Chapter 282: Systemic Rheumatic Diseases

Systemic rheumatic diseases are chronic, inflammatory, autoimmune disorders, such as rheumatoid arthritis, systemic sclerosis (scleroderma), or systemic lupus erythematosus. ED patients with systemic rheumatic diseases have complex clinical and pharmacologic histories and multi-organ system pathology. Many extra-articular manifestations of rheumatic diseases can result in serious morbidity or mortality if not recognized and properly managed. This chapter discusses rheumatologic emergencies from an organ system perspective. Table 282-1 categorizes emergencies associated with systemic rheumatic diseases.¹

Table 282-2 reviews clinical manifestations common to many of the systemic rheumatic diseases. Table 282-3 lists typical clinical manifestations and complications specific to rheumatic diseases. The clinical descriptors may allow suspicion for a systemic rheumatic disease in a previously undiagnosed patient. However, the diagnosis cannot be confirmed during an ED visit. The diagnostic criteria and testing sequence, which are usually completed in the outpatient setting, are beyond the scope of this chapter. The need to admit a patient with a known or suspected systemic rheumatic illness depends on the severity of the patient's presentation. Complications of systemic rheumatic disease frequently require intensive care unit admission, and in 20% of patients with systemic rheumatic disease admitted to the intensive care unit, the diagnosis is made for the first time during the intensive care unit stay.² Rheumatoid arthritis is the most common rheumatic disease requiring intensive care unit admission, followed in decreasing frequency by systemic lupus erythematosus and systemic sclerosis.^2,3,4 Infection is the leading cause for intensive care unit admission, followed by rheumatic disease flare.

Critical airway obstruction may develop (Table 282-4) at the level of the larynx, subglottic region, or trachea.

CRICOARYTENOID JOINT ARTHRITIS

In patients with rheumatoid arthritis, systemic lupus erythematosus, and relapsing polychondritis, arthritis or edema of the cricoarytenoid joints can lead to acute upper airway obstruction.⁵ In addition, secondary infections such as bacterial epiglottitis or tracheitis can quickly compromise the airway. Signs and symptoms of cricoarytenoid arthritis are throat pain or tenderness over cartilaginous structures (aggravated by swallowing or speaking), foreign body sensation or fullness in the throat, voice changes or hoarseness, and, in more severe cases, dyspnea, cough, or stridor.¹ Pain from cricoarytenoid arthritis is sometimes referred to the ear or to the neck.

CT scanning and fiber optic laryngoscopy can evaluate the cricoarytenoid joint. Initial treatment consists of systemic high-dose corticosteroids such as methylprednisolone 250 to 500 milligrams IV.⁵

TRACHEOMALACIA

Relapsing polychondritis can cause inflammation, destruction, and collapse of tracheobronchial cartilage, resulting in airway obstruction. Regions of segmental collapse due to tracheomalacia or refractory stenosis may be resected or treated with stents. The use of noninvasive ventilation may help to prevent airway collapse. Cartilaginous destruction results in a small glottis, so, when intubation is required, use a smaller endotracheal tube than normal.

SUBGLOTTIC STENOSIS

An acute upper airway obstruction can be observed in Wegener's granulomatosis, resulting from subglottic stenosis with inability to clear tracheobronchial secretions. Subglottic stenosis can be a presenting sign of Wegener's granulomatosis. Stenosis often requires surgical intervention.

INTUBATION IN PATIENTS WITH SYSTEMIC RHEUMATIC DISEASES

Endotracheal intubation is considered "difficult" in patients with systemic rheumatic diseases because of airway-related aspects of the disease. Anticipate the need for adjunctive airway techniques. Consider fiber optic intubation and fully prepare to perform an emergency cricothyrotomy. In cases where the airway is patent but intubation is anticipated and the patient can be transferred, it may be preferable to go to the operating room for a "double setup," with preparation for a formal tracheostomy if oral intubation is unsuccessful.

Patients with rheumatoid arthritis and ankylosing spondylitis can develop temporomandibular joint dysfunction with reduced mouth opening. Patients also have a high incidence (25%) of atlantoaxial instability, C1-C2 subluxation, or dislocation. Therefore, avoid neck hyperextension in patients with rheumatoid arthritis.

Neck hyperextension and cervical manipulation are also a hazard in ankylosing spondylitis. Patients with cervical ankylosis are at high risk for cervical fractures (even after minor trauma).

In patients with scleroderma, hardening of the skin of the face and neck can be severe, decreasing the ability to open the mouth and limiting neck mobility.

Lung involvement, due to the underlying disease itself or secondary to infection, is a frequent cause of major morbidity and death (Table 282-4), particularly in systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Wegener's granulomatosis, and polymyositis/dermatomyositis. Pulmonary complications of systemic rheumatic disease manifest primarily as interstitial lung disease and vascular disease. Due to chronic lung injury, interstitial pulmonary fibrosis, or pulmonary hypertension, even mild infection in patients with systemic rheumatic disease can cause respiratory failure.^6,7 Respiratory arrest has been reported in systemic lupus erythematosus and dermatomyositis/polymyositis patients due to phrenic nerve involvement, in rheumatoid arthritis patients due to cervicomedullary compression associated with rheumatoid atlantoaxial dislocation, and in Sjögren's syndrome patients due to hypokalemic paralysis secondary to distal renal tubular acidosis.⁶

Symptoms can develop due to chronic manifestations of the underlying disease (i.e., interstitial lung disease), or new symptoms caused by an acute complication such as pneumonia or alveolar hemorrhage. Rheumatoid arthritis patients treated with methotrexate experience increased adverse respiratory events including pneumonia.⁸ Several complications outside the pulmonary parenchyma cause respiratory symptoms: involvement of the joints of the thoracic cage (in ankylosing spondylitis), pleural effusion, respiratory muscle inflammatory disease (polymyositis/dermatomyositis), cardiac involvement, and anemia. Pulmonary embolism risk is higher in systemic rheumatologic diseases.^9,10

ALVEOLAR HEMORRHAGE

Alveolar hemorrhage is an uncommon but catastrophic pulmonary emergency.^1,3 It is a complication of systemic lupus erythematosus (where it may be the presenting manifestation), antiphospholipid syndrome, systemic vasculitis, Wegener's granulomatosis, dermatomyositis/polymyositis, microscopic polyangiitis, and systemic sclerosis. Early recognition and aggressive management are critical for improved outcome.^3,11 Delay in treatment, age >60 years old, end-stage renal failure, and cardiovascular comorbidity worsen prognosis.¹¹ Patients with alveolar hemorrhage complain of acute shortness of breath, fever, and cough. Symptom onset is usually abrupt, with a progression to respiratory failure requiring mechanical ventilation in more than half of cases.

The classical triad of hemoptysis, pulmonary infiltrates on chest x-ray, and rapid fall in hemoglobin level supports the diagnosis, but the triad is not always present.^12,13 New lung infiltrates (83% to 100%) and anemia (75% to 100%) are more sensitive signs of alveolar hemorrhage; the most common initial diagnosis is "atypical" pneumonia.¹² If symptoms are accompanied by high fever, it is difficult to distinguish between alveolar hemorrhage, acute lupus pneumonia, and infectious pneumonia. The distinction is of utmost importance, because the therapeutic options are exactly the opposite (immunosuppressant vs antibiotics). Emergency bronchoscopy with bronchoalveolar lavage can confirm the diagnosis but is done after admission. Treatment is directed to the underlying condition and includes high-dose glucocorticosteroids, cyclophosphamide, local vessel embolization, or plasma exchange.¹²

INTERSTITIAL LUNG DISEASE

Interstitial lung disease is characterized by infiltration of the pulmonary interstitium by inflammatory cells and matrix, leading to fibrosis, pulmonary hypertension, and respiratory insufficiency. Rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, and Henoch-Schönlein purpura are commonly associated with interstitial lung disease. Interstitial lung disease may be asymptomatic, may produce slowly progressive symptoms (cough and dyspnea), or, rarely, can cause acute respiratory failure. Treatment in the ED is ventilatory support, with oxygen, noninvasive ventilation, and intubation as needed.¹⁴

PULMONARY HYPERTENSION

Pulmonary arterial hypertension can be a complication of any rheumatic disease with associated pulmonary fibrosis and interstitial lung disease, but is especially common in systemic sclerosis and systemic lupus erythematosus. Pulmonary vasculitis and pulmonary thromboembolism (i.e., in antiphospholipid syndrome patients) may also lead to pulmonary arterial hypertension. Clinical symptoms reported by patients with pulmonary arterial hypertension range from cough or mild shortness of breath, to severe dyspnea, cardiac arrhythmias, chest pain, and right ventricular failure. For further discussion, see chapters 57 and 58, "Systemic Hypertension" and "Pulmonary Hypertension," respectively.

Heart disease develops through several pathophysiologic mechanisms, accounting for different manifestations: inflammation, fibrosis, infiltration, vasculitis, thromboembolism, and accelerated coronary atherosclerosis.¹⁵ Pulmonary hypertension can lead to right heart failure. Coronary atherosclerosis can be due to an imbalance between the inflammatory and anti-inflammatory activity and the use of specific drugs, such as corticosteroids. Table 282-5 provides a review of cardiac disorders in patients with systemic rheumatic diseases.^{15,16,17,18,19,20}

ACUTE CORONARY SYNDROMES

Based on epidemiologic, clinical, laboratory, and experimental data, systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and a few other rheumatic diseases promote accelerated coronary atherosclerosis and have an increased rate of cardiovascular morbidity and mortality.^15,16,17 The relative risks for atherosclerosis vary from about 1.6 in ankylosing spondylitis and psoriatic arthritis to 3.0 in rheumatoid arthritis (with a threefold increased adjusted risk of myocardial infarction) and 6.0 in systemic lupus erythematosus.¹⁷ The risk of cardiovascular disease equals that of type 2 diabetes with coronary artery disease more prominent in rheumatoid arthritis and peripheral arterial disease more prevalent in type 2 diabetes.²¹

From a clinical point of view, it is useful to consider systemic rheumatic disease a "new" risk factor for coronary atherosclerosis. Patients with rheumatoid arthritis are less likely to undergo invasive evaluation and treatment.¹⁹ Contributing factors may be low incidence of typical angina symptoms and attribution of chest pain to arthritis.

Coronary atherosclerosis is a major cause of cardiac mortality in young patients with systemic lupus erythematosus.¹⁶ The risk of myocardial infarction in premenopausal women is more than twofold compared with women without lupus.¹⁶ Medical management of acute coronary syndrome is the same as in the normal population. Coronary arteritis, fibrosis, and coronary artery vasospasm may occur in systemic sclerosis and vasculitis.

ACUTE HEART FAILURE

Acute heart failure may develop as a consequence of a myocardial disease (ischemia, cardiomyopathy, myocarditis, fibrosis), pericardial disease (tamponade or constrictive), valvular diseases (acute regurgitation), and/or conduction or rhythm disturbance.^15,16 Acute management of decompensated heart failure does not differ from the normal population, except when a flare of the underlying disease is responsible. In systemic sclerosis, diastolic dysfunction, malignant hypertension during a sclerodermal renal crisis, and decompensated pulmonary hypertension are important causes of acute heart failure.

CARDIAC ARRHYTHMIAS

Rhythm and conduction disturbances are common, especially in rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, and polymyositis/dermatomyositis. The physiopathologic basis for these disorders is complex, involving reentry pathways, fibrosis, altered automaticity, conduction system injury, primary and/or secondary myocardial injury, and side effects of treatment. Population studies demonstrate a 40% higher risk for atrial fibrillation in patients with rheumatoid arthritis.²² Arrhythmias and sudden cardiac death in systemic rheumatic disease have a higher incidence compared with the normal population.^19,20 Ventricular arrhythmias are a risk for sudden cardiac death, especially in patients with systemic sclerosis.²⁰

MALIGNANT HYPERTENSION

Systemic hypertension may be a clinical manifestation of renal injuries or an adverse effect of disease treatment. Severe malignant hypertension is a complication of systemic sclerosis (usually observed during a "renal crisis"), but it can be also observed in catastrophic antiphospholipid syndrome, polyarteritis nodosa, and a few other rheumatic diseases.

VASCULAR AND VALVULAR DISEASE

Valvular heart disease is an extra-articular manifestation of spondyloarthropathies, particularly ankylosing spondylitis. Fibrotic changes of the aortic valve cusps lead to valvular insufficiency of the aortic and/or mitral valves. Arterial lesions can be aneurysmal (frequently complicated by fatal rupture) or, less commonly, occlusive. Aortitis may lead to aortic aneurysms in patients with giant cell arteritis (temporal arteritis), Takayasu's arteritis, and Behçet's disease, and aneurysms may rupture or dissect. In giant cell arteritis, great vessel involvement due to arteritis can result in aortic valve incompetence and aortic rupture as a late complication of the disease.

Any part of the arterial tree can be affected in Behçet's disease, but the abdominal aorta is the most frequently involved site. Pulmonary artery inflammation can be complicated by hemoptysis, aneurysm, thrombosis, hemorrhage, and pulmonary infarction. In Takayasu's arteritis, arterial narrowing and/or aortitis can produce neurologic symptoms or syncope related to the subclavian steal syndrome. Acute coronary syndrome, mesenteric artery ischemia, and peripheral arterial ischemia are other complications of Takayasu's arteritis.

THROMBOEMBOLISM

Superficial thrombophlebitis and deep vein thrombosis are common in Behçet's disease. After the veins of the lower extremities, other affected veins are the inferior and superior vena cavae, veins of the upper extremities, and hepatic and portal veins. Thrombosis is related to vascular inflammation and is not usually complicated by peripheral embolism. Deep venous thrombosis and pulmonary vasculitis can coexist. Hemoptysis, a sign of pulmonary artery inflammation, may mimic signs of pulmonary embolism. Treatment with anticoagulant or fibrinolytic may increase the risk of fatal hemorrhage.

Thromboembolic disease may also be observed in antiphospholipid syndrome and systemic lupus erythematosus. Vessel thrombosis can be venous and/or arterial, affect any vessel, and be recurrent and bilateral. Peripheral gangrene, acute coronary syndrome, renal artery thrombosis, sagittal sinus thrombosis, transient ischemic attack, and Budd-Chiari syndrome due to hepatic vein thrombosis are some examples of thromboembolism resulting from antiphospholipid syndrome and systemic lupus erythematosus.

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME

This uncommon vaso-occlusive process leads to multiorgan failure and is usually associated with systemic lupus erythematosus, but it may be observed in rheumatoid arthritis, systemic sclerosis, dermatomyositis, and other systemic rheumatic diseases.²³ Multiple simultaneous venous and/or arterial occlusive thromboses (involving mainly small vessels) and multiorgan failure develop suddenly and progress rapidly. In half of the cases, a precipitating factor may be identified (i.e., infection, surgery, trauma, cancer, drugs such as oral contraceptives). The kidney is the primary organ involved (acute renal failure), followed by the lungs (adult respiratory distress syndrome, embolism), CNS (stroke, seizures, venous occlusion), the heart (acute myocardial infarction and heart failure), and skin (necrosis). Livedo reticularis (lacelike purplish discoloration of the lower extremities due to vein engorgement) and thrombocytopenia are important diagnostic findings (a decrease in platelet count is observed in 60%), and occasionally, laboratory features of disseminated intravascular coagulation may be present.²³ This dramatic clinical scenario is frequently fatal, with a reported mortality rate approaching 50% despite therapy. Treatment is IV heparin and high-dose glucocorticosteroids with or without plasma exchange and IV immunoglobulins.²³

Neurologic disease can result from accelerated atherosclerosis, direct involvement by the primary disease, vasculitis, arterial aneurysm, rupture or dissection, embolism, or infection²⁴ (Table 282-6). Libman-Sacks valvular endocarditis of lupus can result in embolism of valve vegetations. Vasculitis of the cerebral vessels, with vessel rupture or occlusion, may lead to ischemic or hemorrhagic stroke. Giant cell arteritis affects the extracranial vasculature, causing transient ischemic attacks, especially involving the vertebrobasilar circulation, with signs and symptoms of vertigo, hearing loss, gait disturbance, and other focal neurologic deficits involving the brainstem.

Neurologic disease can also manifest as a consequence of therapy for systemic rheumatic diseases. Medications such as infliximab and adalimumab, which block tumor necrosis factor-α, increase the risk for herpes zoster outbreaks, especially multidermatomal and zoster ophthalmicus.²⁵ Lupus and rheumatoid arthritis are independent risk factors for herpes zoster outbreaks.²⁶

SPINAL CORD COMPRESSION AND SPINAL FRACTURES

Degenerative disease of the cervical spine may result in acute spinal cord compression, vertebral artery compression syndrome (with diplopia and dysphasia), gait abnormalities, paresthesias, or obstructive hydrocephalus in patients with rheumatoid arthritis and ankylosing spondylitis. Rigidity and osteoporosis of the spine in ankylosing spondylitis increase the risk for fracture and spinal cord injury. Occult fracture of the ankylosed spine may occur, even in the absence of trauma, and may result in acute radiculopathy, paraparesis, or tetraparesis. The most common symptom is severe and progressive pain. Cauda equina syndrome is a rare complication.

INSTABILITY OF THE CERVICAL SPINE

The atlantoaxial joint is a preferred target of rheumatoid arthritis. Instability of the cervical spine and spontaneous atlantoaxial subluxation can result in acute cervical myelopathy, even after minor trauma. The signs and symptoms that raise suspicion of an unsTable cervical spine are severe neck pain with occipital radiation and paresthesias or motor weakness involving the upper extremities. Instability may produce vertigo or other signs of vertebral insufficiency. The patient may complain of an electric shock sensation radiating down the back during neck flexion, a change in bladder function, or progressive quadriparesis.

Atlantoaxial instability can be clinically silent, so avoid neck flexion in the patient with rheumatoid arthritis. After even mild trauma, or if neurologic symptoms as described above develop, keep the cervical spine stabilized. CT of the cervical spine will detect fracture, but MRI is needed to assess spinal cord integrity. Neurosurgical (or orthopedic spine specialist) consultation is needed for management.

TRANSVERSE MYELITIS

Transverse myelitis is a rare, devastating acute inflammatory process affecting a focal area of the spinal cord that may lead to rapid onset of irreversible paraplegia. It is clinically manifested with acute or subacute progressive symptoms and signs of neurologic dysfunction of the spinal cord. The clinical picture may be insidious at the beginning, with weakness, back or limb pain, urinary retention, and autonomic and sensory deficits.²⁷

Transverse myelitis occurs more commonly in patients with Sjögren's syndrome and patients with systemic lupus erythematosus, in whom acute transverse myelitis may be the initial manifestation. The clinical picture of transverse myelitis may also be caused by vasculitis, arterial thrombosis, embolism, or artery dissection. An anterior spinal artery syndrome may be observed in other rheumatic diseases and is caused by the blood supply impairment secondary to dissection of the aorta, vasculitis, or embolism involving the anterior spinal artery. The clinical picture is indistinguishable from transverse myelitis.

The eye is a sensitive barometer for onset or flare of rheumatic diseases.²⁸ Ocular pain or discomfort, vision disturbances, red eye, tearing, photophobia, diplopia, or reduced visual acuity should lead to careful evaluation (Table 282-6). Optic neuritis and keratitis are complications of systemic rheumatic diseases and are discussed in brief in chapter 241, "Eye Emergencies."

Sudden and permanent blindness is also a concern in temporal or giant cell arteritis, a systemic disease that may lead to vasculitis and ischemia and that affects middle-aged to elderly individuals. The patient may report amaurosis fugax and complain of new headache, tender scalp, visual disturbance, or jaw, tongue, or upper extremity claudication. Frequently, vision loss is the presenting feature of giant cell arteritis. To prevent permanent vision loss, high-dose steroids are administered based on the clinical diagnosis, even before biopsy of the temporal artery (see chapter 241).

The kidney is almost always involved in systemic rheumatic disease and is a major factor leading to morbidity and mortality (Table 282-7).

A decline in renal function should prompt careful observation and follow-up in any rheumatic disease patient. Kidney impairment may be related to the rheumatic disease itself, the results of therapy, or both. Acute nephritic syndrome, renal thrombotic events, renal artery lesions, and rhabdomyolysis are other possible causes of acute renal failure. In polyarteritis nodosa, rupture of arterial aneurysms can cause a perirenal hematoma.

Renal disease is the most common cause of death in systemic sclerosis, and a sudden catastrophic form of renal involvement, named scleroderma renal crisis, may be the cause. Scleroderma renal crisis typically develops early in the course of systemic sclerosis, and 75% of cases occur during the first 4 years after the onset of disease.²⁹ Scleroderma renal crisis presents with abrupt and rapid deterioration in renal function and is heralded by severe headache, visual disturbance, and hypertensive encephalopathy. Microangiopathic anemia with mild thrombocytopenia is another important but nonspecific diagnostic finding in scleroderma renal crisis.

The mainstay of therapy in scleroderma renal crisis is effective and prompt blood pressure control with angiotensin-converting enzyme inhibitors.²⁹ Start captopril, 6.25 to 12.5 milligrams PO three times daily, and increase as tolerated (during admission or follow-up).²⁹ Enalaprilat can be used if PO therapy is not possible. Consult nephrology for dialysis recommendations; dialysis is required in 50% of patients.³⁰ Avoid diuretics as they can exacerbate renal failure. For further discussion, see chapters 57 and 58.

Distal renal tubular acidosis occurs in 30% of patients with primary Sjögren's syndrome. This condition is characterized by hyperchloremic metabolic acidosis with low bicarbonate levels and hypokalemia. Consider hypokalemia as a cause of progressive weakness in patients with Sjögren's syndrome. Hypokalemia is corrected with standard treatment (see chapter 17, "Fluids and Electrolytes").

GI emergencies are outlined in Table 282-7. GI complications include ischemia (primarily due to vasculitis), infarction, perforation, vascular rupture, infection (i.e., cholecystitis, diverticulitis), and hemorrhage. Vasculitis is the most common GI manifestation and may affect large vessels (giant cell arteritis), medium-sized vessels (polyarteritis nodosa), or small vessels (systemic lupus erythematosus). Lupus mesenteric vasculitis is one of the most serious complications of systemic lupus erythematosus, with mortality of 13%.³¹ Leukopenia, hypoalbuminemia, and elevated serum amylase are associated with poor outcome.³¹ Bowel ischemia can be the result of the same pathophysiologic process that leads to acute coronary syndrome or the result of ischemic stroke or mesenteric artery vasculitis, as in lupus and other systemic rheumatic diseases. The patient may complain of symptoms consistent with "abdominal angina" prior to bowel infarction. Due to chronic or recurrent ischemia, the bowel may develop wall edema, strictures, and stenosis. These changes may account for colicky abdominal pain, diverticular disease, intestinal obstruction, or episodes of paralytic ileus. Acute pancreatitis is common in several systemic rheumatic diseases.

Rheumatic diseases predispose to infection in several ways. The disease itself results in immunocompromise; treatment results in further immunosuppression (see "Adverse Drug Reaction" section below for infections associated with specific drugs used to manage systemic rheumatic diseases); the disease can result in anatomic changes that predispose to infection (see "Pulmonary Emergencies" above). Empiric antibiotics are indicated until infection can be clearly excluded. Using an elevated procalcitonin of 0.5 nanogram/mL is 90% specific for sepsis in patients with autoimmune diseases but is only 75% sensitive.³² Isolated organisms may not differ from the normal population, but chronic immunosuppressive therapy may predispose patients with systemic rheumatic disease to opportunistic infections (i.e., Candida, Pneumocystis jiroveci, Legionella, Mycobacterium tuberculosis).

The prevalence of septic arthritis is doubled in patients with rheumatoid arthritis who are treated with glucocorticoids or tumor necrosis factor-α blockers.³³ The physical findings of severe pain and limited range of motion may be absent in cases of septic arthritis in patients with systemic rheumatic disease or may mimic a typical exacerbation of inflammatory arthritis.³⁴ Procalcitonin can help to differentiate septic from nonseptic arthritis, but using the standard cutoff of 0.5 nanogram/mL yields a sensitivity of only 46% to 67% with a specificity of 91%.³⁴ Using a lower cutoff of 0.25 nanogram/mL yields a sensitivity of 93% and a specificity of 75%.³⁴ Patients suspected of having septic arthritis should have arthrocentesis. See chapter 284, "Joints and Bursae" for further discussion of diagnosis and treatment.

Several hematologic complications and other emergencies are encountered in patients with rheumatic diseases (Table 282-8).

Anemia, thrombocytopenia, leukopenia, and coagulation abnormalities are some of the important hematologic emergencies. Severe hemolytic anemia may develop in systemic lupus erythematosus (autoimmune) and in systemic sclerosis during renal crisis (microangiopathic). Thrombocytopenia is also observed in antiphospholipid syndrome patients and may present as thrombotic thrombocytopenic purpura. A low WBC count may also occur as a part of underlying disease or secondary to drug use. Pancytopenia can be observed when autoimmune rheumatic disorder affects all the cellular lines, in acute hemophagocytic syndrome, and in medullar suppression secondary to cytotoxic drugs. In autoimmune hematologic emergencies, transfusion of blood product may carry some risk of transfusion reaction.

Raynaud's phenomenon, digital ulcers, spontaneous finger ischemia, rash, and cellulitis are some examples of skin manifestations. In systemic lupus erythematosus, toxic epidermal necrolysis can be triggered by medication.

Patients with steroid-dependent rheumatic diseases are at risk for acute adrenal insufficiency either from unexpected stressors or from abrupt cessation of prescribed steroid medication.

Orchitis is one of the most characteristic manifestations of polyarteritis nodosa, and reports of scrotal involvement in boys with Henoch-Schönlein purpura range from 2% to 38%. Clinical findings include pain, tenderness, and swelling of the involved testicle and/or scrotum. The presentation may mimic testicular torsion. Ultrasonography confirms the correct diagnosis.

Table 282-9 lists the more common clinical manifestations of adverse reactions associated with drugs used to manage systemic rheumatic diseases. When patients with systemic rheumatic diseases develop new alarming and unexplained symptoms, a drug reference guide or similar resource should be consulted for a listing of rare adverse drug reactions.

IMMUNOSUPPRESSION CAUSED BY DRUGS USED TO MANAGE SYSTEMIC RHEUMATIC DISEASES

Immunosuppressants and disease-modifying antirheumatic drugs are used to treat multiple types of systemic rheumatologic diseases with the aim to induce or maintain remission, to reduce exacerbations or relapse, and/or to allow tapering of glucocorticoids. These drugs have a variety of actions that are not completely understood but that modify critical pathways in the inflammatory process. They may cause immunosuppression primarily or as a side effect and lead to secondary diseases, infections, and reactivation of latent diseases or malignancies^{35,36,37,38,39,40,41,42,43} (Table 282-10).

Risk factors for infection during immunosuppression include the drug, dose, duration of use, concomitant use of immunomodulators, the nature of the disease process, the functional status of the patient, healthcare facility exposure, and older age.⁴⁴

Glucocorticoids impact both the innate and acquired immune system through a variety of inhibitory mechanisms. Immediate effects on the innate immune system include decreased phagocyte migration, eosinophil apoptosis, decreased macrophage production and function, decreased degranulation of mast cells, decreased inflammatory cytokine production, and decreased proinflammatory mediators. Neutrophils are affected by decreased ability to bind to and exit the endothelium, increased release from bone marrow, and decreased apoptosis resulting in increased overall leukocytosis but decreased effectiveness.

Acquired immunity is also affected by a decrease in dendritic cells, rapid depletion of T cells, increased apoptosis of CD4 and CD8 cells, B-cell reduction (although to a lesser extent than T cells), and in chronic use, a decrease in immunoglobulin G and immunoglobulin A.⁴⁵ Glucocorticoid therapies are associated with a dose-dependent increase in risk of infection. In trials, infection occurs more often with steroid therapy (relative risk, 1.6). Infection rates increase in therapy doses greater than 10 milligrams/d or cumulative doses greater than 700 milligrams.