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🌱 來自: Huppert’s Notes
ANA-Associated Connective Tissue Disorders🚧 施工中
ANA-Associated Connective Tissue Disorders
• Rheumatologic conditions associated with a +ANA:
1. Systemic lupus erythematosus (SLE)
2. Systemic sclerosis (SSc)
3. Myositis (often ANA-negative; ~50% of dermatomyositis/polymyositis cases are ANA-positive)
4. Mixed connective tissue disease (MCTD)
5. Primary Sjögren’s
• ANA Testing Pearls:
- Antinuclear antibodies (ANA) are autoantibodies that bind to the contents of the cell nucleus. The ANA test detects the ANA autoantibodies that are present in the patient’s serum.
- ANA can be elevated in many disorders including autoimmune conditions, infection, and malignancy. 20% of healthy women have a positive ANA. Therefore, it is non-specific and should only be sent if clinical suspicion is high for one of the disorders above.
- The level of autoantibody is reported as a titer, which is the highest dilution of the serum at which the autoantibodies are still detectable (e.g., 1:640 is more dilute than 1:80, suggesting more autoantibodies are present in the 1:640 sample). The probability of autoimmunity increases with higher ANA titers:
• ANA ≥1:80 required by EULAR/ACR SLE classification criteria
• ANA ≥1:640 → 95.8% specific for SLE
- If an ELISA-based ANA test is negative but clinical suspicion for CTD high, ask the lab to carry out an immunofluorescence (IF)-microscopy-based ANA test, which is more specific.
TABLE 9.3 • Test Characteristics & Clinical Associations for ANA & Sub-Serologies
Systemic lupus erythematosus (SLE)
• Pathogenesis:
- Decreased clearance and increased responsiveness to self-nucleic acids → excessive IFNα production by innate immune cells (especially plasmacytoid dendritic cells) → inappropriate activation of autoreactive B cells → autoantibody production, immune complex deposition in skin, glomeruli, joints, and other tissues
• Epidemiology:
- 90% of affected patients are women of childbearing age (F:M = 1:1 before adolescence, 9:1 after)
- US prevalence: 100 per 100,000 white women, 400 per 100,000 black women
• Clinical features: Features in the 2019 EULAR/ACR SLE Classification Criteria are noted in red (# points)
- Constitutional: Fever (2); fatigue; weight loss
- MSK: Arthralgias/myalgias (95% prevalence); inflammatory polyarthritis of the hands/wrists/knees (6; 60% prevalence). Jaccoud arthropathy (reducible finger swan neck deformities)
- Derm: Acute cutaneous lupus (6; e.g., malar “butterfly” rash); discoid lesions (4); subacute cutaneous lupus lesions (4); oral ulcers (2); non-scarring alopecia (2); Raynaud’s; photosensitivity
- Heme: Leukopenia (3); thrombocytopenia (4); autoimmune hemolysis (4); APLS (antiphospholipid antibodies and clinical thrombosis); 7× risk non-Hodgkin’s lymphoma
- CNS: Acute confusional state (2); psychosis (3); seizures (5); transverse myelitis
- Cardiac: Acute pericarditis (6); pericardial effusion (5); myocarditis; Libman-Sacks endocarditis; 3–10× risk of ASCVD
- Pulm: Pleural effusion (5; 30–50% lifetime prevalence); chronic ILD; acute lupus pneumonitis; DAH (high DLCO); shrinking lung syndrome
- Renal: Proteinuria ≥0.5 g/24 hrs (4; 30–50% lifetime prevalence); Class II or V nephritis (8); Class III or IV nephritis (10). +Anti-dsDNA is associated with an increased risk of lupus nephritis.
- GI: Hepatitis, peritonitis, mesenteric vasculitis (all rare)
- Autoantibodies/hypocomplementemia: Antiphospholipid antibodies (2; may be lupus anticoagulant, anti-cardiolipin, or anti-β2GP1; IgG, IgM or IgA); ↓C3 (3), ↓C4 (3), both (4); anti-dsDNA OR anti-Smith antibody (6)
• Notable syndromes:
- Drug-induced lupus
• Arthritis/arthralgias, serositis, and rash. Notably, no CNS or renal involvement.
• Culprit medications:
- Associated with +anti-histone (95%): hydralazine, procainamide, isoniazid
- Associated with +anti-dsDNA: minocycline, penicillamine, TNFi
- Other: HCTZ, ACEi, chlorpromazine
- Discoid lupus erythematosus (DLE)
• Cutaneous plaques with central hypopigmentation and peripheral hyperpigmentation
• Pearl: Most patients with DLE do NOT have systemic lupus symptoms
• Diagnosis:
- 2019 EULAR/ACR Classification Criteria: For patients with ANA ≥1:80, score the clinical features in red above. Only count the highest weighted criteria in each category and do not count features better explained by another disease process. Patients with a score ≥10 are classified as having SLE.
- Caveat about classification criteria: Clinician diagnosis is still the gold standard! These classification criteria are more specific than sensitive; intended to ensure homogeneity of clinical trial patients, not as diagnostic criteria.
Clinical reasoning pearl: Lupus flare or infection?
- Favors lupus flare: Predominant ESR elevation, normal CRP; no fever; C3/C4 below the patient’s baseline; dsDNA above the patient’s baseline; leukopenia; thrombocytopenia
- Favors infection: Concomitant ESR and CRP elevation; fever; C3/C4 at baseline; dsDNA at baseline; leukocytosis; thrombocytosis (including relative thromobocytosis above the patient’s normal platelet baseline)
• Serial disease assessment:
- Each clinic visit: CBC with differential, BMP, ESR, CRP, C3/C4, UA, UPCR, anti-dsDNA
• Treatment:
- Non-organ threatening disease:
• Start hydroxychloroquine (Plaquenil) for all patients regardless of disease activity unless contraindications
- Reduces flare frequency and incidence of renal disease, and it is also effective for arthritis/arthralgias and skin disease
- Need annual ophthalmologic exams while taking
• Arthritis: Low-dose prednisone can be helpful
• Arthralgias: Limited evidence to guide sequence of therapy
• Skin disease: Depending on the severity of skin disease involvement, start with sunscreen/hydroxychloroquine → topicals (steroids, tacrolimus) → mycophenolate → belimumab
- Moderate organ-threatening disease: Profound cytopenias, acute CNS lupus with seizures, DAH, myocarditis
• Prednisone 1 mg/kg OR methylprednisolone 1 g IV daily ×3–5 days followed by prednisone taper
• IVIG may be effective for SLE-related ITP
- Severe organ-threatening disease: Proliferative class III/IV nephritis
• See Table 9.4 for features and management of lupus nephritis
TABLE 9.4 • Features and Management of Lupus Nephritis
Systemic sclerosis (SSc)
• Pathogenesis: Poorly understood confluence of 1) microvasculopathy, 2) fibrosis, and 3) humoral autoimmunity
• Epidemiology: Prevalence 275 cases per 1 million; SLE is ten times more common than SSc
• Clinical features: Features in the 2013 EULAR/ACR SSc Classification Criteria are noted in red (# points)
- Derm: Skin thickening of the hands (9 points if proximal and 4 points if distal to the MCPs; finger skin thickening is called sclerodactyly, best seen as loss of skin wrinkles between the finger joints); puffy fingers/non-pitting edema (2); facial skin tightening; telangiectasias (2, often facial); calcinosis. Skin involvement is typically most severe over the first 18–24 months, then improves with or without therapy.
- Vascular: Raynaud’s phenomenon (3, present in 95% of SSc patients), nail-fold capillary disease (2, reduced density of nailfold capillaries), fingertip ulcers or pitting scars (2 or 3, respectively)
- Pulm: ILD (2, especially in diffuse SSc), WHO Group I pulmonary HTN (2, especially in limited SSc)
- Cardiac: Arrhythmias, HFpEF, rarely myocarditis
- GI: Reduced oral aperture, GERD, gastric antral vascular ectasia (GAVE, a.k.a. “watermelon stomach”, usually heralded by iron deficiency anemia), colonic pseudo-obstruction (Ogilvie’s), SIBO
- Renal: Scleroderma renal crisis (SRC)
• Can be conceptualized as “Raynaud’s of the kidneys”: Narrowing of renal arterioles leads to hypoperfusion of the juxtaglomerular apparatus and consequent excess renin production
• Presents with hypertensive emergency (may have retinopathy, PRES), proteinuric AKI and MAHA
• SRC is the presenting manifestation in ~20% of patients with SSc
• 60% of patients are Anti-RNA-Pol-III+
- MSK: Inflammatory non-erosive polyarthritis of the hands and wrists, involving the DIPs
- Autoantibodies: Anti-Scl70 (3), anti-centromere (3), anti-RNA-pol-III (3). Max points from auto-Ab = 3.
• Limited vs. diffuse disease: These terms refer ONLY to the extent of skin involvement – both can feature organ fibrosis and vasculopathy (Table 9.6)
• Diagnosis: Clinical diagnosis, but score ≥9 on 2013 EULAR/ACR SSc Classification Criteria is highly specific
• Treatment: Treatments are tailored to the involved organ system(s):
- Derm: Mycophenylate if severely symptomatic and early in disease course (e.g., <1 yr as symptoms often improve without treatment within 2 yr)
- ILD: Mycophenylate is the treatment of choice depending on ILD severity. Lung transplantation may be considered.
- Pulmonary HTN: Monotherapy with an endothelin receptor antagonist (e.g., ambrisentan) or PDE inhibitor (e.g., tadalafil) for patients with WHO functional class I symptoms; combination therapy with ERA and PDEi for patients with WHO class II and III symptoms. Consider evaluation for lung transplantation.
- Myocarditis: Glucocorticoids
- Scleroderma renal crisis: Titrate ACEi to max dose (captopril PO or enalaprilat IV), then add CCB (amlodipine PO or nicardipine IV). Do not reduce MAP by more than 20 mmHg in the first 24 hrs, goal is normotension within 72 hrs. No role for immunosuppression.
TABLE 9.5 • Comparison of Limited and Diffuse Systemic Sclerosis (SSc)
Inflammatory and non-inflammatory myopathies
• Differential diagnosis for inflammatory myopathies: Dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myositis (IMNM), and inclusion body myositis (IBM). See Table 9.6.
TABLE 9.6 • Inflammatory Myopothies
• Differential diagnosis for non-inflammatory myopathies:
- Endocrine: Hypothyroid myopathy, glucocorticoid-related myopathy (Cushing’s or exogenous steroids)
- Medication/toxin-induced myopathies: Alcohol, cocaine, NRTI (AZT in particular), colchicine, gemcitabine, statins
- Inherited myopathies: Glycogen storage diseases, disorders of muscle lipid export (e.g., carnitine transporter deficiency), mitochondrial myopathies (impairment in oxidative phosphorylation, e.g., MERRF), Duchenne/Becker muscular dystrophy, Limb-Girdle muscular dystrophy
• Distinguishing inflammatory vs. non-inflammatory myopathies: Clinical features of the myopathy can provide clues. See Table 9.7
TABLE 9.7 • Inflammatory vs. Non-Inflammatory Myopathies
Mixed connective tissue disease (MCTD)
• Pathogenesis: Not known in detail, presumably similar to constituent diseases SLE, SSc, and myositis
• Epidemiology: Rare (exact prevalence not described); F:M = 4:1
• Diagnosis: MCTD is an overlap syndrome in which patients satisfy classification criteria for ≥2 of SLE, SSc, and DM/PM, AND have high titer anti-U1-RNP autoantibodies. See Table 9.8 for disambiguation from Overlap Syndrome and Undifferentiated Connective Tissue Disease.
TABLE 9.8 • Comparison of MCTD, UCTD, and Overlap Syndromes
• Clinical features:
- Vascular: Raynaud’s, pulmonary hypertension. Vascular manifestations are common and are the main driver of mortality.
- Other: Arthritis, puffy fingers, sclerodactyly, serositis, esophageal dysmotility, myositis, ILD. Renal disease is uncommon.
• Treatment: Targeted toward organ-system-specific manifestations; see SLE/SSc/myositis sections
Sjögren’s syndrome
• Pathogenesis: Autoimmune destruction of the lacrimal and salivary glands; unclear underlying mechanism but increased risk associated with specific HLA alleles implicates cell-mediated autoimmunity.
• Epidemiology: Prevalence of 0.3–1 in 1000 worldwide. F:M = 9:1
• Clinical features:
- Glandular manifestations:
• Severe dry eye (may cause corneal ulceration)
• Dry mouth (may cause dental caries, result in malnutrition)
- Extraglandular manifestations:
• Constitutional: Fatigue
• Derm: Xerosis; cutaneous leukocytoclastic vasculitis (small vessel, 30% of these cases associated with cryoglobulins); subacute cutaneous lupus rash (annular photosensitive lesions) associated with anti-Ro antibodies
• Articular: Inflammatory polyarthritis resembling RA except non-erosive
• Pulm: 5–9% overall incidence including bronchiolitis obliterans, ILD
• Renal: 5–6% overall incidence including type 1 RTA, interstitial nephritis, immune-complex GN
• Vascular: Cryoglobulinemic vasculitis; Raynaud’s phenomenon (16%)
• Neuro: 8–27% overall incidence including CNS demyelinating lesions, myelopathy/transverse myelitis, cranial neuropathies, mononeuritis multiplex, distal symmetric polyneuropathy
• GI: Primary biliary cholangitis; autoimmune hepatitis
• Heme: Lymphoma (2% overall risk, 15–20-fold increase in risk of non-Hodgkin lymphoma, largely MALT lymphoma in the salivary glands with marginal-zone histology)
• Immunologic: Cryoglobulinemia; positive Rf in ~50%
• Disease categories:
- Primary Sjögren’s: Not meeting criteria for another CTD or rheumatic disease
- Secondary Sjögren’s: Occurring in the context of another rheumatic disease, most commonly RA or SLE (10–30% prevalence in these groups), but also scleroderma, myositis
• Diagnosis:
- 2017 EULAR/ACR Sjögren’s classification criteria: See Table 9.9
TABLE 9.9 • Sjögren’s Classification Criteria (2017 ACR/EULAR)
- Description of special tests for Sjögren’s:
• Ocular fluorescein/lissamine staining: Performed by ophthalmology, scored 0–12
• Schirmer test: Strip of filter paper applied to the conjunctiva, tear output saturates the length of the strip via capillary action. The total distance moistened is measured over 5 min. Normal is >5 mm.
- Differential diagnosis for sicca symptoms:
• Inflammatory and malignant diseases with tropism for parotid glands: Sarcoidosis, IgG4-related disease, GPA, lymphoma
• Viral infections with tropism for parotid glands: Mumps, HCV, HIV
• Medications: Anticholinergics, cannabinoids
• Treatment:
- Eye care:
• Artificial tears
• Topical cyclosporine
• Pilocarpine or cevimeline (muscarinic agonists) to stimulate tear production
- Oral care:
• Sugar-free candies to stimulate saliva flow
• Meticulous oral hygiene and regular dental exams
• Pilocarpine or cevimeline (muscarinic agonists) to stimulate saliva production
- Extraglandular manifestations:
• Arthritis: Methotrexate, hydroxychloroquine
• Severe CNS disease (demyelinating disease, transverse myelitis): Cyclophosphamide + rituximab