ACR/EULAR Classification Criteria for IgG4 Related Disease Save

IgG4-related disease (IgG4-RD) is a relatively new disorder since 2003, and may present as a diagnostic challenge as it can cause fibroinflammatory pathology in nearly any organ. 

A EULAR workgroup set out to develop and validate an international set of classification criteria for IgG4-RD.  This international group of 86 physicians utilized consensus exercises, existing literature, and developed criteria using cohorts of 1879 subjects (1086 cases, 793 mimickers).

Classification requires a three-step process.

1. A potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD.
2. Exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification.
3. 8 weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied.

Using this approach on a validation cohort, a threshold of 20 points had a specificity of 99.2% and a sensitivity of 85.5%. In the second cohort, the specificity was 97.8% and the sensitivity was 82.0%

To meet these criteria you must go through the 3 steps

I. ORGAN SYSTEMS - MUST HAVE AT LEAST ONE Below

• Immunostaining - IgG+cells can be identified using either IgG staining or CD138 staining.
• Head and neck gland involvement - lacrimal glands or both submandibular glands - usually is bilateral (but can be asymmetric)
• Chest - Peribronchovascular and septal thickening in the lung or paravertebral band-like soft tissue that does not encase the aorta.
• Pancreas and biliary tree - Diffuse pancreas enlargement or biliary involvement (mos consistent with IgG4-related sclerosing cholangitis is proximal biliary tract involvement)
• Kidney - Renal pelvic wall thickening (without severe stenosis), low-density lesions in both renal cortices (patchy or round-shaped). Hypocomplementemia pertains to low serum levels of C3, C4 or both.
• Retroperitoneum - IgG4-related retroperitoneal fibrosis or periaortitis is typically circumferential or on the anterolateral sides of the aorta or infrarenal aorta (extending to include the iliac vessels).

II. EXCLUSION CRITERIA - MUST NOT HAVE ANY OF THESE CLINICAL, LAB, PATHOLOGY OR DISEASE CRITERIA

1. Fever: Documented, recurrent temperature>38°C.
2. No objective response to glucocorticoids
3. Leucopenia and thrombocytopenia without alternative explanation
4. Peripheral eosinophilia: To a concentration of>3000 mm3
5. Positive antineutrophil cytoplasmic antibody (ANCA)
6. Positive antibodies: Ro, La, double-stranded DNA, RNP, or Sm antibodies positive in titrers greater than normal suggest an alternative diagnosis. (This does not include autoantibodies of low specificity, such as rheumatoid factor, antinuclear antibodies, antimitochondrial antibodies, anti-smooth muscle antibodies, and antiphospholipid antibodies)
7. Cryoglobulinemia
8. Radiological findings suspicious for malignancy or infection
9. Rapid radiological progression within a 4–6 week interval
10. Long bone abnormalities consistent with Erdheim-Chester disease: Multifocal osteosclerotic lesions of the long bones, usually associated with bilateral diaphyseal involvement
11. Splenomegaly:>14 cm in the absence of alternative explanation (eg, portal hypertension)
12. Pathology: cellular infiltrates suspicious for malignancy
13. Markers consistent with inflammatory myofibroblastic tumour
14. Prominent neutrophilic inflammation on pathology
15. Necrotising vasculitis
16. Prominent necrosis
17. Primary granulomatous inflammation
18. Pathological features of a macrophage/histiocytic disorder
19. Any of the following diagnoses are exclusion criteria: Multicentric Castleman’s disease, Crohn’s disease (if pancreatobiliary disease is present), ulcerative colitis (if pancreatobiliary disease is present), Hashimoto thyroiditis (if the thyroid is the only proposed disease manifestation).: Patients with IgG4-RD can certainly have Hashimoto thyroiditis separately from IgG4-RD, but Hashimoto thyroiditis is part of the IgG4-RD spectrum.

III. WEIGHTED CRITERIA FOR DIAGNOSIS - MUST HAVE 20 POINTS OR MORE 

 Step 3. Inclusion criteria: domains and items¶  

• Histopathology   Uninformative biopsy  0
• Dense lymphocytic infiltrate +4
• Dense lymphocytic infiltrate and obliterative phlebitis +6
• Dense lymphocytic infiltrate and storiform fibrosis with or without obliterative phlebitis +13
• Immunostaining** 0–16, as follows:
• Assigned weight is 0 if the IgG4+:IgG+ ratio is 0%–40% or indeterminate and the number of IgG4+ cells/hpf is 0–9.‡‡
• Assigned weight is 7 if: (1) the IgG4+:IgG+ ratio is ≥41% and the number of IgG4+cells/hpf is 0–9 or indeterminate or (2) the IgG4+:IgG+ ratio is 0–40% or indeterminate and the number of IgG4+ cells/hpf is ≥10 or indeterminate.
• Assigned weight is 14 if: (1) the IgG4+:IgG+ ratio is 41%–70% and the number of IgG4+ cells/hpf is ≥10 or (2) the IgG4+:IgG+ ratio is ≥71% and the number of IgG4+ cells/hpf is 10–50.
• Assigned weight is 16 if the IgG4+:IgG+ ratio is ≥71% and the number of IgG4+ cells/hpf is ≥51.
•  Serum IgG4 concentration -Normal or not checked  0
• >Normal but 2× upper limit of normal +4
• 2–5× upper limit of normal +6
• ≥>5× upper limit of normal +11
• Bilateral lacrimal, parotid, sublingual and submandibular glands - No set of glands involved  0
• One set of glands involved +6
• Two or more sets of glands involved +14
• Chest  -  Not checked or neither of the items listed is present  0
• Peribronchovascular and septal thickening +4
• Paravertebral band-like soft tissue in the thorax +10
• Pancreas and biliary tree -Not checked or none of the items listed is present  0
• Diffuse pancreas enlargement (loss of lobulations) +8
• Diffuse pancreas enlargement and capsule-like rim with decreased enhancement +11
• Pancreas (either of above) and biliary tree involvement +19
• Kidney -Not checked or none of the items listed is present  0
• Hypocomplementemia +6
• Renal pelvis thickening/soft tissue +8
• Bilateral renal cortex low-density areas +10
• Retroperitoneum -Not checked or neither of the items listed is present  0
• Diffuse thickening of the abdominal aortic wall +4
• Circumferential or anterolateral soft tissue around the infrarenal aorta or iliac arteries +8

IV. DIAGNOSIS

A case meets the classification criteria for IgG4-RD if the entry criteria are met, no exclusion criteria are present, and the total points is ≥20