Genetic susceptibility, mostly due to linkage to particular HLA molecules
Environmental triggers (e.g., drugs, chemicals)
Infectious agents (e.g., Mycoplasma pneumoniae, HIV)
Loss of regulatory T cells
Defects in cytokine production
ORGAN-SPECIFIC AUTOIMMUNE DISEASES
Organ-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 6, Endocrine Diseases
Bile ducts (e.g., primary biliary cirrhosis). See Chapter 5, Digestive Diseases
Blood cells: RBC (e.g., autoimmune hemolytic anemia), WBC (e.g., autoimmune neutropenia), platelets (e.g., immune thrombocytopenic purpura). See Chapter 9, Hematologic Disorders
Blood vessels (e.g., autoimmune vasculitis). Discussed in this Chapter and in Chapter 3, Cardiovascular Disorders
Gastrointestinal tract (e.g., celiac disease, Crohn disease, ulcerative colitis). See Chapter 5, Digestive Diseases
Kidney (e.g., anti–glomerular basement membrane antibody disease). See Chapter 12, Renal Disorders
Liver (e.g., autoimmune hepatitis). See Chapter 5, Digestive Diseases
Nervous system (e.g., myasthenia gravis [a disorder of the neuromuscular junction], multiple sclerosis, Guillain-Barré Syndrome, autoimmune autonomic failure). See Chapter 4, Central Nervous System Disorders
Thyroid gland (e.g., Hashimoto thyroiditis, Graves disease). See Chapter 6, Endocrine Diseases
SYSTEMIC AUTOIMMUNE DISEASES
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.
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).
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are very elevated.
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.
MIXED CONNECTIVE TISSUE DISEASE
Mixed connective tissue disease (MCTD) represents an overlap syndrome with features of systemic lupus erythematosus (SLE), systemic sclerosis, and polymyositis.
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.
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. Anticardiolipin antibodies (ACAs) are present in approximately 15% of MCTD patients.
Elevated ESR and CRP.
Positive RF and anti-CCP antibodies in approximately 50% of the patients.
Anemia, leukopenia, and hypergammaglobulinemia may present.
Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol. 2012;26(1):61–72.
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 rheumatoid factor 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.
PMR develops in nearly 50% of patients with giant cell arteritis (GCA), and 15–30% of patients with PMR eventually develop GCA.
Laboratory finding are nonspecific.
ESR is markedly elevated (>40 mm/hour, but values >100 may be seen). However, some patients with mild disease may have only slight elevations of ESR.
CRP is elevated and considered a more sensitive marker than ESR.
Serologic tests such as RF, ANA, and anti-CCP antibodies are typically negative.
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(4):484–492.
POLYMYOSITIS, DERMATOMYOSITIS, AND INCLUSION BODY MYOSITIS
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 to PM and DM, patients with IBM typically have slowly progressive weakness in both proximal and distal muscles, rarely have other extra-muscular 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.
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.
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.
Other muscle enzymes including lactate dehydrogenase (LDH), aldolase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are also elevated. Similar to CK, elevations are less profound in IBM than in PM or DM.
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.
Myoglobin is elevated in the serum and urine.
Mammen AL. Dermatomyositis and polymyositis: clinical presentation, autoantibodies, and pathogenesis. Ann N Y Acad Sci. 2010;1184:134–153.
Psoriatic arthritis (PsA) is a type of arthritic inflammation that occurs in approximately 15% 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 papule 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 psoriatic arthritis in up to 40% of patients.
Laboratory finding are not specific.
ESR and CRP are elevated in approximately 50% of cases; levels correlate with the number of involved joints.
RF is negative.
Anemia of inflammation, hypergammaglobulinemia with increased IgA levels, and hypoalbuminemia have been reported in some cases.
Hyperuricemia, related to either increased skin cell turnover or metabolic defect, is found in nearly 20% of patients.
HLA testing can be helpful: HLA Cw6 is the most important allele for susceptibility to early-onset psoriasis; HLA-B17 may be associated with a more severe phenotype.
Cantini F, Niccoli L, Nannini C, et al. Psoriatic arthritis: a systematic review. Int J Rheum Dis. 2010;13(4):300–317.
Reactive arthritis, formerly known as Reiter syndrome, is an autoimmune spondylarthritis that develops 1–4 weeks after an infection with a pathogen elsewhere in the body. Most often, causing pathogens are urogenital (e.g., Chlamydia) or enteric (e.g., Campylobacter, Salmonella, Shigella, or Yersinia).
Who Should Be Suspected?
A likely patient is a young adult (20– 40 years of age) who develops postinfectious asymmetric oligoarthritis (affecting most often the knees, ankles, and heels), enthesitis, dactylitis, and lower back pain. In addition, patients may have extra-articular signs including urinary (urethritis, balanitis, dysuria, prostatitis in men, cervicitis, salpingitis or vulvovaginitis in women), ocular (conjunctivitis or anterior uveitis), and/or constitutional (malaise, fever, weight loss) symptoms.
Diagnosis is primarily clinical.
Culture and serology tests are helpful in identifying the infectious etiology of the disease in only a fraction of cases since pathogens may no longer be retrievable by the time arthritis develops. Nevertheless, a trial to identify the following pathogens by stool or urine cultures, or in some cases by serology, should be attempted:
Chlamydia, especially Chlamydia trachomatis and Chlamydia pneumoniae. PCR for urinary Chlamydia DNA has high sensitivity.
Yersinia enterocolitica and Yersinia pseudotuberculosis.
Salmonella of various serovars.
Shigella, especially Shigella flexneri and Shigella dysenteriae.
Campylobacter, especially Campylobacter jejuni.
Possibly other organisms (e.g., HIV, Escherichia coli, Mycoplasma genitalium).