Autoimmune Diseases
M. Rabie Al-Turkmani
INTRODUCTIONThis chapter provides the latest information on the diagnosis of systemic autoimmune diseases. Each entry is organized with a brief definition of the disease, information regarding clinical presentation, and laboratory findings. The chapter also provides a list of common organ-specific autoimmune diseases, with an indication to where these diseases are discussed elsewhere in this book.
Autoimmune disease is the pathologic result of autoimmunity, whereby the immune system attacks the person’s healthy body tissues. Autoimmunity is caused by the inappropriate activation of T cells or B cells, or both, in the absence of a definite cause. B lymphocytes can produce autoantibodies, which may interfere with a cellular function (e.g., Graves disease, myasthenia gravis) or cause tissue damage, either directly or by forming immune complexes that are deposited in tissues or blood vessels. T lymphocytes may aggregate in tissues (or a tissue) with resultant destruction.
There are more than 80 different autoimmune disorders, and more than one autoimmune disorder can be manifested by one patient. These disorders can be classified as systemic, affecting multiple organs or tissues (e.g., connective tissue autoimmune diseases such as systemic lupus erythematosus [SLE], Sjögren syndrome [SjS], or scleroderma), or organ specific, targeting one particular organ.
Multiple factors contribute to the development of autoimmune diseases:
ORGAN-SPECIFIC AUTOIMMUNE DISEASESOrgan-specific autoimmune diseases involve a particular organ or tissue of the body in which the target autoantigen is found. Examples of these autoimmune diseases and their target organs:
Adrenal glands (e.g., autoimmune adrenal insufficiency). See Chapter 8, Endocrine Diseases
Bile ducts (e.g., primary biliary cirrhosis). See Chapter 7, Digestive Diseases
Blood cells: RBC (e.g., autoimmune hemolytic anemia), WBC (e.g., autoimmune neutropenia), platelets (e.g., immune thrombocytopenic purpura). See Chapter 11, Hematologic Disorders
Blood vessels (e.g., autoimmune vasculitis). Discussed in this chapter and in Chapter 5, Cardiovascular Disorders
Gastrointestinal tract (e.g., celiac disease, Crohn disease, ulcerative colitis). See Chapter 7, Digestive Diseases
Kidney (e.g., anti-glomerular basement membrane antibody disease). See Chapter 14, Renal Disorders
Liver (e.g., autoimmune hepatitis). See Chapter 7, Digestive Diseases
Nervous system (e.g., myasthenia gravis [a disorder of the neuromuscular junction], multiple sclerosis, Guillain-Barré Syndrome, autoimmune autonomic failure). See Chapter 6, Central Nervous System Disorders
Pancreas: type 1 diabetes mellitus (see Chapter 8, Endocrine Diseases), autoimmune pancreatitis (see Chapter 7, Digestive Diseases)
Thyroid gland (e.g., Hashimoto thyroiditis, Graves disease). See Chapter 8, Endocrine Diseases
SYSTEMIC AUTOIMMUNE DISEASESFELTY SYNDROME
□ Definition
Felty syndrome is characterized by the triad of long-standing, aggressive rheumatoid arthritis (RA), neutropenia, and splenomegaly.
It develops in a minority of patients with RA (<1%).
□ Who Should Be Suspected?
Patients typically present with general malaise, fatigue, loss of appetite, and unintentional weight loss. Some patients have recurrent infections, such as respiratory or skin infections, attributed to the neutropenia.
The syndrome is more common in women >30 years of age and in patients with a family history of RA.
□ Laboratory Findings
Neutropenia (<2,000 granulocytes/µL) is required for diagnosis. WBC count is usually <2,500/µL.
Elevated levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies (high titers).
Antinuclear antibodies (ANAs), antihistone antibodies, and antineutrophil cytoplasmic antibodies (ANCAs) are found in more than two thirds of patients.
Anti-glucose-6-phosphate isomerase antibody titer is elevated in the majority of patients.
Anemia and thrombocytopenia may develop or be aggravated by splenomegaly (hypersplenism).
Circulating immune complexes and immunoglobulin levels are higher than those found in RA.
Peripheral blood smear review and bone marrow aspirate or biopsy may be indicated to exclude other causes of neutropenia.
IgG4-RELATED DISEASE
□ Definition
IgG4-related disease is a multiorgan immune-mediated condition composed of multiple disorders that share particular pathologic, serologic, and clinical features.
Common features of IgG4-related disorders include tumor-like swelling of involved organs, lymphoplasmacytic infiltration enriched in IgG4-positive plasma cells, and variable degree of storiform fibrosis.
□ Who Should Be Suspected?
IgG4-related disease has a slight predominance in middle-aged and older men.
Patients often present with development of a mass in the affected organ or enlargement of an organ. Multiple organs are affected in 60-90% of patients.
Major presentations include type 1 (IgG-4 related) autoimmune pancreatitis, salivary gland disease, orbital disease, or retroperitoneal fibrosis.
□ Laboratory Findings
Tissue biopsy is the gold standard for diagnosis.
Elevated serum concentration of IgG4 is found in 60-70% of patients, and it aids the diagnosis, although it is not diagnostic. The concentration tends to correlate with the number of organs involved and usually decreases after initiation of therapy.
Serum C3 and C4 concentrations are typically low.
Suggested Reading
Kamisawa T, Zen Y, Pillai S, et al. IgG4-related disease. Lancet. 2015;385:1460-1471.
MIXED CONNECTIVE TISSUE DISEASE
□ Definition
Mixed connective tissue disease (MCTD) represents an overlap syndrome with features of SLE, systemic sclerosis (SSc), and polymyositis (PM).
The disease can be serious with development of kidney, cardiovascular, gastrointestinal, and central nervous system manifestations. Pulmonary disease is associated with the highest mortality.
□ Who Should Be Suspected?
Presenting symptoms are often nonspecific, such as fatigue, myalgia, arthralgia, and low-grade fever. In the early stages of disease, 90% of MCTD patients have Raynaud phenomenon, arthralgia, swollen hands, fingers with “sausage-like” appearance, and muscle weakness. Other common symptoms that may develop gradually include swollen joints, esophageal dysfunction, sclerodactyly, and calcinosis.
MCTD usually develops in the second or third decade of life and is more common in women than men.
□ Laboratory Findings
Positive ANA, with a high-titer speckled pattern (>1:1,000 and often >1:10,000) using the indirect fluorescent antibody test (IFA).
Presence of high titers of anti-U1 ribonucleoprotein (anti-RNP) antibodies, especially antibodies to the 68 kDa protein, is highly suggestive of an MCTD diagnosis and separates it as an independent disease.
Anti-SSA/Ro, anti-single-stranded DNA (ssDNA), anti-Smith (Sm), and anti-double-stranded DNA (dsDNA) antibodies have also been detected, but they are not specific for MCTD.
Antiphospholipid antibodies have been reported in patients with MCTD, with a lower frequency than that found in SLE.
Positive RF and anti-CCP antibodies in approximately 50% of the patients.
Anemia, leukopenia, and hypergammaglobulinemia may be present.
Suggested Reading
Gunnarsson R, Hetlevik SO, et al. Mixed connective tissue disease. Best Pract Res Clin Rheumatol. 2016;30:95-111.
POLYMYALGIA RHEUMATICA
□ Definition
Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder characterized by morning stiffness and pain in the muscles of the shoulders, neck, back, hip, and thighs.
The 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for PMR use a scoring algorithm that applies to patients >50 years of age, presenting with new bilateral shoulder pain (not better explained by an alternative diagnosis) and elevated CRP/ESR. The elements of this algorithm include the following:
▼ Morning stiffness for more than 45 minutes (2 points)
▼ Hip pain/limited range of motion (1 point)
▼ Absence of RF and/or anti-citrullinated protein antibody (2 points)
▼ Absence of peripheral joint pain (1 point)
A score of 4 or more has 68% sensitivity and 78% specificity for distinguishing PMR patients. Ultrasound findings of bilateral shoulder abnormalities or abnormalities in one shoulder and hip were found to significantly improve both sensitivity and specificity of the clinical criteria.
□ Who Should Be Suspected?
The disease is almost exclusively found in individuals >50 years of age. Patients typically present with general malaise, fatigue, as well as aches and morning stiffness in the shoulder, hip girdles, neck, lower back, and knees. Loss of appetite, unintentional weight loss, and depression are also common findings.
□ Laboratory Findings
Laboratory findings are nonspecific.
Suggested Reading
Dasgupta B, Cimmino MA, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2012;71:484-492.
POLYMYOSITIS, DERMATOMYOSITIS, AND INCLUSION BODY MYOSITIS
□ Definition
Polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM) are related inflammatory myopathies that share common features, including muscle weakness and inflammatory infiltrates on a muscle biopsy.
PM and DM are characterized by a subacute onset of symmetric proximal muscle weakness, common involvement of other organ systems such as lung and skin, a strong association with autoantibodies, and responsiveness to immunosuppression. Both are widely accepted as having
an autoimmune basis. Cutaneous involvement is the primary clinical feature distinguishing patients with DM from those with PM.
In contrast with PM and DM, patients with IBM typically have slowly progressive weakness in both proximal and distal muscles, rarely have other extramuscular involvement or autoantibodies, and most often do not respond to immunosuppressive therapies. A muscle biopsy showing the presence of typical inclusion bodies is diagnostic for IBM.
□ Who Should Be Suspected?
Patients with PM and DM typically present with progressive proximal muscle weakness and evidence of muscle inflammation. They may also have constitutional symptoms and evidence of involvement of other organs (e.g., interstitial pulmonary disease, polyarthritis). DM patients can be differentiated by having specific cutaneous signs such as Gottron papules or heliotrope eruption.
Patients with IBM generally have a more insidious onset compared to PM and DM, and more prominent distal muscle weakness.
PM and DM can occur at any age, with peak incidence between the ages of 40 and 50, whereas IBM mainly affects individuals >50 years of age.
□ Laboratory Findings
Diagnosis of the three conditions is based on clinical manifestations, serum muscle enzymes, autoantibodies, EMG findings, and muscle biopsy. The latter is the definitive test for establishing the diagnosis of IBM and in PM or DM patients presenting with atypical clinical or laboratory findings.
Muscle enzymes:
▼ Levels of the muscle enzyme creatine kinase (CK) are greatly elevated in PM and DM patients (typically >10 folds the upper limit of normal but may be >50 folds) and to a lesser extent in patients with IBM.
ANA test is positive in up to 80% of patients with DM or PM.
Myositis-specific antibodies are positive in 30% of patients with PM or DM. The most common antibodies are those against histidyl-tRNA synthetase (anti-Jo-1), and titers of these antibodies have been found to correlate with disease activity. Other myositis-specific antibodies include anti-Mi-2 and anti-signal recognition particle (anti-SRP) antibodies. Presence of other connective disease conditions associated with myositis is suggested when another type of autoantibodies is positive (e.g., anti-SSA/Ro, anti-SSB/La, anti-Sm, or anti-RNP).
ESR is normal or mildly increased, and myoglobin is elevated in the serum and urine.
Suggested Reading
Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;373:393-394.
PSORIATIC ARTHRITIS
□ Definition
Psoriatic arthritis (PsA) is a type of arthritic inflammation that occurs in approximately 30% of patients with psoriasis. It can affect any joint in the body causing pain, swelling, and stiffness. CD8+ T cells and T-cell-derived cytokines play a central role in the pathogenesis of PsA.
The Classification Criteria for Psoriatic Arthritis (CASPAR) require the presence of joint, spine, or entheseal inflammatory disease plus a minimum score of 3 points from the following five categories (98.7% specificity and 91.4% sensitivity):
▼ Current psoriasis (2 points); personal or family history of psoriasis (1 point)
▼ Typical psoriatic nail dystrophy (1 point)
▼ Negative rheumatoid factor (1 point)
▼ Current dactylitis or history of dactylitis (1 point)
▼ Hand or foot plain radiography demonstrating juxta-articular new bone formation (1 point)
□ Who Should Be Suspected?
Most patients who develop PsA have skin symptoms of psoriasis first (erythematous papules and plaques with a silver scale), followed later by arthritis symptoms characterized by pain, tenderness, and stiffness in the joints and back.
Several HLA types have been identified to be associated with PsA, suggesting a genetic predisposition. This is also indicated by the presence of a family history of psoriasis and PsA in up to 40% of patients.
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