A. Introduction. Systemic autoimmune diseases (often referred to as “connective tissue diseases”) are a large and clinically diverse cluster of disorders. They share in common inappropriate targeting of normal tissues by immune and inflammatory mechanisms leading to self-injury. Although some of these conditions predominantly affect one target tissue (e.g., Sjögren’s affecting salivary glands), they all share the potential to cause disease in multiple organ systems. Systemic autoimmune diseases are thought to be linked because they can occur together in the same patient and are often associated with overlapping patterns of autoantibodies. The lack of molecular-level understanding of etiology, sensitive and specific tests to aid in diagnosis, and diverse clinical features render systemic autoimmune diseases a challenging but extraordinarily interesting group of diseases to diagnose and treat.
B. Clinical Patterns
a. Completely or partially diagnostic. Some autoimmune diseases present with features that immediately suggest a diagnosis. For example, an older adult patient who appears systemically ill and has recent-onset temporal headache and facial muscle claudication, with an erythrocyte sedimentation rate (ESR) >100 mm/hr, is very likely to have temporal arteritis. Similarly, individuals with oral and/or ocular sicca are more likely to have Sjögren’s syndrome than another autoimmune disease. A patient with a sun-sensitive rash, symmetric small-joint peripheral arthritis, pericarditis, and renal insufficiency with an active urinary sediment is also likely to have systemic lupus erythematosus (SLE).
b. Nonspecific. Most systemic autoimmune diseases, however, present in ways that lack diagnostic specificity. Often, a patient with disease concurrently affecting multiple organ systems is enough to trigger consideration of an autoimmune disease.
c. Fever and/or high ESR. Some patients with autoimmune disease present with a fever that becomes persistent and resistant to medical diagnosis, that is, the syndrome of “fever of unknown origin” (see Chapter 51). Approximately one-third of such cases will eventually be attributed to a systemic autoimmune disease, whereas two-thirds are attributable to infectious or neoplastic etiologies. Some patients present with very high inflammatory marker values (e.g., ESR >100 mm/hr or very high C-reactive protein [CRP] levels). A significant proportion will ultimately be diagnosed with autoimmune disease.
C. Role of Laboratory Testing. Because the molecular basis of autoimmune diseases has yet to be elucidated, laboratory tests do not directly relate to pathogenesis and therefore lack precision. While conventionally used tests have some positive and negative predictive value, none are diagnostic. Clinicians should therefore order laboratory tests only after developing an initial differential diagnosis based on the clinical features. Because tests lack strong diagnostic specificity, indiscriminate testing will generate large numbers of false-positive results. Laboratory tests that can be diagnostically helpful are discussed here in the context of disease associations and also summarized in Table 75.1.
a. General laboratory tests. Some tests could be considered extensions of the physical examination and are ordered in any systemically ill patient. These include complete blood count (CBC), complete biochemical profile, urinalysis for blood and protein, ESR, and CRP.
b. When antinuclear antibody (ANA)-associated disease is possible. ANA-spectrum diseases include systemic lupus erythematosus (SLE), Sjögren’s syndrome, systemic sclerosis, and autoimmune muscle diseases. The preferred ANA methodology is the time-tested indirect immunofluorescence assay using a cultured cell line or tissue substrate. However, this assay is not available in all laboratories, and other methods lack specificity. If the ANA is reported as positive, then subsequent testing should include a panel of antibodies to extractable nuclear antigens (ENAs) and antibody to double-stranded DNA (dsDNA). Positive results with some of these antibodies can be diagnostically very specific. For example, a positive dsDNA antibody or positive Smith antibody (part of the ENA panel) can be considered diagnostic of SLE. Assays of C3 and C4 complement factors are helpful indicators of disease activity because the immune complexes associated with SLE consume complement (and thereby lead to low C3 and C4 levels).
c. When Sjögren’s syndrome is possible. Approximately 70% of Sjögren’s patients have antibodies to either Ro/SS-A or La/SS-B antigen complexes. These tests are always included in ENA antibody panels.
d. When systemic sclerosis is possible. More than 90% of systemic sclerosis patients are ANA positive; they may also have other related antibodies with diagnostic and prognostic significance. Centromere antibodies are detected by immunofluorescence using proliferating cultured cells as a target and in ENA assays. They are associated with limited cutaneous disease but are also associated with vascular complications such as pulmonary hypertension. Scl-70 antibodies are associated with diffuse cutaneous disease and interstitial lung disease. RNAIII polymerase antibodies correlate with rapidly progressive diffuse cutaneous disease.
e. When autoimmune muscle disease is possible. Most cases are classified as either polymyositis or dermatomyositis (but other less common types of muscle disease with distinctive histopathology also occur). Creatine phosphokinase (CPK) is typically the first test obtained to assess muscle injury and can be repeated to evaluate response to treatment.
Up to 80% of patients with autoimmune muscle diseases have a positive ANA test.
They may also have myositis-specific autoantibodies, including antibodies to:
i. Aminoacyl-transfer (t)RNA synthetases, the most prevalent of which is Jo-1. Jo-1 testing is available as part of most extended ENA panels or can be specifically ordered.
ii. Signal recognition particle (SRP). Antibodies to SRP are tested in reference laboratories.
iii. Other myositis-specific antibodies. Multiple other myositis-specific antibodies have been identified, and testing for these is usually restricted to reference laboratories.
These antibodies have significant diagnostic and prognostic significance and may identify associated neoplastic diseases; they are important components in the diagnostic assessment of myositis.
Assay of aldolase to assess muscle injury is discouraged because the assay lacks specificity.
f. When adult-onset Still’s disease is possible. Ferritin is an acute phase reactant that is elevated in association with systemic inflammation; but especially high levels are found in Still’s (and only a few other conditions). The higher the level, the greater the specificity for diagnosing Still’s disease.
g. When vasculitis is possible. Some of the diseases causing systemic vasculitides are associated with antineutrophil cytoplasmic antibodies (ANCAs), and ANCA testing should be requested. In addition, antibodies to two of the known specific targets of ANCA, proteinase 3 (PR-3) and myeloperoxidase (MPO), should be assayed. PR-3 antibodies are associated with granulomatosis with polyangiitis; MPO antibodies are associated with microscopic polyangiitis and other conditions. Cryoglobulin testing should be ordered because cryoglobulinemia often manifests with a vasculitis syndrome, as well as causing disease in the kidneys and other organs. Hepatitis C testing is also indicated because of the common association of this infection with cryoglobulinemia. Because extraarticular manifestations of rheumatoid arthritis (RA) may include vasculitis, rheumatoid factor testing is also warranted.
h. When hyperimmunoglobulin G4 (hyper-IgG4) disease is possible. This condition is characterized by increased proportions of IgG4-expressing plasma cells in affected tissues. Most cases also have elevated serum levels of IgG4, and IgG subclasses 1–4 should be assayed.
i. When autoimmune thrombotic disease is possible. Most cases of antiphospholipid syndrome are associated with persistent antibodies to β2-glycoprotein 1 (B2GP1), cardiolipin, or both. Some cases are also associated with lupus anticoagulant, in which antibody inhibitors of coagulation assays can be detected with special mixing studies. More sensitive functional assays include the dilute Russell’s viper venom test (DRVVT) and hexagonal phospholipid neutralization assay. These assays require expert interpretation and are confounded by treatment with anticoagulants.
Table 75.1 Laboratory Testing in Systemic Autoimmune Diseases
Tests to Order
Any systemically ill patient
Complete blood count with platelets, complete biochemical profile, ESR, CRP, urinalysis for blood and protein
Systemic lupus erythematosus and related ANA-associated diseases
ANA, double-stranded DNA antibody, ENA panel, C3, C4
ANA, ENA panel for SS-A and SS-B
ANA, ENA panel for Scl-70 and centromere antibodies, RNAIII polymerase antibody
Autoimmune muscle disease
CK, ANA, ENA panel for Jo-1, panel of myositis antibodies
Adult-onset Still’s disease
ANCA, PR-3 Ab, MPO antibody, cryoglobulins, hepatitis C antibody, rheumatoid factor
Cardiolipin antibodies, β2-glycoprotien 1 antibodies, lupus anticoagulant test
AB = antibody, ANA = antinuclear body, ANCA = antineutrophil cytoplasmic antibodies, CK = creatine kinase, CRP = C-reactive protein, ENA = extractable nuclear antigens, ESR = erythrocyte sedimentation rate, MPO = myeloperoxidase, PR-3 = proteinase 3.
D. Role of Tissue Diagnosis. Many systemic autoimmune diseases lack definitive clinical features or diagnostic laboratory tests, and diagnosis is thus more dependent on definitive histopathology from tissue biopsy. Choice of tissue to biopsy depends on evidence of clinical involvement and also is influenced by accessibility, safety issues, and knowledge of historical yield.
E. Mimics of Systemic Autoimmune Diseases. Some systemic autoimmune diseases have clinical features that can be mimicked by other completely different types of disease. For example, vasculitis affecting peripheral arteries and bacterial endocarditis with septic emboli can be clinically (and sometimes histopathologically) indistinguishable. Similarly, cocaine use can cause arterial occlusive disease that mimics vasculitis, and levamisole (which is a common adulterant in drugs of abuse) can also cause a vasculitis-like syndrome. These are just a few examples from a very large and clinically diverse list; considering and excluding the possibility of an autoimmune disease mimic is an expected part of the assessment of autoimmune disease.
F. Identifying Underlying Conditions Triggering Systemic Autoimmune Diseases. Some autoimmune diseases are triggered by specific, identifiable stimuli. Multiple medications can cause SLE and different types of vasculitis. Hepatitis B virus infection can cause polyarteritis nodosa, and hepatitis C infection is a very common cause of cryoglobulinemia with associated vasculitis. Some vasculitis is paraneoplastic. Considering the possibility of a specific underlying cause is an integral element of the assessment of autoimmune disease.
G. Signs and Symptoms of Systemic Autoimmune Disease. This section describes some specific symptoms and signs that may be associated with systemic autoimmune diseases. While very specific clinical and laboratory features do sometimes suggest a diagnosis, more often it is the overall clinical presentation, with relatively nonspecific clinical features involving multiple organ systems concurrently, that is the strongest indicator of systemic autoimmune disease. It is also important to remember that involvement of internal organs may be clinically occult and can only be identified with appropriate testing.
Renal involvement is especially important to identify because the kidneys are frequent targets of autoimmune diseases, and preservation of renal function depends on early recognition.
a. Raynaud’s phenomenon. This is a process of cold-induced episodic color change and discomfort occurring in the digits (hands more often than feet) as a result of reversible vasospasm. Many cases are primary (not associated with autoimmune diseases) or are provoked by cigarette smoking. However, in some cases, the phenomenon is an indicator of underlying systemic autoimmune disease, mostly in the SLE/RA/scleroderma spectrum of disorders. Severe Raynaud’s phenomenon, complicated by permanent ischemia with tissue loss and secondary infection, is a common feature of scleroderma.
b. Skin lesions. Many distinctive skin lesions can lead directly to a specific autoimmune disease diagnosis. Well-characterized examples include the butterfly rash or alopecia areata of SLE; the heliotrope rash, shawl sign, and Gottron’s papules of dermatomyositis, and the predominantly distal diffuse skin thickening of systemic sclerosis. However, many skin lesions do not have distinctive clinical characteristics, and biopsy may be necessary to elucidate a specific diagnosis.
Skin lesions may not be readily evident to the patient or clinician, and careful skin examination (including that of the scalp) is an important element of the physical examination in patients with suspected autoimmune disease.
c. Ocular lesions. Complaints of ocular dryness are common in Sjögren’s syndrome. Patients may describe needing to use eye drops, intolerance of contact lenses, and inability to make tears. Many systemic autoimmune diseases target the sclera, uveal tract, retina, and optic nerve and elicit visual disturbance and pain. In contrast, some conditions such as sarcoid can cause completely asymptomatic lesions with diagnostic features on examination.
d. Oral lesions. Oral sicca is also a common presenting feature in Sjögren’s, and patients may describe needing to take frequent sips of water, especially when eating dry foods. Excessive dental caries are common complications. Intraoral aphthous ulcers commonly occur in SLE, and especially painful aphthae are almost universal in Behçet’s syndrome.
e. Serositis. Pain from pleural and pericardial inflammation is a common finding in these diseases.
f. Thrombosis. Venous—more than arterial—thrombosis is the major clinical manifestation of antiphospholipid syndrome, and this syndrome often overlaps with SLE. Thrombosis also occurs as a complication of vasculitis; clots form in small and large blood vessels. Major venous thrombotic disease is a notable feature of Behçet’s syndrome.
g. Weakness. Patients often complain of subjective weakness; however, this sometimes reflects underlying pain that inhibits movement. Clinical evaluation can help distinguish true muscle disease causing objective weakness from pain in joints or other structures that lead to subjective weakness.
H. Specific Syndromes. This section provides brief snapshots of some key features of individual systemic autoimmune diseases and guidance for building a differential diagnosis.
a. SLE, the prototypical systemic autoimmune disease, can manifest with typical clinical features. A woman with a polyarthritis, butterfly rash, serositis, and evidence of glomerulonephritis could hardly have any disorder other than SLE. Yet, it is the extraordinary diversity of clinical features that can and do occur that truly characterizes SLE. SLE must be in the differential diagnosis for any patient with possible systemic autoimmune disease. Almost all patients with SLE will have a positive ANA test. However, a false-positive ANA is so common that while a positive ANA is permissive for a diagnosis of SLE, more than an ANA is required. Diagnosis can come through finding the more specific Smith and double-stranded DNA antibodies, the presence of characteristic clinical features, or specific tissue histopathology. Published diagnostic criteria are applied primarily for validating the diagnosis in clinical research studies; however, they can provide useful guidance in ambiguous cases. The classic prevalent clinical features include Raynaud’s phenomenon, small-joint arthritis, sun-sensitive or other rash, focal alopecia, aphthous oral ulceration, serositis, hematologic involvement causing cytopenia of any cell line, and evidence of renal disease. However, as stressed above, involvement of any organ system can occur and must be considered.
About 90% of patients with SLE are women, with the incidence of disease increasing in the presence of female sex hormones.
b. Sjögren’s syndrome. Sjögrens may present as glandular disease or with systemic signs and symptoms.
i. Glandular disease. Sjögren’s frequently affects only the salivary glands, causing ocular and oral dryness because of autoimmune destruction of acini and ducts. Confirmation of dryness is usually done with the Schirmer test, measuring migration of ocular secretions into blotting paper test strips placed in the lower conjunctival sac. Diagnosis is usually made by a combination of excluding other conditions that can cause dryness (e.g., medications such as psychotropic agents or antihistamines that both have anticholinergic activity) and finding serologic evidence of Sjögren’s (positive ANA, SS-A, and SS-B). Patients may also have polyclonal hypergammaglobulinemia and a positive rheumatoid factor test. Definitive diagnosis can be made by minor salivary gland biopsy from within the lower lip, but this is rarely required. Some patients have more widespread exocrine glandular involvement, causing anhidrosis and dyspareunia.
ii. Systemic inflammatory disease. A very wide variety of infiltrative mass lesions and vasculitic lesions can occur; cutaneous vasculitis, peripheral nerve vasculitis, and nephritis are especially common, as are interstitial and other types of lung disease.
iii. Lymphoproliferative disease. Sjögren’s is complicated by lymphoproliferative disease in up to 10% of cases. This is often mucosa-associated lymphoid tissue (MALT) lymphoma that develops in association with affected salivary glands in the head and neck, but disseminated disease and other types of lymphoma occur.
c. Rheumatoid Arthritis (RA). RA typically presents as a symmetric polyarthritis and prolonged morning stiffness. Women are affected two to three times more often than men; peak incidence of disease is between 30 and 60 years of age. Patients with RA can also develop a very wide range of extraarticular manifestations. This tends to occur in patients with extensive and destructive joint disease with high levels of rheumatoid factor.
Clinical manifestations of RA include vasculitic, inflammatory, and infiltrative lesions affecting virtually any body system (see Chapter 74).
d. Systemic sclerosis. Multiple skin disorders are associated with localized or diffuse skin thickening, but based on the most recent diagnostic criteria, systemic sclerosis can be identified based on finding skin thickening that involves the fingers of both hands and that extends proximally to the metacarpophalangeal joints.
i. Hand involvement is often prominent with a mix of vascular manifestations (Raynaud’s phenomenon, permanent ischemia causing digital ulcers and secondary infection, telangiectasia), extensive digital cutaneous fibrosis, and other features such as calcinosis and an early generalized edematous phase.
ii. Renal involvement is predominantly vascular and can lead to systemic hypertension and scleroderma renal crisis.
iii. Lung involvement can include fibrotic interstitial lung disease and/or pulmonary hypertension.
iv. Esophageal involvement with autonomic dysmotility leads to dysphagia and reflux that can be complicated by aspiration.
v. Intestinal involvement can include gastric antral vascular ectasia causing bleeding and diffuse intestinal dysmotility/fibrosis, complicated by a bacterial overgrowth syndrome, both causing malabsorption.
vi. Cardiac involvement can include pericardial effusion, arrhythmia, and myocardial fibrosis.
e. Autoimmune myositis
i. Muscle disease. There are many distinct types of autoimmune muscle disease;* the most frequently encountered are dermatomyositis, polymyositis, and necrotizing myopathy. These can be differentiated based on muscle biopsy histopathology, by myositis-specific serology, and also in some cases by distinctive extramuscular clinical features. However, these conditions all present with progressive muscle weakness that is initially and predominantly proximal, that is, affecting truncal and limb-girdle muscles. Unless recognized and treated, weakness may progress and become generalized.
1. Awareness of the risks for thoracic musculature involvement, which can lead to respiratory failure, and pharyngeal musculature involvement, which can result in aspiration, is important. Myocardial involvement can also occur.
2. Almost all cases are associated with elevated CPK, but the actual level of enzyme elevation may not correlate with degree of weakness. Very high CPK levels can indicate rhabdomyolysis and may lead to renal injury in the form of acute tubular necrosis.
3. Have a low threshold to obtain a muscle biopsy in a patient presenting with acute myositis because biopsy is often helpful in reaching a diagnosis. Electromyography (EMG) can be valuable in ambulatory care situations in which there is uncertainty as to whether there is an irritative myopathy and in differentiating myositis from other types of neuromuscular illness.
EMG has a limited role in assessing patients in an acute care setting who clearly have a myositis, as it can still assist in determining the underlying etiology.
ii. Extramuscular manifestations. Dermatomyositis usually (but not always) presents with both skin and muscle involvement, and the pattern of skin abnormalities can be so typical as to immediately suggest this diagnosis. Prototypic features include heliotrope rash, the shawl sign, and Gottron’s papules; other less stereotyped types of skin lesion also occur. Mechanic’s-hands–like changes suggest the antisynthetase syndrome. Cutaneous lesions may be subtle and need to be sought out.
iii. Underlying diseases. Autoimmune myositis is a paraneoplastic manifestation of an underlying malignant neoplasm in a significant proportion of cases, and it is necessary to carry out aggressive cancer screening in these patients as part of the initial assessment.
iv. Associated diseases. Some patients with autoimmune myositis also have an additional related autoimmune disease at the same time. The presence of extramuscular clinical features should therefore prompt a search for an additional disorder rather than a single unifying diagnosis. As an example, the combination of autoimmune myositis and systemic sclerosis is quite common.
v. Other autoimmune diseases causing myositis. Most other systemic autoimmune diseases can affect skeletal muscle in the same way as they affect other organ systems, and it is important to decide in a patient with myositis whether it is a case of an autoimmune myositis syndrome or whether muscle is one of multiple organ systems affected by a different autoimmune disease (e.g., SLE, sarcoid, vasculitis).
vi. Other causes of myositis. An integral element of the clinical assessment is differentiating autoimmune muscle disease from other types of myositis, especially infectious, medication-induced, and metabolic diseases. A directed history that focuses on the time course of onset and progression, a comprehensive physical examination that searches for extramuscular features of autoimmune myositis, laboratory testing, and biopsy will usually yield an accurate diagnosis.
f. Overlap or undifferentiated autoimmune disease versus mixed connective tissue disease (MCTD).
i. Some individuals exhibit elements of multiple autoimmune diseases at the same time, or sequentially, and their diagnosis is termed overlap autoimmune diseases (or sometimes, undifferentiated connective tissue diseases [UCTD]). The clinician’s priority should be to ascertain that disease in all affected target organs has been identified, and only secondarily to specify the individual autoimmune diseases that together account for all clinical features. Patients in the SLE/Sjögren’s/autoimmune myositis/systemic sclerosis/RA spectrum most commonly exhibit these overlaps, but virtually any systemic autoimmune disease can be included.
ii. The term MCTD is incorrectly used as synonymous with overlap autoimmune diseases. MCTD represents a special subset of this grouping, characterized by high levels of antibody to U1-RNP. Whether MCTD represents a distinct syndrome remains controversial; however, making the diagnosis is of value. Patients commonly have clinical features of a relatively mild form of systemic sclerosis (although with risk for complicating pulmonary hypertension), an associated inflammatory myopathy, and a generally good outcome.
g. Antiphospholipid syndrome. Antiphospholipid syndrome is included with the group of diseases that can be associated with a positive ANA test because autoimmune thrombophilia was first recognized in SLE patients. Yet, although many cases occur in patients with SLE, antiphospholipid syndrome is now recognized as an independent condition that can occur in isolation.
i. Clinical context. Of patients presenting with thrombotic disease, a small but significant proportion (4% in one series of patients with acute venous thrombosis) are caused by antiphospholipid syndrome.
1. Thrombosis. Patients characteristically present with overt thrombotic disease (venous in 80%).
2. Any ischemic lesion. It is important to consider the possibility of antiphospholipid syndrome or other primary thrombotic disease in any patient for whom vasculitis is under consideration as the cause of ischemic injury.
3. Pregnancy loss has become a well-recognized manifestation of antiphospholipid syndrome.
4. Other clinical manifestations. Antiphospholipid syndrome has been linked to a wide variety of abnormalities in many organ systems. However, many conditions are associated with phospholipid antibodies, and differentiating laboratory epiphenomena from actual disease manifestations is an active area of investigation.
5. Catastrophic antiphospholipid syndrome (CAPS). This is an unusual but very serious form of antiphospholipid syndrome, in which the primary pathology appears to be thrombosis in the microvasculature. Patients develop disease in multiple organ systems, as well as a microangiopathy with non-antibody-based intravascular hemolysis and thrombocytopenia.
iii. Laboratory testing is an integral element of the clinical assessment.
iv. Diagnosis. Antiphospholipid syndrome is diagnosed in patients who present with a thrombotic event or recurrent pregnancy loss and have phospholipid antibodies or a lupus-type anticoagulant, after taking into account other causes of thrombosis. The most recent consensus diagnostic criteria include a stipulation that patients must have persistent phospholipid antibodies (testing ≥12 weeks apart) because patients with many different types of intercurrent illnesses may also develop short-lived circulating phospholipid antibodies. However, in acutely ill individuals, this requirement needs to be set aside.
h. Adult-onset Still’s disease (AOSD)
i. Diagnosis. This is an especially difficult condition to diagnose, and the question of possible AOSD is raised frequently in an acute care hospital setting. Diagnosis is challenging because it is unusual for all the clinical features to be present. When present, features may be evanescent and/or equivocal, and they overlap with other conditions. The published diagnostic criteria suggest high sensitivity and high specificity. Yet, in actual clinical practice, the published specificity data appear overstated because many different diseases could satisfy formal diagnostic criteria for AOSD.
ii. Clinical features
1. Fever is often a prominent feature, and patients may first come to medical attention because they are being investigated for “fever of unknown origin” (see Chapter 51). They may have a single daily (quotidian) temperature spike, but other patterns can occur.
2. Arthritis. Joint pain, either arthralgia or clinically evident arthritis, occurs in most patients with AOSD. The arthritis in AOSD has no distinctive features, occurring in any temporal pattern (persistent or evanescent) and anatomic pattern (monoarthritis, oligoarthritis, or polyarthritis). The arthritis may become destructive over time, and wrist joint fusion is a notable feature, more commonly observed in pediatric Still’s disease.
3. Rash. The AOSD rash, classically described as evanescent patchy indistinct salmon-pink lesions occurring in any location, is nonspecific. There are no diagnostic skin biopsy features, and this is therefore not recommended if AOSD is being considered.
4. Other clinical features. Noninfectious pharyngitis, noninfectious hepatitis, lymphadenopathy and hepatosplenomegaly, serosal effusions, myalgia, and abnormalities in other organ systems can also occur.
iii. Laboratory features. Elevated liver transaminases and neutrophilia are common but lack specificity. While ferritin is an acute phase reactant and levels can increase in association with any inflammatory process, levels are often strikingly elevated in AOSD.
The higher the level of ferritin, the greater the positive predictive value for diagnosing AOSD.
In an appropriate context, that is, in a patient with features suspicious for AOSD, ferritin >1000 ng/mL is supportive and ferritin >3000 ng/mL is highly suggestive of the diagnosis. Hyperferritinemia is especially useful diagnostically because there are few other conditions associated with very high levels. One other disease spectrum associated with hyperferritinemia is macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), and this is particularly important to consider in the differential diagnosis.
AOSD not only shares clinical and laboratory features with MAS/HLH but also may be complicated by MAS/HLH.
iv. Accurate diagnosis of AOSD. This condition is usually considered in a patient with an undiagnosed fever, a nondescript arthritis and/or rash, and possibly additional clinical features. Suggestive clinical features and a strikingly elevated ferritin that is otherwise unexplained can quickly lead to diagnosis. However, many patients have ambiguous or uncertain clinical features and/or more modest elevations of ferritin. A critically important component of the diagnosis comes from excluding, to the extent possible, other conditions that could cause the same clinical and laboratory features (not only other autoimmune diseases but also infectious, neoplastic, and other disease processes). In some patients, a diagnostic treatment trial is warranted. Specifically, patients with AOSD may respond very rapidly to treatment with the interleukin-1 (IL-1) receptor antagonist anakinra, whereas patients with other systemic conditions do not respond at all.
i. Polymyalgia rheumatica (PMR). This is an unusual condition with distinctive clinical features centered on pain in the region of the shoulder and hip girdles without obvious disease in regional muscles or joints.
i. Clinical features. Patients are almost always older than 50 years, and prevalence increases with age. Pain develops over weeks to months in the shoulder and/or hip girdle regions (but can be quite acute) and is usually diffuse: patients do not describe pain in a way that gives the impression of a process limited to shoulder or hip joints. Pain sometimes includes arms and thighs and occasionally extends distally. Patients very commonly describe weakness rather than pain, partly because they are not aware of the distinction and partly because pain impedes movement. However, careful history taking and physical examination can distinguish pain from weakness; any evidence of intrinsic muscle disease should immediately raise other diagnostic considerations.
ii. Physical examination. There should be no physical examination abnormalities attributable to PMR. As discussed previously, patients are not weak when carefully evaluated (and creatine kinase levels are normal). Joint examination should be unremarkable (although many patients in the PMR-prone age group have some element of coincidental degenerative osteoarthritis).
iii. Laboratory tests. ESR and CRP are almost always moderately elevated; marked elevations (ESR >100 mm/hr) can also occur but should lead to consideration of the more serious associated condition of giant cell arteritis (described later). Other abnormalities, such as a mild anemia, can occur but have no diagnostic utility.
iv. Imaging. Recent imaging studies indicate that pain from PMR may be attributable to inflammation of periarticular bursal and other structures. In fact, identification of these abnormalities by ultrasound or magnetic resonance imaging (MRI) is part of the most recent diagnostic criteria. Nevertheless, most cases are diagnosed and managed without any imaging.
v. Diagnosis of PMR is based partly on the clinical (limb girdle pain) and laboratory (abnormal ESR/CRP) features described previously. An additional very important component of the diagnosis comes from observing the expected response to treatment. Almost all patients with PMR respond very quickly (often in 24 hours or less) and very completely (patients often describe being >80% better within that time period) to a relatively modest corticosteroid dose (15 mg prednisone per day or equivalent). No other condition with similar features responds in this way. It is essential to use only modest corticosteroid dosing in this therapeutic/diagnostic trial because responses to high dosages lack specificity; many conditions with overlapping clinical features will improve to some extent on very high dose prednisone.
vi. Related conditions
1. Giant cell arteritis (GCA). Approximately 10% of patients presenting with PMR will also receive a diagnosis of GCA at some stage; GCA is described in the section below on vasculitis. It is especially important not to miss or delay the diagnosis of GCA because of the potential serious adverse consequences of untreated disease.
2. Remitting seronegative symmetric synovitis with pitting edema (RS3PE). Patients present with acute-onset diffuse hand pain and have diffuse hand swelling, and imaging demonstrates florid tenosynovitis. This syndrome occurs in the same age group as PMR, is also associated with elevations in ESR and CRP, and responds just as quickly and completely to modest corticosteroid doses. Thus, it is now considered to be a related condition.
vii. Differential diagnosis. Some patients with PMR have evidence of arthritis and differentiating PMR from atypical RA can be difficult. Diffuse bone lesions from myeloma or other neoplastic disease causing pain also need to be considered in the differential diagnosis.
j. Sarcoidosis. Patients with sarcoidosis most often present to a pulmonologist with lung manifestations. African Americans and Northern Europeans are at increased risk. The most common rheumatologic presentation is Löfgren’s arthritis and dermatitis syndrome, described in Chapter 74. However, some cases present as noncaseating granulomatous disease in a body system, with the diagnosis made after biopsy of an affected tissue. Cases that include characteristic mediastinal and pulmonary involvement are readily diagnosed as sarcoidosis, but in some individuals the only specific diagnostic feature is the histopathologic evidence of multiorgan granulomatous disease. Distinguishing sarcoid from other granulomatous diseases is often difficult, but the designation does provide some guidance for approaching treatment.
k. Polychondritis. This rare disease is characterized by destructive inflammation of cartilaginous structures. Polychondritis usually presents with otherwise unexplained (i.e., noninfectious) inflammation of the cartilaginous outer ear, and the diagnosis is most often suggested because of simultaneous bilateral ear involvement. Nasal cartilage is also commonly affected. Biopsy is required to confirm that the inflammation involves cartilage and not just the overlying skin. It is considered a systemic autoimmune disease because other structures are also sometimes involved; some structures are cartilaginous (trachea, joints), but others are not (eyes, aorta, other vasculature). There are no diagnostically useful laboratory tests. Although collagen II antibody testing has pointed to this as a target of the immune response, it has no diagnostic utility.
l. Cogan’s syndrome. Like polychondritis, with which it sometimes shares overlapping features, Cogan’s syndrome is characterized by disease in specific tissues, in this case the cornea (although other parts of the eye can also be affected) and inner ear. It is considered to be a systemic autoimmune disease because it also sometimes causes aortitis and other types of vasculitis.
m. Hyper-IgG4 disease. This recently recognized autoimmune disease was initially identified as causing pancreatitis. Subsequently, it was shown to affect the biliary tree, to cause infiltrative disease of salivary glands (Mikulicz’s syndrome), and more recently as potentially affecting any organ system. As with many of the diseases described in this section, the most important element in making this diagnosis is considering it as a possibility, either because of characteristic clinical features (e.g., autoimmune pancreatitis or bulky parotitis) or because of a presentation with unknown disease in multiple organ systems. Elevated serum IgG4 levels can be helpful (but abnormally high levels also occur in other conditions, and normal levels are found in 25% of patients). The diagnosis is established by biopsy of an affected tissue that demonstrates characteristic histopathology (lymphoplasmacytic inflammation, storiform pattern fibrosis, and obliterative phlebitis), associated with large numbers of IgG4-expressing plasma cells.
n. Behçet’s syndrome. This is an unusual condition characterized by severe mucosal ulceration as well as other (mostly vasculitic) manifestations.
i. Clinical features. Patients virtually always have a history of recurrent oral, and often genital, mucosal ulceration. These lesions are unusually severe and painful, may scar, and are readily differentiated from benign aphthae and other conditions causing less severe mucosal ulceration. Patients may develop any of a very broad variety of other clinical manifestations, often reflecting vasculitis that can affect both the venous and arterial circulations (including the pulmonary circulation). Skin, eyes, and central nervous system are commonly affected, but any organ system can be involved. Thrombosis may occur (often affecting large veins) and is attributable to venous vasculitis.
ii. Epidemiology. Populations vary markedly in prevalence of Behçet’s. Prevalence is high in the ancient silk-road East Asia to Mediterranean regions, is lower in North Americans of Northern European origin, and is distinctly low in African Americans.
iii. Laboratory and other testing. No laboratory tests have any specific role in diagnosis of Behçet’s. As a research tool, HLA-B51 allotyping provides an indicator of genetic risk for developing Behçet’s, but this finding does not have sufficient positive or negative predictive value to be of clinical utility and should not be ordered for diagnostic purposes. Tissue histopathology also lacks distinctive features. Pathergy testing can be useful; a positive result occurs when a papular inflammatory reaction is induced by introducing a needle into the skin under strictly controlled conditions. This test is usually performed only in specialty centers and is probably less often positive in North American Behçet’s patients than in other populations.
iv. Diagnosis. There are multiple published sets of diagnostic criteria. All heavily weigh mucosal ulceration and have lesser requirements for other manifestations. In practice, when alternative diagnoses to explain severe recurrent mucosal ulceration and other clinical manifestations have been excluded, diagnosis of Behçet’s is usually not difficult.
o. Cryoglobulinemia. Cryoglobulins are immunoglobulins that have the physicochemical characteristic of precipitating out of solution in the cold. Paradoxically, these immunoglobulins primarily cause disease in (warm) internal organs because of their activity as immune complexes that activate inflammatory mechanisms.
i. Clinical features. From the perspective of systemic autoimmune disease, patients with cryoglobulinemia present with vasculitis syndromes (although cryoglobulinemia can also independently affect the kidneys), and the main challenge in the diagnosis of cryoglobulinemic vasculitis is considering this as a possibility in a patient with clinical features consistent with vasculitis.
ii. Laboratory tests. Cryoglobulins are directly assayed in serum derived from clotted blood.
Always keep blood samples warm during the process of collection and evaluation for cryoglobulinemia. Failure to do so may lead to cryoglobulin precipitation and removal during specimen processing, producing false-negative results.
Additional assays can sometimes provide clues to detection of a cryoglobulin. Many cryoglobulins have rheumatoid factor activity, and RF testing can be positive, often at very high levels. The immune complex activity of cryoglobulins can result in complement consumption; C4 levels, in particular, can be especially low. Many cryoglobulins are monoclonal immunoglobulins, in whole or in part, and can be identified by serum electrophoresis.
iii. Underlying conditions. Cryoglobulins can develop (1) secondary to multiple myeloma with associated generation of large quantities of monoclonal immunoglobulins that sometimes have cryoglobulin activity; (2) in association with hepatitis C infection and less commonly other viral infections; and (3) in association with systemic autoimmune diseases, such as SLE and RA.
p. Immune complex disease. Multiple systemic autoimmune diseases, such as SLE and cryoglobulinemia, can cause tissue pathology through generation of antigen-antibody immune complexes that, in turn, activate proinflammatory pathways and result in vasculitis and other clinical syndromes. However, quite often immune complex disease is triggered by an exogenous antigen, such as an infectious agent or medication. The inciting antigen and the antibody elicited to this antigen generate an antigen-antibody immune complex with proinflammatory activity. These “hypersensitivity” reactions tend to cause small-vessel vasculitis but may also present as other types of clinical syndromes. These different types of underlying conditions must be considered when assessing a patient with clinical and laboratory features that are potentially explained by immune complex–based disease.
q. Vasculitis refers to the clinical syndromes resulting from inflammatory reactions that damage blood vessels. As with other types of systemic autoimmune disease, sometimes vasculitis is suspected because of very specific clinical features, but often this diagnosis is considered simply because multiple organ systems are concurrently affected. Vasculitis causes disease through different pathogenic mechanisms. Thickening of the arterial wall because of an inflammatory infiltrate and associated fibrosis causes disease by occluding flow, leading to downstream tissue ischemia. Vessel wall necrosis causes vascular rupture and hemorrhage. Some forms of vasculitis are associated with generation of an inflammatory mass that extends into tissue parenchyma from the affected blood vessels. Many cases of vasculitis are also associated with generalized systemic symptoms that are quite separate from any local vascular pathology.
i. Vasculitis syndromes. There are many discrete vasculitic syndromes. The most useful classification schemes are based on an empiric consideration of the size of affected blood vessels: large, medium, or small. Large arteries include the aorta and its branches, down to the levels that penetrate internal organs to supply them with blood. Arteries with an internal lumen >0.3 mm are considered as medium-sized muscular arteries, and <0.3 mm as small arteries/arterioles. Vasculitis also affects the microcirculation (arterioles, capillaries and postcapillary venules). Most vasculitides affect the arterial and microcirculation, but some syndromes—such as Behçet’s—can affect the venous circulation. There is considerable overlap in the sizes of blood vessels affected by individual vasculitis syndromes, but this size-based classification is still extremely useful. Inferring the size of the blood vessels affected often occurs directly from the presenting clinical features but may also be assisted by laboratory testing and imaging, with confirmation by tissue histopathology. Obtaining tissue confirmation of a vasculitis diagnosis whenever possible is important because many diseases can mimic the clinical and other features of vasculitides. Patients who have been given a tentative clinically based vasculitis diagnosis at presentation can quickly deteriorate when they fail to respond to initial treatment and develop unexpected complications; therefore, a histopathologic diagnosis can be invaluable in this setting.
ii. Large-artery vasculitis.
1. The most prevalent large-artery vasculitis is GCA, also known as temporal arteritis. Patients are usually older than 60 years.
GCA does not occur before 50 years of age.
a. Clinical manifestations. Focal presenting symptoms are attributable to arterial occlusion with ischemia in the extracranial circulation. Patients may have headache from ischemia in the distribution of the superficial temporal and sometimes other cranial arteries and may also have claudicant or fixed pain from facial muscle and intraoral ischemia. Involvement of the ocular and optic nerve circulation is especially concerning because of the risk for sudden and permanent visual loss. Thus, any visual symptoms usually mandate emergent empiric treatment with systemic steroids. Intracranial involvement causing stroke syndromes can also occur. Patients with occlusive or occasionally aneurysmal involvement of thoracic, upper limb, or abdominal arteries may have related symptoms. In contrast, some patients lack any specific features and present with nonspecific fever or even a wasting illness. Physical examination is often unremarkable, but occasional patients will have specific tenderness or an erythematous reaction over the temporal arteries. Patients with thoracic arterial involvement may have arterial bruits and reduction in limb arterial pressures.b.Laboratory testing can be informative: almost all patients have elevation in ESR and CRP levels, and these are often at very high levels (e.g., ESR >100 mm/hr). Arterial imaging (by computed tomography [CT] or magnetic resonance [MR] angiography) may demonstrate occlusive and aneurysmal disease in large proximal arteries if they are affected. However, imaging studies are not commonly performed in patients with typical temporal arteritis. Diagnosis is made from biopsy of a superficial temporal artery. A confirmed tissue diagnosis is important, in particular, because countless causes of headache, other than GCA, may also respond, at least temporarily, to treatment with corticosteroids. Biopsy of a substantial length (≥1 inch) of a single temporal artery is considered sensitive and specific, but occasionally biopsy of the contralateral artery is needed, and some centers routinely perform bilateral biopsies. The expected histopathology is a panvascular chronic inflammatory infiltrate that often includes giant cells.
c. Treatment. Patients with visual symptoms are at risk for sudden complete and permanent visual loss and emergent treatment with high-dose corticosteroids (≥1 mg/kg prednisone) is required. Patients are also treated with aspirin as initial treatment because GCA can be associated with acute thrombosis in affected arteries. There is no justification for withholding this treatment while awaiting temporal artery biopsy results (and treatment delays can result in irreversible injury). The histopathologic changes take weeks or months to resolve. Response to treatment is an important part of the diagnostic assessment. Weeks or months of debilitating symptoms from GCA typically resolve very rapidly (often within a day) and very completely (>80% improvement); this response is very distinctive.
2. Takayasu’s arteritis, while histopathologically indistinguishable from GCA, has very different clinical features.
a. Clinical manifestations. Most cases of Takayasu’s arteritis occur in the pediatric population, some occur in young adults, and it is not diagnosed beyond age 30 years. Patients present with symptoms and signs from occlusive disease affecting the thoracic aorta and its proximal branches, with some cases affecting more distal arteries. Takayasu’s arteritis is one of the vasculitides that can also affect the pulmonary circulation. Patients may also have systemic features such as unexplained fever, and ESR and CRP are typically very high.
b. Diagnosis is usually made from the imaging characteristics of affected arteries, usually by CT or MR angiography, and tissue diagnosis is rarely available (only if patients require arterial exo-grafting).
3. Other types of vasculitis can also affect large arteries. Idiopathic aortic vasculitis is a frequent diagnosis in patients who come to surgery for thoracic aortic aneurysms and have tissue histopathology demonstrating vasculitis. Vasculitis can also rarely affect the abdominal aorta, and those cases need to be distinguished from patients with retroperitoneal fibrosis with periaortic involvement. Other systemic autoimmune diseases such as hyper IgG4-disease, SLE, Behçet’s, Cogan’s, and polychondritis can rarely also cause aortic vasculitis (all discussed previously). Multiple inherited diseases of the aorta can mimic the clinical and imaging characteristics of vasculitis.
1. Polyarteritis nodosa (PAN) is the prototypic medium-vessel vasculitis. Patients present with both nonspecific systemic features, such as fever and wasting, and very specific symptoms from arterial disease. Occlusive arterial disease causes downstream ischemia and can affect virtually any circulation; involvement of the skin, peripheral nervous system, and kidneys is common. Necrotizing inflammation with perforation can present with an acute hemorrhagic syndrome, and involvement of the abdominal circulation with hemorrhagic shock and an acute abdomen is a familiar presentation of PAN. The specific symptoms and physical examination signs depend on which regions/organ systems are involved. Laboratory testing is not useful. Diagnosis of PAN can sometimes come from demonstrating typical microaneurysmal arterial lesions (nodosities) and other abnormalities on angiography, especially in the abdominal circulation. Although CT and MR angiography are often performed, they are generally uninformative because arteries of the caliber affected by PAN cannot be adequately visualized. While PAN can be diagnosed from the clinical features and typical angiographic findings, angiography can be negative or misleading because other diseases can result in identical angiographic findings. A tissue-based diagnosis, with demonstration of a focal or diffuse panvascular neutrophil-rich infiltrate and associated vascular necrosis, should be sought whenever possible. Biopsy should be directed at affected organ systems; blind biopsy is discouraged.
iv. Medium-small artery vasculitis, ANCA associated. This group comprises syndromes that affects medium to small arteries that are associated with antibodies to neutrophil cytoplasmic antigens.
1. Granulomatous polyangiitis (GPA, previously known as Wegener’s granulomatosis) often presents with characteristic involvement of the upper airways. Patients frequently have a long history of facial sinus symptoms attributed to sinusitis, lower airways disease with many different types of pulmonary infiltrative lesions, and kidney disease with glomerulonephritis. However, some or all of these features may be absent, and essentially any other region or organ system may be affected. Patients have vasculitic involvement that is usually occlusive causing ischemia, sometimes necrotizing causing hemorrhage, and sometimes infiltrative causing a mass to develop. GPA is one of the few autoimmune diseases that can generate an inflammatory mass that spreads from a vasculitic focus. This mechanism underlies the infiltrative lung lesions that are often found in GPA. Laboratory testing should include both immunofluorescence-based testing for ANCA (usually identifying a cANCA diffuse cytoplasmic staining pattern in GPA) and specific testing for antibody to PR-3, which is the target of antibodies that cause the cANCA pattern. Most GPA patients are both cANCA and PR-3 antibody positive, but seronegative cases can occur. False-positive serology also occurs, and diagnosis should be based, whenever possible, on biopsy of an affected tissue. Characteristic histopathology consists of a granulomatous necrotizing vasculitis without associated immune-deposits (i.e., pauciimmune).
2. Microscopic polyangiitis (MPA) can be very difficult to distinguish from GPA and is generally considered a variant condition. Clinically, patients are less likely to have facial sinus and upper airways disease, more likely to have the p- or perinuclear pattern on ANCA testing (i.e., positive pANCA), with antibodies directed against MPO. Most important, affected patients will have histopathology demonstrating necrotizing vasculitis without the granulomatous inflammation that characterizes GPA.
3. Eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss syndrome). This condition is also considered related to GPA but with distinctive features. Almost all patients have a background of very significant atopic disease including asthma. The lung is frequently targeted by the vasculitis, as is the skin and peripheral nervous system. The heart is less commonly affected, but when present cardiac disease causes considerable morbidity and mortality. The kidneys are less commonly affected by EGPA than in GPA. As with other vasculitides, virtually any organ system can be affected. pANCA and MPO antibody testing can be positive, but only in half of cases, and the remainder are seronegative. Patients usually have a substantial peripheral blood eosinophilia, and this is matched by characteristic lesions that consist of an eosinophil-rich necrotizing vasculitis with well-developed granulomas that contain giant cells.
v. Medium-small artery vasculitis, non-ANCA-associated. Cryoglobulinemia is discussed previously and manifests with necrotizing vasculitis associated with immune deposits (immunoglobulins and complement components) that can affect any organ system but commonly targets skin, kidney, and peripheral nerve. Other conditions causing this type of vasculitis include systemic autoimmune diseases such as SLE, Sjögren’s syndrome, and RA. Behçet’s syndrome is discussed previously. This unusual condition can cause vasculitis among other clinical manifestations, and although most cases affect small to medium-sized arteries and the microvasculature, any sized vessel can be affected, including the venous circulation; venous vasculitis is thought to be the cause of Behçet’s-associated venous thrombosis. Thromboangiitis obliterans (also known as Buerger’s disease) is a clinically distinctive condition that targets the arteries supplying the hands and feet, causing ischemia that is usually restricted to the distal limbs/digits. Most patients are male, and the pathogenesis is thought to relate to a hypersensitivity reaction to smoked tobacco; almost all patients are very heavy smokers.
vi. Vasculitis affecting the microcirculation (arterioles, capillaries, postcapillary venules). This type of vasculitis usually causes disease that manifests with hemorrhage caused by vascular necrosis. This is readily apparent in the skin as purpura, and with bleeding into other organs such as the kidneys and intestines, but also affects other organ systems. Larger arteries may also be affected, and occlusion of these blood vessels can also result in tissue ischemia. This type of vasculitis is often idiopathic. Some cases can be linked to a hypersensitivity reaction to viral and other infections, hypersensitivity to medications and other exogenous antigens, an underlying systemic autoimmune disease (usually in the SLE/Sjögren’s spectrum), or a paraneoplastic syndrome related to an underlying malignancy. Henoch-Schönlein purpura is a special type of microcirculatory vasculitis and is characterized by vascular IgA deposition in lesions.
vii. Single-organ vasculitis. Sometimes vasculitis that is histopathologically indistinguishable from vasculitis affecting multiple organ systems is restricted to a single organ. The most frequent syndrome is isolated central nervous system vasculitis, but occasionally single-organ vasculitis occurs in other organs, including skin, gallbladder, and urogenital tract.
r. Autoinflammatory diseases. These are not autoimmune diseases, but are mentioned here because they can generate similar clinical features. They have the common feature of being caused by mutations in genes controlling inflammatory pathways that result in overactivation and consequent tissue injury. These almost always manifest in the pediatric population, but occasional cases are diagnosed in adulthood. These diseases often manifest with otherwise unexplained periodic fevers. The first of these diseases to be recognized and attributed to a monogenic mutation was familial Mediterranean fever, caused by mutation in the gene encoding pyrin. Other conditions with distinctive multiorgan manifestations have been identified in association with mutations in other genes.
Suggested Further Readings
Felson DT, Klareskog L. The genetics of rheumatoid arthritis: new insights and implications. JAMA 2015;313:1623–4.Find this resource:
Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015;385:1460–71.Find this resource:
Solow E, Scielzo SA, Kazi S. Update in rheumatology: evidence published in 2016. Ann Intern Med 2017;166:W44–W7.Find this resource:
Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017;376:1921–32.Find this resource:
Wigley FM, Flavahan NA. Raynaud’s phenomenon. N Engl J Med 2016;375:556–65.Find this resource: