Medicine Marrow Pg No 447-456 (Rheumatology)

Etiology

• Genetic Factors:
  • HLA DR3 associated with Subacute cutaneous Lupus
  • Non-HLA factors like early complement deficiency: C1q deficiency is the strongest risk factor, followed by C4 and C2 deficiency.
  • Increased number of X-chromosomes associated with increased risk.
  • IRAK gene on the X-chromosome.
  • TREX gene on chromosome 3.
• Environmental Factors:
  • Oral contraceptive pills (OCP)
  • Hormonal replacement Therapy (HRT)
  • UV-B rays
  • Epstein-Barr virus
  • Silicosis: Exposure can stimulate pulmonary alveolar macrophages leading to an autoimmune trigger.
  • Vitamin D deficiency
  • Smoking

Features of SLE

• Predominantly affects women in reproductive age (20-40 years) with a 9:1 female to male ratio.
• There is a strong family history, with over 40% of identical twins having positive concordance.

Lupus Nephritis

• Occurs in 50-60% of adult cases.
• Almost 100% of children with SLE develop lupus nephritis.

Postmenopausal SLE

• SLE diagnosed after menopause has generally a good prognosis, especially if patients do not experience CNS or renal symptoms.
• Common symptoms include dryness, serositis, musculoskeletal symptoms, and presence of Anti Ro antibodies.
• Anti-dsDNA antibodies are usually absent, and complements are often normal.

Male SLE

• Often presents a poorer prognosis.

Active SLE

• Anti-dsDNA antibodies and decreased complement levels are good markers of active SLE.

Diagnosis

• ANA (Anti-Nuclear Antibody) is a screening test for connective tissue disorders (CTD).
  • If positive:
    • Quantitative assessment by ELISA
    • Indirect IF: Titre higher than 1:80
    • Hep 2: Positive
• IIF (Indirect Immunofluorescence) pattern helps differentiate potential CTD, based on antibodies.
  • Dense fine speckled pattern: Suggest anti Ro/La, likely Sjogren's
  • Fine speckled pattern: Suggestive of anti Smith (Sm) antibodies, likely pointing to SLE.
  • Coarse speckled pattern: Associated with anti Ul RNP antibodies, indicating mixed connective tissue disease (MCTD).
  • Nucleolar pattern: Associated with anti Jo I antibodies, likely polymyositis or dermatomyositis (antisynthetase syndrome)
• ANA profile: Provides information about the specific antibodies present.
  • Done once, not repeated as it is costly.
• ENA profile (Extractable nuclear antigen): Tests for 6 antibodies.
  • 100% of MCTD cases are ANA positive.
  • 85% of Sjogren's syndrome cases are ANA positive.
  • 50% of IgG4 related disease cases are ANA positive.
• ANA is not diagnostic for rheumatoid arthritis, although it can be found in 97% of SLE cases.

Clinical Approach in SLE

• Drug-induced Lupus Erythematosus is characterized by 100% ANA positivity, a homogenous pattern on IIF, and positive anti-histone antibodies.
  • Procainamide is a common cause.
• Elderly SLE frequently shows positive Anti Ro antibodies even with negative ANA.

IgG4 Related Disease

• Presence of elevated IgG4 levels.

Associated findings with IgG4 Related Disease

• Primary sclerosing cholangitis in the bile duct.
• Non-specific interstitial pneumonia (NSIP) and thickening of the bronchovascular bundle in the lungs.
• Periaortitis and associated paravertebral mass in the aorta.
• Membranonephropathy is often associated with low complement levels.
• RCD 2020 criteria include pathologic findings, serology (elevated IgG4), and clinical features.
• Miklulicz Disease: Enlargement of salivary glands (parotid, submandibular, and lacrimal).
• High likelihood of chronic sinusitis, nasal obstruction with eosinophilia.
• IgG4/IgG ratio is often a better marker than just IgG4.
• Prognosis is good with a positive response to steroids.

Sjogrens Syndrome vs IgG4 Related Disease

• Salivary gland enlargement is present in both.
• Sicca symptoms are more common in IgG4 related disease.
• Response to steroids is good in IgG4 related disease, and the symptoms are not responsive in Sjogren's.

Manifestations of IgG4 Related Disease

• Type 1 autoimmune pancreatitis: Most common manifestation, presenting with obstructive jaundice.
  • ERCP: Diffuse irregular narrowing of the pancreatic duct
    • Sausage pancreas on CT.
• Salivary glands: Painless enlargement of the submandibular gland with minimal sicca symptoms.
• Orbital/periorbital lesions: Orbital inflammatory pseudo tumors
• Lacrimal gland: Enlargement known as dacryoadenitis.
• Retroperitoneal fibrosis:
• CNS: Lymphocytic hypophysitis (post-partum women, associated with increased intracranial pressure), Pachymeningitis (no parenchymal involvement).
• Kidney: Tubulointerstitial disease is most common, and it may lead to CKD.
• Image: Sausage-shaped pancreas with feathery borders on CT scan. Non-tender enlargement of the submandibular gland.

Pathogenesis of SLE

• Dysregulation of immune system arising from a combination of genetic and environmental factors.
• Defective clearance of apoptotic and neutrophil extracellular trap (NET) debris.
• Activation of innate immune system via TLR-7 and TLR-9, which are pattern recognition receptors.
  • Hydroxychloroquine (HCQ) blocks these TLRs.
• Activation of plasmacytoid dendritic cells (PDCs).
  • Anifrolumab targets type 1 interferons (IFNα) produced by PDCs.
• Activation of APCs (professional antigen-presenting cells): macrophages and Langerhans dendritic cells.
• Type I interferons (IFNα), a key pathogenic cytokine in SLE, leads to endothelial injury.
• Upregulation of CD40 ligand, involved in CD40 interaction, and B-lymphocyte stimulator (BLYS) in SLE.
  • Belimumab targets BLYS, thereby inhibiting B cell activation.
• Formation of immune complexes leads to tissue deposition via type 3 hypersensitivity reactions.
  • Deposition in glomerulus: causing glomerulonephritis
  • Deposition in synovial cavity: causing synovitis
  • Deposition in vessels: causing vasculitis

Pathogenesis of IgG4 Related Disease

• Antigenic stimuli trigger the infiltration of IgG4-predominant plasma lymphocytes.
• These cells activate myofibroblasts which then release TGF-β and PDGF, leading to fibrosis.
• TGF-β is the most potent fibrogenic cytokine.

Sjogren's Syndrome

• Associated with Lymphocytic Interstitial Pneumonitis (LIP), along with HIV.
• Anti-Nuclear antibodies are positive in 85% of Sjogren's cases.
• Anti Ro/La antibodies are often present when ANA is negative.
  • Anti Ro is positive in 50% of cases.
  • Anti LA is positive in 33% of cases.
• The fine speckled pattern of the ANA suggests anti Ro/La.

Investigations for Sjogren's Syndrome

• Minor salivary gland biopsy is the gold standard.
• Sialography is no longer commonly used.
• USG of salivary glands can demonstrate a loss of homogenicity.

Criteria for Diagnosis of Sjogren's Syndrome

• 2016 American College of Rheumatology/European League Against Rheumatism Classification:
  • Primary Sjogren's diagnosis requires at least one symptom of ocular or oral dryness and a total score of 24 points based on specific criteria.
  • Scoring system: Points are awarded for histological findings (focal lymphocytic sialadenitis), presence of Anti-Ro/SS-A antibodies, SICCA ocular staining, Rose Bengal score, Schirmer's test, and unstimulated whole salivary flow rate.