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.

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).

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].

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.

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.

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.

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.

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.

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.

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.

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].

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].

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 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.

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.

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.