Distinguishing Between IgG4-related Disease and Erdheim-Chester Disease: A Challenging Diagnostic Journey

To the Editor,

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated condition that mimics many malignant, infectious and inflammatory disorders. ¹ Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytic multisystem disorder. ECD most commonly manifests as multifocal sclerotic lesions of the long bones demonstrating sheets of foamy histiocytes on biopsy, with or without histiocytic infiltration of extra-osseous tissues. ² Clinical symptomatology and histopathology help in the diagnosis and differentiation of both diseases. However, ECD is a close differential of IgG4-related disease in presentation and organ involvement. We report a rare case of IgG4-related disease with a biopsy showing features of IgG4 RD plus ECD and how clinico-radiological features along with therapy helped in the diagnosis. Written consent from the patient was taken for publishing this case including images.

A 64-year-old male patient presented to our OPD with a history of swelling in the right upper eyelid for the past eight months and a history of bilateral submandibular areas for the past two months. He reported a painless nodular swelling on the lateral aspect of the right upper eyelid that progressively increased in size and caused the narrowing of the lateral palpebral fissure. The patient also had two small, painless oval swellings in the submandibular area. There were no other accompanying symptoms like visual disturbances, redness of eyes, sicca symptoms, purpura, epistaxis, nasal polyps, arthritis, photosensitivity oral ulcer, Raynaud’s phenomenon, fever, weight loss, dry cough, shortness of breath. The patient was previously diagnosed with Gilbert syndrome at the age of 15 (asymptomatic since then). Physical examination revealed a 2 × 2 cm swelling in the right upper eyelid resulting in closure of the lateral palpebral fissure and two symmetrical oval swellings in the submandibular area. The differential diagnoses considered were IgG4-related disease, sarcoidosis and DILS and Sjogren’s syndrome. Investigations: Hemogram, thyroid function test, viral markers (HIV, HbsAg, HCV) and urine routine were normal. ESR was elevated (50 mm/h), and bilirubin levels were raised which was attributed to Gilbert syndrome. ANA done by IIF (indirect immunofluorescence) was negative. Anti-MPO and anti-PR3 were negative with normal C3, C4, however, IgG4 levels were elevated (>3.56 g/dL). MRI of the orbit showed an ill-defined heterogeneously enhancing soft tissue lesion in the superolateral quadrant of the right orbit without bony erosions (Figure 1a). Histopathology of the soft tissue showed features of both IgG4-related disease (lymphoplasmacytic infiltrate, IgG4 positive cells >10/hpf, showing IgG4/CD 138⁺ plasma cells >40%) and ECD (sheets of foam cells, histiocytes and multinucleated Touton type giant cells with CD 68 positivity, CD1a-, BRAF V600 mutation-negative). However, BRAF V600 E mutation is positive only in 55% of cases of ECD. To assess the systemic involvement PET CT was done which showed high metabolic uptake in the right orbit, bilateral submandibular gland, GGOs in the lungs, tail and uncinate process of pancreas and walls of the infra-abdominal aorta (Figure 1b). Several features supported a diagnosis of IgG4 Related disease over Erdheim-Chester disease in this patient, including high metabolic uptake in the large vessels (aorta), salivary glands, and lung (GGOs). Additionally, Immunohistochemical staining revealed IgG4/CD138+ > 40%. Given these findings, the patient was started on treatment with prednisolone at 50 mg (1 mg/kg) and rituximab induction at a dose of 1 g administered at weeks 0 and 2. ³ Dose of Prednisolone was tapered over six months. At the end of one month, the swelling in the eyelid and submandibular areas regressed, and at the end of six months, repeat PET CT showed complete resolution in the right orbit, submandibular gland, walls of the abdominal aorta and GGOs in both lungs except a small residual patch in the right lung (Figure 1c). He was given a maintenance dose of rituximab 500 mg in view of residual inflammation in the lung and a repeat PET CT was done after six months. At the end of one year of initiating treatment PET CT showed complete resolution of inflammation.

Figure 1.

(a) MRI Brain Showing Heterogeneously Enhanced Soft Tissue in Superolateral Quadrant of Right Orbit Without Any Evidence of Bone Erosion (Arrow Pointing). (b) PET CT Before Therapy Showing Metabolic Uptake in Right Orbit (i), Submandibular Gland (ii), Basal Areas of Lungs (iii), Walls of Abdominal Aorta (iv )(Arrows Pointing). (c) PET CT After Six Months Showing Complete Resolution in Right Orbit (i), b/l Submandibular Gland (ii), b/l Basal Lung Fields Except for a Residual Patch in Right Middle.

The 2019 ACR EULAR Classification criteria for IgG4-related diseases strictly mentions the exclusion criteria according to which biopsy showing markers of Macrophage or histiocytic disorder should not classified as IgG4. However, the problem with our index case is that the biopsy showed features of both IgG4RD and Erdheim-Chester. ⁴ Elevated IgG4 levels and IgG4 staining are non-specific in biopsy as they can be seen in both these diseases. However clinical picture and some features on PET CT (major salivary gland involvement, infrarenal aorta involvement), IgG4/CD 138⁺ plasma cells >40% on IHC pointed more towards IgG4RD. ⁵ Overall, the resolution of symptoms with therapy suggested IgG4-related disease and this case highlights the approach and how therapy helped us in solving the case. The treatment approach for IgG4 RD includes initial therapy with glucocorticoids along with second-line immunosuppression like Azathioprine or Rituximab. In ECD the therapy is usually started with targeted agents like Vemurafenib or MEK inhibitor based on the underlying mutation—BRAF or MEK, respectively. In patients negative for mutations, IFN alpha therapy is preferred. Unlike in IgG4 RD, there is no survival benefit from steroids in ECD. ¹⁶ The patient is under our follow-up for the last two years without any new symptoms. At present, he is off therapy (steroids and Rituximab) for nine months. A written consent was taken from the patient for publishing this case. Differences between IgG4-related disease and ECD are illustrated in Table 1.

Table 1.

Differences Between IgG4-related Disease and Erdheim-Chester Disease.

IgG4-related Disease	Erdheim-Chester Disease
Multisystem autoimmune disorder	Multisystem rare non-Langerhans histiocytic disorder
Bony involvement is rare (apart from rare IgG4 angiocentric eosinophilic fibrosis of the head and neck)6	>95% of the patients have bony involvement and have symmetrical bony sclerotic lesions6
Skin involvement is rare and presents as a subset of cutaneous pseudo lymphoma typically scalp, face, neck and pinna of the ear7	Yellow periorbital Xanthelasmas are very common in ECD6
The major salivary gland (parotid, submandibular), and lacrimal gland are commonly involved8	Only one-quarter of the patients can present with exophthalmos (U/L or b/l infiltration of orbits)9
The abdominal aorta is more commonly involved than the thoracic aorta—mostly the infrarenal portion of the aorta is involved10	Thoracic and abdominal can be involved (periaortic fibrosis-coated aorta), however, more of thoracic involvement11
CT KUB shows multiple round or wedge-shaped low-density lesions12	Infiltration of perinephric tissues with a rind or mass-like lesion leading to ‘hairy kidney’ is common in CT KUB13
Tissue biopsy—Demonstrates dense lymphoplasmacytic infiltrates enriched with IgG4 + plasma cells, obliterative phlebitis and storiform fibrosis14	Tissue biopsy—Demonstrates foamy histiocytes with CD 68+S100-CD1a—and Touton giant cells9
Good response to Glucocorticoids and various second-line immunosuppressants15	Glucocorticoids have demonstrated clinical activity in ECD but have no survival benefit16