by vasculitis (as opposed to premature atherosclerosis) can be difficult; however, most patients with coronary artery vasculitis have evidence of active vasculitis in other organs. Serologic evidence of active lupus and markers of systemic inflammation including low hemoglobin and albumin are likely to be present. Acute therapy would include high-dose corticosteroids. In the face of widespread vasculitis, additional intervention with parenteral immunomodulatory therapy may be indicated.³³

The systemic autoimmune diseases are characterized by the presence of sterile inflammation in multiple organs and multiple autoantibodies. The prototypical disease is SLE, which is characterized by the widest clinical and serologic spectrum. Other diseases include scleroderma, Sjögren syndrome, polymyositis, dermatomyositis, rheumatoid arthritis, and syndromes with overlapping features (overlap syndrome or undifferentiated connective tissue disease). The clustering of clinical features and the nature and diversity of autoantibodies may strongly suggest one disorder rather than another, but the overlap of clinical, serologic, and pathologic features among these diseases can be large, leading to considerable consternation for clinicians. Debates about whether a given patient has SLE, primary Sjögren syndrome, or an overlap syndrome are tiring, usually unresolvable, and generally irrelevant. The therapy for the immunologically active phase of these disorders is not disease specific. The absence of a consensus label should not delay therapeutic efforts.

Within the ICU, advanced age, elevation of the ESR, anemia, and various nonspecific clinical features—chiefly fever—may converge to raise the question of temporal arteritis. Temporal arteritis is a granulomatous vasculitis that affects those over age 60 (mean age 70) and has a proclivity to affect extracranial vessels and branches of the aorta. Myriad uncommon clinical features may develop, but headache, polymyalgia rheumatica, visual disturbance, scalp tenderness, and jaw claudication are the common fingerprints of this disease. Treatment is highly effective with prednisone in doses of 40 to 60 mg/d.³⁴ The onset of this disease is typically insidious, and its complications rarely prompt admission to the ICU. Therefore, the question is more commonly framed in terms of whether the patient has developed new-onset temporal arteritis in the ICU (probably not) or did they have it as a comorbid state at admission? History and old records are critical in this regard. Temporal artery biopsy is the gold standard, although sensitivity varies with the institution. A classical clinical scenario that includes headache, visual symptoms, jaw claudication, scalp tenderness, and polymyalgia rheumatica may be sufficiently compelling to prompt treatment. Usually the situation is murkier. There is no substitute for the temporal artery biopsy, which can be done under local anesthesia with little morbidity. A sufficiently large piece (3-4 cm) should be obtained and adequate cuts done for pathology. Contralateral biopsy is done routinely by some if a first biopsy is negative. That decision will be influenced by the details of the clinical scenario and the risk of an empiric trial with steroids. A negative biopsy in a marginal clinical situation is reasonable grounds to withhold therapy.

The clinical presentation of abdominal pain in association with an elevated ESR raises the diagnostic possibility of vasculitis. If the patient is already known to have systemic vasculitis, the differential diagnosis of the abdominal pain and elevated ESR is a bit more straightforward. In the unusual situation when a patient with relatively limited or no vasculitic findings in skin, renal, neurologic or pulmonary systems develops fulminant symptoms affecting the bowel, the diagnosis may remain elusive until angiography or surgical exploration is performed. Patients already on moderate to high dose corticosteroid therapy for pre-existing systemic vasculitis may develop bowel ischemia or perforation with relatively few physical findings. Mesenteric vasculitis can occur in polyarteritis nodosa, microscopic polyangiitis, mixed cryoglobulinemia and occasionally in granulomatous polyangiitis (GPA—formerly referred to as Wegener disease), Churg-Strauss and Henoch-Schonlein purpura. Diarrhea and profound protein-losing enteropathy and acute bowel obstruction secondary to adhesive serositis have occurred rarely in SLE. Acute pancreatitis has also been observed in the patient with SLE; appropriate biochemical and imaging assessment will confirm this diagnosis. Abdominal pain is the most common presenting symptom in those ultimately found to have mesenteric vasculitis and approximately 30% will present with an acute (or surgical) abdomen. Gastrointestinal hemorrhage is uncommon, occurring in less than 30%. Gastrointestinal tract involvement in the setting of systemic vasculitis has a particularly bad outcome; however, mortality rates appear to have decreased since the 1970s.³⁵ The evaluation of these patients traditionally started with plain abdominal films which might show free air or distended bowel loops. The relatively low sensitivity for finding these lesions has led to a more common use of computed tomography (CT) early in the evaluation.³⁶ Endoscopic evaluation (with biopsy) may have an appearance suggestive of ischemia but biopsies have a low sensitivity to diagnose vasculitis.³⁵ Angiography may be necessary to make an appropriate diagnosis in less urgent situations. The role of MRI and/or MR angiography is still unclear. Patients with mesenteric ischemia should undergo urgent laparotomy with resection of affected areas.³⁷ Medical therapy includes supportive therapy and intravenous corticosteroids; cyclophosphamide is often added. In patients with vascular infarction, known to have antiphospholipid antibodies, anticoagulation may be indicated.³⁶ Rituximab, IVIg, and TNF antagonists have been used in refractory cases and the role of plasma exchange or plasmapheresis is unclear.^35,37