IgG4-related disease: neurologic manifestations

Neuroimmunology

Updated 01.15.2024
Released 10.13.2021
Expires For CME 01.15.2027

IgG4-related disease: neurologic manifestations

Authors: Christine Lebrun-Frenay MD PhD, Michael Levraut MD

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Editor: Francesc Graus MD PhD

IgG4-related disease: neurologic manifestations

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Introduction

Overview

IgG4-related disease is an insidiously progressive autoimmune systemic condition characterized by IgG4+ plasma cell proliferation and infiltration of the affected organs associated with storiform fibrosis. It can affect nearly all the organs and the CNS--particularly the meninges and the pituitary. The disease affects men more frequently than women, and the median age at disease onset is around 50 to 60 years old.

The main presentations of the disease rely on inflammatory pseudotumors or infiltrative lesions. The most commonly affected organs are the biliopancreatic area, the lymph nodes, and the salivary glands. CNS involvement during IgG4-RD relies on hypertrophic pachymeningitis (affecting the brain, the spine, or both) and hypophysitis. The prevalence of IgG4-HP and IgG4-H is unknown; large cohorts of IgG4-RD patients usually report a very low prevalence (about 1% to 5% of all cases), whereas small cohorts report a prevalence of near 35%. This discrepancy is primarily due to the difference in the diagnostic workup, which uses whole-body imaging to diagnose asymptomatic locations of the disease. Thus, many instances of CNS involvement of IgG4-RD remain poorly symptomatic. Despite its low prevalence, neurologists must be aware of this disease because instances of idiopathic pachymeningitis or hypophysitis have been found to correlate with IgG4-RD pathological findings retrospectively.

Many symptoms have been described for IgG4-HP and IgG4-H and are mostly related to the compression of adjacent structures or organ failure. A clinical examination of patients with suspected CNS IgG4-RD should focus on extraneurologic symptoms because a systemic form of the disease occurs in about 60% of patients (16; 13; 14; 15).

In 2019, the American College of Rheumatology and the European League Against Rheumatism provided a "3 steps" new diagnostic criteria for IgG4-RD (24). This study provides an accurate life characterization of the disease and allows diagnosing IgG4-RD without pathological analysis. However, it is essential to understand that CNS involvement during IgG4-RD can present as isolated organ disease, and in such cases, most of the established diagnostic criteria may not apply. Thus, pathological analysis remains essential.

Apart from pathological analysis, there is no reliable biomarker to assess IgG4-HP or IgG4-H diagnosis. Serum IgG4 concentration increases in about half of the patients with IgG4-HP and 75% of patients with IgG4-H, mainly when other organs are involved. Therefore, elevated serum concentration of IgG4 should encourage physicians to perform whole-body scans, looking for a location that could guide a non-neural biopsy but cannot be sufficient to allow the diagnosis alone.

Treatment of IgG4-RD is based on steroid therapy, usually begin between 0.6 to 1 mg/kg/d. Steroids are often tapered over a 3- to 6-month period. During specific CNS involvement, decompressive surgery is often needed, and intravenous pulse methylprednisolone can be performed.

Relapses often occur during CNS IgG4-RD, and long-term immunosuppressive treatment can be necessary for such patients. Many therapies are studied in IgG4-RD, but the B-cell-depletive treatment rituximab has shown remarkable efficacy in reducing relapse rate, steroid use, inflammatory mass volume, and blood IgG4 concentrations. However, for CNS IgG4-RD, only retrospective data are available to support rituximab efficacy.

Key points

	Little is known about IgG4-HP and IgG4-H, and our knowledge comes from case series and literature reviews.
	IgG4-HP and IgG4-H are unusual syndromes, but many instances of idiopathic pachymeningitis or hypophysitis have been found to be IgG4-RD retrospectively.
	The pathological analysis is essential to the diagnosis.
	Systemic disease occurs in more than 50% of patients.

Historical note and terminology

The IgG4-RD is a recognized pathology with the following historical timeline:

In 2001	First description of IgG4-RD (10).
In 2003	First description of extra-pancreatic location of IgG4-RD.
Since 2003	Nearly all anatomic sites were described in association with IgG4-RD.
In 2004	First description of IgG4-related hypophysitis (22).
In 2009	First description of IgG4-related hypertrophic pachymeningitis (06).
In 2011	First diagnostic criteria for IgG4-related hypophysitis.
In 2012	Two Japanese teams provide the first comprehensive diagnostic criteria for systemic IgG4-RD (21).
In 2012	Massachusetts General Hospital physicians developed the Responder Index as a revised tool to assess IgG4-RD activity and severity (04).
In 2015	Massachusetts General Hospital IgG4-RD team shows the importance of blood total plasmablast count to assess IgG4-RD activity (23).
In 2015	A multicentric American prospective trial showed the efficacy of B-cell depletion in IgG4-RD (05).
In 2019	The American College of Rheumatology and the European League Against Rheumatism provided new international diagnostic criteria for IgG4-RD (24).

Clinical manifestations

Presentation and course

	Clinical manifestations of IgG4-HP or IgG4-H are related to local inflammation, mass effect to adjacent structures, or organ insufficiency.
	Extraneurologic manifestations occur in more than 50% of cases.
	Magnetic resonance imaging is essential to identify the infiltrative or pseudotumoral lesion, assess the damage to adjacent structures, monitor disease activity, and identify alternative diagnoses.
	Whole-body CT scan helps to identify extraneurologic manifestations of the disease.

IgG4-related hypertrophic pachymeningitis

Neurologic symptoms. IgG4-RD is a common cause of inflammatory hypertrophic pachymeningitis. There are no characteristic symptoms related to IgG4-HP because it presents as a nonspecific inflammation of the meninges. However, it can affect the brain, the spinal cord, or both in 70%, 20%, and 10% of the cases, respectively (13). Local dural involvement of the periorbital areas, vestibular structures, and the clivus, brainstem, or spinal nerve roots typically causes focal signs such as visual impairment, cranial or spinal motor nerve palsies, and sensory deficits. More diffuse symptoms, such as headache and seizures, occur if meningeal inflammation spreads along the hemispheric and basal dura or the tentorium (16).

The main neurologic symptoms and their frequency are detailed in table 1.

Table 1. Main Neurologic Clinical Symptoms During IgG4-HP

	(16) n=33	(13) n=60
Male sex, n (%)	21 (64)	40 (66.6)
Median age, n (range)	53 (32-82)	53 (19-82)
Location
Brain, n (%)	-	44 (73.3%)
Spine, n (%)	-	11 (18.3%)
Both brain and spine, n (%)	-	5 (8.3%)
Headache, n (%)	22 (67)	36 (65.4)
Epilepsy, n (%)	2 (6)	7 (12.7)
Cranial nerve palsies, n (%)	11 (33)	16 (29.1)
Visual abnormalities, n (%)	7 (21)	16 (29.1)
Hearing loss, n (%)	3 (9)	-
Motor weakness, n (%)	5 (15)	16 (29.1)
Sensory deficits, n (%)	4 (12)	9 (16.4)

Extraneurologic symptoms. Special attention should be given to extraneurologic symptoms as they may be present in more than 50% of the cases. Common systemic involvement along with IgG4-HP includes eyes (orbital pseudotumors and lacrimal gland infiltrate), salivary glands, and lungs (parenchymal pseudotumors and infiltrative pneumonia).

Radiological symptoms. Imaging in IgG4-HP is used to (1) identify the pachymeningitis, (2) assess the damage to adjacent structures, (3) monitor disease activity, and (4) look for alternative diagnoses.

Magnetic resonance imaging. MRI is the exam of choice to identify meningeal fibrotic lesions and disease activity and eliminate other CNS inflammatory diseases. On T2-weighted images, IgG4-HP appears as a hypointense mass or thickening of the meninges. On T1-weighted images, IgG4-HP appears isointense and enhances with gadolinium, revealing an active inflammatory process.

IgG4-HP (MRI)

(A) On T2-weighted images, IgG4-HP appears as a hypointense mass or thickening of the meninges. (B) On T1-weighted images, IgG4-HP appears isointense and enhances with gadolinium, revealing an active inflammatory process. (Cont...

Brain and spine MRI also should focus on (1) other locations of IgG4-RD, such as orbital pseudotumors, and (2) alternative diagnoses, such as CNS vasculitis (ie, anti neutrophil cytoplasmic antibody-associated vasculitis) or parenchymal inflammatory diseases (ie, sarcoidosis or CNS lymphoma).

Computed tomography scan. CT scan should be performed to:

	Assess adjacent bone infiltration of the pachymeningitis.
	Look for extraneurologic manifestations of the disease (eg, orbital or lung pseudotumors, retroperitoneal fibrosis).
	Look for alternative diagnoses that can mimic IgG4-RD, such as neoplasm, infection, vasculitis, or granulomatous disease.

Nuclear imaging. Because IgG4-RD is an inflammatory disease, 18FDG-PET/CT has proven helpful for:

	(1) Identification of the different locations of the disease (presenting as highly glucose-consuming infiltrates).
	(2) Assessment of treatment efficacy (28).
	(3) Identification of alternative diagnoses.

Fibroblast activation protein-targeted imaging (68Ga-FAPI PET/CT) has shown great effect in monitoring active fibrosis in patients with IgG4-RD (17). The 68Ga-FAPI PET/CT was more effective than classical PET/CT to detect the different locations of the disease, but further studies are needed to confirm this result, particularly during CNS involvement.

IgG4-related hypophysitis

Neurologic symptoms. As for IgG4-HP, the symptoms of IgG4-H are not specific to the disease and result from a sellar mass effect (visual abnormalities and headaches) or pituitary insufficiency (polyuro-polydipsic syndrome because of diabetes insipidus and anterior pituitary hormone deficiency). However, compared to other causes of hypophysitis, posterior or anterior pituitary hormone deficiency occurs frequently--in more than 90% of the patients. Table 2 provides the frequency of symptoms seen in IgG4-H (14; 15).

Table 2. Main Neurologic Symptoms During IgG4-H

	Li and colleagues 2019 (14) n=76	Lojou and colleagues 2020 (15) n=59
Male sex, n (%)	46 (61)	40 (68)
Median age, n (range)	54.1 (14-87)	55
Polyuro-polydipsic syndrome, n (%)	30 (39)	26 (45)
Asthenia, n (%)	31 (41)	21 (36)
Nausea or vomiting, n (%)	-	9 (15)
Headache, n (%)	20 (26)	17 (29)
Visual abnormality, n (%)	14 (18)	12 (20)
Panhypopituitarism, n (%)	44 (58)	Most of the patients
Isolated diabetes insipidus, n (%)	12 (16)	-
Isolated anterior pituitary hormone insufficiency, n (%)	14 (18)	-
Isolated hypogonadism, n (%)	5 (10)	-
Isolated hypothyroidism, n (%)	1 (2)	-
Isolated ACTH deficiency, n (%)	1 (2)	-

Extraneurologic symptoms. Extraneurologic location of the disease is present in about 60% of the cases (14). The most frequent extraneurologic organs involved are the lungs, retroperitoneum, and kidneys; also often affected are the submandibular, lacrimal, and parotid glands and lymph nodes.

Radiological symptoms. As for IgG4-HP, MRI should be performed to confirm the diagnosis of hypophysitis, look for other diagnoses, and assess the damage of adjacent structures. IgG4-H often presents as a mass or a thickened pituitary gland and stalk. However, the typical bright signal of the posterior pituitary seen on T1-weighted images is usually absent in IgG4-H, even in cases presenting with diabetes insipidus.

CT or PET/CT scans are useful to find other locations of the disease.

Prognosis and complications

Complications of IgG4-related pachymeningitis and hypophysitis. There are 3 main complications of CNS involvement during IgG4-RD:

	Mass effect on adjacent structures related to local fibrosis.
	Organ failure related to local inflammation or fibrosis.
	High relapse rate.

Mass effect on adjacent structures. The mass effect occurs in both IgG4-HP and IgG4-H.

During spinal cord meningeal involvement, a spinal cord compression syndrome can occur with walking disorders or gait disturbance due to a motor or sensory impairment.

During cranial meningeal involvement, numerous compressive symptoms have been reported and are mainly due to neurologic or vascular compression.

During pituitary involvement, compressive symptoms can mimic a pituitary tumor presentation with visual field loss or headaches in about 20% of the patients.

When such symptoms occur, early decompressive surgery is often needed and allows assessing for histological proof.

Organ failure. This complication frequently occurs during IgG4-H, whereas more than 90% of the patients presented with diabetes insipidus or anterior pituitary hormone insufficiency (14). Panhypopituitarism occurred in around 60% of the cases, whereas isolated diabetes insipidus and isolated anterior hormone insufficiency were seen in about 15% and 20% of the cases.

Relapse and recurrence. Almost half of the patients will relapse, mainly when the steroids are tapered to low doses. Detailed information is available in the Outcomes section below.

Prognosis of IgG4-related pachymeningitis and hypophysitis. The overall prognosis of IgG4-HP and H depends on the rapidity of the diagnosis and treatment.

There are no available data on the long-term outcomes of patients suffering from IgG4-HP or H. However, the morbidity and mortality related to CNS IgG4-RD depend on (1) neurologic complications (ie, compression of vascular or neurologic adjacent structures), (2) a high relapse rate, and (3) long-term treatment side effects. Indeed, IgG4-RD frequently appears as a steroid-dependent disease and occurs in the sixth decade of life while cardiovascular diseases and risk factors develop.

The association of IgG4-RD with malignancies has been investigated and is still under consideration. Many observational studies from China, Korea, and the United States provide a 2.5 standardized incidence ratio of cancer in the IgG4-RD population, and many different malignancies have been reported associated with IgG4-RD.

Biological basis

Etiology and pathogenesis

	The cause of IgG4-RD is still unknown, but many findings support that an auto-antigen (or auto-antigens) is (are) the initiating factor(s) of the disease.
	Pathophysiology comprised a complex immune mechanism involving activated B-cells, different T-cell phenotypes, and fibroblasts.
	The role of serum IgG4 is unclear.

Pathological findings

Our knowledge into IgG4-RD pathophysiology came from tissue biopsy showing:

	Storiform fibrosis of the affected organs, meaning that activated fibroblasts could be key during IgG4-RD.
	A lymphoplasmacytic infiltrate made of CD4+ T-cells and IgG4+ plasma cells, suggesting a crucial T- and B-cell role.
	Obliterative phlebitis destroying the walls and lumens of the veins inside the fibrosis.

IgG4-RD pathophysiology (tissue biopsy)

Tissue biopsies showing storiform fibrosis (A) of the affected organs and a lymphoplasmacytic infiltrate made of CD4+ T-cells (B) and IgG4+ plasma cells (C). (Contributed by Dr. Christine Lebrun-Frenay.)

The accumulation of IgG4+ plasma cells per high field and a high IgG4+/IgG ratio in affected tissue strongly suggest IgG4-RD. However, the percentage of IgG4+ plasma cells infiltrate needs to be interpreted with caution because (1) it can be different depending on the affected organ, and (2) other autoimmune diseases can present with IgG4+ plasma cell infiltrate. In short, the diagnosis of IgG4-RD should never be done based on the results of immunostaining features alone but should be considered in association with other clinical, biological, and pathological findings.

Because of its pseudotumoral presentation, pathological analysis should be performed to rule out tumors, infections, or other autoimmune diseases that can mimic IgG4-RD. Typically, IgG4-RD should not be considered when histology reveals granuloma, necrosis, vasculitis, tumoral cells, or positive infectious staining.

Immunology

Role of B-cells. Many studies focused on the role of B-cells in IgG4-RD. The primary pieces of evidence that B-cells play a central role in IgG4-RD are:

	The identification of high IgG4 and IgE gammaglobulin level in the peripheral blood of patients, indicating a humoral immune response.
	The presence of IgG4+ plasma cell infiltrates in the affected organs.
	The reported efficacy of B-cell depletive treatment in many different IgG4-RD populations (08; 09; 03).
	The identification of expanded specific IgG4+ oligoclonal-activated B-cells in the blood of patients with IgG4-RD that correlates with disease activity (23).

Role of T-cells. Our knowledge on the role of T-cells is derived from 3 observations:

	The presence of CD4+ T-cell infiltrate in affected tissue biopsy.
	The recognition that circulating plasmablast expansion is generated in a T-cell-dependent manner (19).
	The discovery of blood expansion of CD4+ specific T-cells.

IgG4-RD patients present with a blood expansion of CD4+ T follicular helper (TFH) cells, and the CD4+ TFH-2 cell subset correlates with the number of affected organs, circulating plasmablasts, and serum IgG4 concentration (01). Furthermore, CD4+ TFH-2 and CD4+ TH2 cells are implicated in the class-switching of B-cell to both IgG4 and IgE. An expansion of CD4+ cytotoxic T cells has also been reported that could induce tissue damage by the secretion of granzyme B and perforins, leading to the activation of resident fibroblasts.

Role of fibroblasts. The exact mechanism of fibroblast activation leading to fibrosis in IgG4-RD is mainly unknown but underlies probable complex immune mechanisms in which different cell types are involved:

	CD4+ cytotoxic T-cells could activate fibroblast by secreting TGFβ, IL-1β and INF-γ.
	B-cells could activate fibroblasts by secreting platelet-derived growth factor.
	Pro-inflammatory macrophages could activate fibroblasts by secreting IL-10.

The role of fibroblasts in IgG4-RD is also supported by a study showing the efficacy of a specific fibroblast-activated, protein-targeted nuclear imaging (68Ga-FAPI PET/CT) to identify the different locations of IgG4-RD (17).

Role of serum IgG4. The role of serum IgG4 in the pathogenesis of the disease is still under investigation, but:

	Serum IgG4 concentration is not specific for IgG4-RD as it can rise in many other autoimmune diseases and can be in the normal range in IgG4-RD.
	Blood IgG4 concentration does not correlate with fibrosis measurement but correlates with the number of affected organs and the risk of relapse.

For a better and deeper understanding of the pathophysiology of IgG4-RD, we invite you to read the review by Perugino and Stone (20).

Differential diagnosis

Confusing conditions

IgG4-related hypertrophic pachymeningitis mimickers

Granulomatosis polyangiitis. Granulomatosis with polyangiitis is a systemic vasculitis mediated by antineutrophil cytoplasmic antibodies and is, with IgG4-RD, the leading cause of noninfectious inflammatory hypertrophic pachymeningitis. Both granulomatosis with polyangiitis and IgG4-RD share standard clinical and biological features, leading to a possible misdiagnosis:

	The same range of age at diagnosis.
	Multiple organ involvement, particularly the kidneys, lungs, sinuses, eyes, and meninges.
	Elevated serum IgG4 concentrations.
	Moderate hypereosinophilia.

Some case series report overlapping granulomatosis with polyangiitis and IgG4-RD (07). This condition highlights the importance of pathological analysis because granulomatosis with polyangiitis will present as a granulomatous and necrotizing arterial vasculitis, which is entirely different from IgG4-RD histology.

Other IgG4-HP mimics. Many disorders can mimic IgG4-HP, and the more frequent are described in table 3.

Table 3. Non-Exhaustive List Of Common IgG4-HP Mimics

Etiology of pachymeningitis	Shared features with IgG4-HP	Differences with IgG4-HP
Non-infectious inflammatory disorders
Sarcoidosis	Multiple organ involvement with masses and fibrotic lesions	ECA increase, normal blood IgG4, granuloma
Primary Sjögren syndrome	Multiple organ involvement (eg, salivary glands, eye, lymph node) with possible fibrosis	SSA-Ro 52kD antibodies positivity, normal blood IgG4, lymphocytic sialadenitis without IgG4+ plasma cells
Infectious disorders
Tuberculosis	Multiple organ involvement (eg, lung mass, lymph nodes)	Fever, weight loss, exposure, normal IgG4, positive Ziehl-Neelsen staining, mycobacterium PCR and cultures
Neoplastic disorders
Erdheim-Chester disease	Same age and sex predominance at diagnosis, multiple organ involvement with both fibrosis (eg, retroperitoneum, aorta) and masses	Long bone osteosclerosis (90%) with typical x-ray and nuclear imaging findings, biopsy +++ (foamy histiocytes CD68+, CD1a-)
Lymphoma	Multiple organ involvement with masses (eg, lymph nodes)	Weight loss, fever, specific monoclonal lymphocyte expansion, tumoral lymphocyte cells
Intracranial hypotension	None but common cause of pachymeningitis	No other organ involvement, normal blood IgG4

IgG4-related hypophysitis mimickers

Lymphocytic hypophysitis. Lymphocytic hypophysitis is the most common cause of primary hypophysitis, representing more than 75% of all cases (02). Lymphocytic hypophysitis and IgG4-H share common pathological findings whereas lymphocytic hypophysitis can present with a diffuse lymphocytic infiltrate associated with variable fibrosis but can be differentiated by:

	A female predominance in lymphocytic hypophysitis (male to female ratio = 1:8).
	Different median ages at diagnosis: lymphocytic hypophysitis often occurs during the fourth decade of life, particularly during late pregnancy or peripartum.
	The absence of systemic involvement in lymphocytic hypophysitis.
	The absence of elevated blood IgG4 concentration in lymphocytic hypophysitis.
	The differences in pituitary hormonal insufficiency between the two diseases with a frequent ACTH insufficiency during lymphocytic hypophysitis whereas patients with IgG4-H often present with gonadotrophin insufficiency or panhypopituitarism.

Other IgG4-H mimics. A list of the most common mimics is shown in table 4.

Table 4. Non-Exhaustive List Of Common IgG4-H Mimics

Etiology of pachymeningitis	Shared features with IgG4-HP	Differences with IgG4-HP
Primary hypophysitis
Granulomatous hypophysitis	Same MRI findings with frequent sellar involvement	Female sex predominance, no systemic involvement, normal blood IgG4
Drug-induced hypophysitis
Immune checkpoint inhibitors	Possible other organ involvement but rarely presenting as organ masses	Anamnesis and immune checkpoint inhibitor treatment, normal blood IgG4
Secondary granulomatous hypophysitis
Sarcoidosis	Multiple organ involvement with masses and fibrotic lesions	ECA increase, normal blood IgG4, granuloma
Granulomatosis with polyangiitis	Same range of age, possible elevated blood IgG4	Multiple organ involvement, granulomatous, necrotizing vasculitis
Tuberculosis	Multiple organ involvement	Fever, weight loss, exposure, normal IgG4, positive Ziehl-Neelsen staining, mycobacterium PCR and cultures
Neoplastic associated hypophysitis
Erdheim-Chester disease	-	-
Langerhans-cell histiocytosis	Multiple organ involvement, including fibrotic events (retroperitoneum, etc.)	Normal blood IgG4, biopsy +++ (CD1a+ CD207+ histiocytes infiltrate)
Lymphoma

Diagnostic workup

	The exclusion of IgG4-RD mimickers is the cornerstone of diagnosis.
	The histopathological analysis must be performed to assess IgG4-RD diagnosis in isolated (single-organ) pachymeningitis or hypophysitis.
	The 2019 ACR/EULAR diagnostic criteria allow the diagnosis of CNS IgG4-RD without pathological analysis in patients with multiple organ involvement.

Diagnostic criteria

Many diagnostic criteria have been proposed for IgG4-RD, mainly because physicians have presented specific organ diagnostic criteria for each disease location. However, our knowledge of IgG4-RD has advanced, and the American College of Rheumatology and the European League Against Rheumatism provided three diagnostic criteria for IgG4-RD in 2019 (24). These criteria were based on the analysis of more than 1,000 IgG4-RD patients and were mainly based on excluding IgG4-RD mimics:

	Step 1: The patient should present with clinical or radiological characteristics suggestive of IgG4-RD (swelling or masses of typically affected organ) OR a pathological analysis showing a lymphoplasmacytic infiltrate of unknown origin in a specific affected organ.
	Step 2: Exclusion criteria. The patient should not present with any clinical, serological, radiological, or pathological findings that can support a diagnosis other than IgG4-RD (Table 5).
	Step 3: Inclusion criteria. If the patient meets the entry criteria and does not meet any exclusion criteria, the physician can proceed to step 3 to diagnose (or not) IgG4-RD ultimately (Table 6). Each inclusion criterion has a specific numerical weight. In the end, if the sum of all criteria is 20 or more points, IgG4-RD can be confirmed.

Table 5. ACR/EULAR Exclusion Criteria for IgG4-RD Diagnostic

ACR/EULAR exclusion criteria
Clinical	Fever No objective response to glucocorticoids
Serological	Leucopenia or thrombocytopenia with no explanation Peripheral eosinophilia > 3 G/L Antineutrophil cytoplasmic, SSA/Ro, SSB/La, double-stranded DNA, Sm, RNP antibodies positivity Any other disease-specific autoantibody positivity Positive cryoglobulinemia
Radiological	Findings suspicious for malignancy or infection that have not been sufficiently investigated Rapid radiological progression Long bone abnormalities suggestive of Erdheim-Chester disease Splenomegaly
Pathological	Cellular infiltration suggesting malignancy Markers consistent with inflammatory myofibroblastic tumor Predominant neutrophilic inflammation Necrotizing vasculitis Prominent necrosis Primarily granulomatous inflammation Pathologic features of macrophage or histiocytic disorder

Table 6. ACR/EULAR Inclusion Criteria for IgG4-RD Diagnostic

ACR/EULAR inclusion criteria		Points
Clinical	Bilateral gland involvement (lacrimal, parotid, sublingual and submandibular) No 1 set of glands ≥ Two sets of glands	0 +6 +14
	Chest Not checked or normal Peribronchovascular and septal thickening The paravertebral band-like soft tissue in the thorax	0 +4 +10
	Pancreas and biliary tree Not checked or normal Diffuse pancreas enlargement Diffuse pancreas enlargement and capsule-like rim with decreased enhancement Pancreas (either of the above) associated with biliary tree involvement	0 +8 +11
	Kidney Not checked or normal Renal pelvis thickening/soft tissue Bilateral renal cortex-low-density areas	0 +8 +10
	Retroperitoneum Not checked or normal Diffuse thickening of the abdominal aortic wall Circumferential or anterolateral soft tissue around the infrarenal aorta or iliac arteries	0 +4 +8
Serological	Hypocomplementemia	+6
	Serum IgG4 concentration Not checked or normal High but < 2x upper limit of normal 2-5x upper limit of normal ≥ 5x upper limit of normal	0 +4 +6 +11
Pathological	Histopathology Uninformative biopsy Dense lymphocytic infiltrate Dense lymphocytic infiltrate and obliterative phlebitis Dense lymphocytic infiltrate and storiform fibrosis with or without obliterative phlebitis	0 +4 +6 +13
	Immunostaining IgG4+/IgG+ ratio ≤ 40% and IgG4+/HPF* ≤ 9 IgG4+/IgG+ ratio ≥ 41% and IgG4+/HPF ≤ 9 IgG4+/IgG+ ratio ≤ 40% and IgG4+/HPF ≥ 10 IgG4+/IgG+ ratio 41-70% and IgG4+/HPF ≥ 10 IgG4+/IgG+ ratio ≥ 71% and IgG4+/HPF ≥ 51	0 +7 +7 +14 +16
*HPF: High power field

ACR/EULAR diagnostic criteria are available for systemic IgG4-RD, but the meninges and pituitary are not listed as specific organs. Therefore, it is impossible to diagnose single-organ IgG4-HP or IgG4H without pathological analysis, whatever the serum IgG4 concentration and the presence of complement consumption.

Although meningeal biopsy is routinely performed by many medical centers, pituitary biopsy is not. Therefore, many physicians still use the specific IgG4-H diagnostic criteria made in 2011 (12), allowing diagnosing IgG4-H without pathological analysis. However, these criteria are only based on the review of 14 cases and must be applied with caution. Regardless, pituitary pathological analysis remains the gold standard for IgG4-H diagnosis.

IgG4-H diagnostic algorithm

(Contributed by Dr. Christine Lebrun-Frenay.)

IgG4-related pachymeningitis and hypophysitis findings

Usual blood and cerebrospinal fluid findings during IgG4-HP.

Blood analysis. IgG4-HP may present with:

	Elevated serum gammaglobulins associated with another raised inflammatory marker (ie, C-reactive protein) in about 35% of the cases.
	Elevated serum IgG4 (> 135 mg/L) in about 55% of the cases. Raised blood IgG4 level is often associated with multiple organ involvement.
	Elevated specific IgG4+ plasmablasts (CD19low CD38+ CD20- CD27+ cells), particularly during systemic involvement.
	Moderate eosinophilia and complement consumption are not reported in association with IgG4-HP (13).

Cerebrospinal fluid analysis. Cerebrospinal fluid analysis is often performed in the diagnostic workup of pachymeningitis to look for infection or tumoral cells. IgG4-RD can present with:

	Moderate elevation of CSF proteins in 75% of the patients.
	Aseptic lymphocytic meningitis in about 60% of the patients.
	Elevated CSF IgG concentration in about 85% of the patients and associated with specific oligoclonal bands in most of the cases.

The CSF IgG4 concentration and IgG4 index ([CSF IgG4/blood IgG4]/Albumin quotient) could be an excellent diagnostic tool for IgG4-HP but have been investigated in a small number of patients (16) and need to be studied in a larger cohort.

Usual blood findings during IgG4-H. Usually, IgG4-H can present with:

	Elevated serum IgG4 concentration in about 75% of the cases.
	Pituitary hormonal insufficiency in more than 90% of the cases.

Management

	There is no curative treatment for IgG4-RD.
	All patients presenting with IgG4-HP or IgG4-H need to be treated.
	First-line treatment is based on steroid therapy.
	Rituximab is the second-line treatment of choice and can be used as a steroid-sparing agent in relapsing patients or first-line therapy in patients with a high risk of severe side effects from steroids.

Who needs to be treated?

Most patients with IgG4-RD need to be treated. Before initiating treatment, physicians need to consider:

	The clinical symptoms: looking for organ failure or compression of adjacent structures.
	Disease activity in measuring the Responder Index and IgG4+ plasmablast count.
	Specific locations of the disease that need to be treated whatever their clinical presentation, including CNS involvement.

Every patient with IgG4-HP or IgG4-H needs to be treated.

What is the treatment target?

Treating a patient with IgG4-RD aims to:

	Reduce polyclonal activated B-cell and T-cell expansion and inflammatory infiltrate to reduce swelling or mass volume.
	Reduce resident fibroblast activation to stop fibrosis deposits.
	Prevent organ failure.
	Prevent early relapse.

Which treatment should be given?

All treatments are palliative drugs, whereas there is no curative treatment for IgG4-RD.

Reduce risk factors. All patients diagnosed with IgG4-RD must cease cigarette smoking.

First-line treatment. In 2015, an international group of experts recommended the use of glucocorticoids as a first-line treatment (11). Usually, glucocorticoids begin at 0.6 mg/kg/d, but neurologists often use higher doses (1 mg/kg/d). Intravenous methylprednisolone of 1 gram per day for 3 to 5 days has been used in several neurologic cases and has shown efficacy to prevent early relapse (13).

Glucocorticoid maintenance treatment is not universal as American and European teams often tapered steroids progressively on a short period from 3 to 6 months and Japanese teams often continue low doses for 1 to 3 years to prevent relapses (18). The best course is to balance the benefits and risks of every patient (age, cardiovascular risk factors, IgG4-RD disease activity) to choose the best treatment ultimately.

Steroid-sparing agents used as second-line treatment. Since 2015, two trials explored the efficacy of low-dose cyclophosphamide and mycophenolate-mofetil (26; 27).

Cyclophosphamide. In this trial, adding low-dose cyclophosphamide to usual steroid therapy as first-line treatment prevented short-term relapses without severe side effects. However, 39% of the patients experienced a relapse despite a 1-year cyclophosphamide maintenance treatment (26).

Mycophenolate mofetil. In this trial, adding mycophenolate mofetil to steroids did not change the 1-month clinical response, suggesting that steroids alone are enough in achieving early response (27). However, patients experienced fewer relapses during the 1-year follow-up.

Other conventional steroid-sparing agents. Many other treatments have been retrospectively reported as effective in IgG4-RD, such as azathioprine, methotrexate, hydroxychloroquine, and tacrolimus. The reported efficacy of azathioprine suggests a possible treatment for pregnant women.

B-cell targeted therapy. Rituximab is the most studied immunosuppressant in IgG4-RD. The clinical effects of this treatment are frequently dramatic and often produce a reduction in the size of the pseudotumoral masses characteristic of IgG4-RD. The durability of clinical remission following initial induction with rituximab varies between patients, but in most patients, remission persists for at least 6 months and can extend beyond 18 months (09). This therapy has also been studied for remission maintenance and showed similar efficacy (03). In addition, rituximab reduces serum IgG4 concentrations, plasmablast numbers, CD4+ CTL numbers in the blood and tissue, serum markers of fibrosis, and tissue myofibroblast activation (08; 11).

B-cell depletive agent is the treatment of choice in patients with a steroid-dependent disease.

Surgery. Surgery is not a specific treatment of IgG4-RD. However, decompressive surgery should be considered in patients presenting with compressive emergencies.

How to treat IgG4-HP and/or IgG4-H?

All patients should begin oral steroids at 1 mg/kg/d. This dose needs to be maintained for at least 2 to 4 weeks and progressively tapered over a 3- to 6-month period. Depending on patient comorbidities and IgG4-RD activity, steroids can be maintained at a low dose for several years to prevent relapses.

Early decompressive neurosurgery should be considered in patients presenting with compressive symptoms, and intravenous methylprednisolone pulse therapy could be effective in such cases.

An immunosuppressive agent should be considered in 2 situations:

	As second-line treatment in relapsing disease cases.
	As first-line treatment in patients presenting with a high risk of developing serious adverse events of prolonged steroid therapy.

If indicated, immunosuppressive treatment should first rely on rituximab.

Outcomes

Outcome after first-line treatment. Patients with IgG4-related disease often relapse. Nearly 42% of IgG4-HP patients present early relapse after steroid therapy (13), and the relapse rate of IgG4-H is unknown. Maintaining a low-dose steroid could prevent relapse in some patients, but this approach is not preferred worldwide.

Fibrosis removal neurosurgery can effectively prevent early relapse in IgG4-HP (13) but is not performed in uncomplicated cases because of high related morbidity.

Outcome under immunosuppressive drugs. B-cell depletive treatment, such as with rituximab, permits clinical remission in most patients with IgG4-RD for 6 to 18 months, and rituximab maintenance therapy has shown similar efficacy.

However, long-term side effects of rituximab are now well known, and patients can develop hypogammaglobulinemia-associated infections. Therefore, blood gammaglobulins and IgG concentrations need to be monitored in such patients.

Long-term steroid therapy side effects are also well known (eg, steroid-induced diabetes, increased risk of cardiovascular events, osteoporosis). If IgG4-RD occurs in patients with potential steroid side effect susceptibility, steroid-sparing agents should be discussed.

Media

References

01: Akiyama M, Suzuki K, Yamaoka K, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast number in IgG4-related disease. Arthritis Rheumatol 2015;67(9):2476-81. PMID 25989153
02: Angelousi A, Alexandra K, Tsoli M, Kaltsas G, Kassi E. Hypophysitis (including IgG4 and immunotherapy). Neuroendocrinology 2020;110(9-10):822-35. PMID 32126548
03: Campochiaro C, Della-Torre E, Lanzillotta M, et al. Long-term efficacy of maintenance therapy with Rituximab for IgG4-related disease. Eur J Intern Med 2020;74:92-8. PMID 31901297
04: Carruthers MN, Stone JH, Deshpande V, Khosroshahi A. Development of an IgG4-RD Responder Index. Int J Rheumatol 2012;2012:259408. PMID 22611406
05: Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis 2015;74(6):1171-7. PMID 25667206
06: Chan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol 2009;33:1249-52. PMID 19561447
07: Danlos FX, Rossi GM, Bloxkmans D, et al. Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: a new overlap syndrome. Autoimmun Rev 2017;16(10):1036-43. PMID 28780079
08: Della-Torre E, Feeney E, Deshpande V, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. Ann Rheum Dis 2015;74(12):2236-43. PMID 25143523
09: Ebbo M, Grados A, Samson M, et al. Long-term efficacy and safety of rituximab in IgG4-related disease: data from a French nationwide study of thirty-three patients. PLoS One 2017;12(9):e0183844. PMID 28915275
10: Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344(10):732-38. PMID 11236777
11: Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol 2015;67(7):1688-99. PMID 25809420
12: Leporati P, Landek-Salgado MA, Lupi I, Chiovato L, Caturegli P. IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab 2011;96(7):1971-80. PMID 21593109
13: Levraut M, Cohen M, Bresch S, et al. Immunoglobulin G4-related hypertrophic pachymeningitis: a case-oriented review. Neurol Neuroimmunol Neuroinflamm 2019;6(4):e568.** PMID 31355304
14: Li Y, Gao H, Li Z, Zhang X, Ding Y, Li F. Clinical characterisitics of 76 patients with IgG4-related hypophysitis: a systematic literature review. Int J Endocrinol 2019;2019:5382640.** PMID 31929792
15: Lojou M, Bonneville JF, Ebbo M, Schleinitz N, Castinetti. IgG4 hypophysitis: diagnosis and management. Presse Med 2020;49(1):104016. PMID 32234384
16: Lu LX, Della-Torre E, Stone JH, Clark SW. IgG4-related hypertrophic pachymeningitis: clinical features, diagnostic criteria, and treatment. JAMA Neurol 2014;71(6):785-93. PMID 24733677
17: Luo Y, Pan Q, Yang H, Peng L, Zhang W, Li F. Fibroblast activation protein-targeted PET/CT with 68Ga-FAPI for imaging IgG4-related disease: comparison to 18F-FDG PET/CT. J Nucl Med 2021;62(2):266-71. PMID 32513902
18: Masamune A, Nishimori I, Kikuta K, et al. Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis. Gut 2017;66(3):487-94. PMID 27543430
19: Mattoo H, Mahajan VS, Della-Torre E, et al. De novo oligoclonal expansions of circulating plasma blasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol 2014;134(3):679-87. PMID 24815737
20: Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol 2020;16(12):702-14.** PMID 32939060
21: Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22(1):21-30. PMID 22218969
22: Van der Vliet HJ, Perenboom RM. Multiple pseudotumors in IgG4-associated multifocal systemic fibrosis. Ann Intern Med 2004;141(11):896-7. PMID 15583245
23: Wallace ZS, Mattoo H, Carruthers M, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis 2015;74(1):190-5. PMID 24817416
24: Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis 2020;79(1):77-87.** PMID 31796497
25: Wallwork R, Perugino CA, Fu X, et al. The association of smoking with immunoglobulin G4-related disease: a case-control study. Rheumatology (Oxford) 2021;60(11):5310-17. PMID 33751033
26: Yunyun F, Yu C, Panpan Z, et al. Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids. Sci Rep 2017;7(1):6195. PMID 28733656
27: Yunyun F, Yu P, Panpan Z, et al. Efficacy and safety of low dose mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial. Rheumatology (Oxford) 2019;58(1):52-60. PMID 30124952
28: Zhang J, Chen H, Ma Y, et al. Characterizing IgG4-related disease with 18F-FDG PET/CT: a prospective cohort study. Eur J Nucl Med Mol Imaging 2014;41(8):1624-34. PMID 24764034
29: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Christine Lebrun-Frenay MD PhD

Dr. Lebrun-Frenay of Pasteur2 University Hospital has no relevant financial relationships to disclose.
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Michael Levraut MD

Dr. Levraut of Nice University Hospital and Cote d'Azur University has no relevant financial relationships to disclose.
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Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: Typical: 50 to 60 years
Sex preponderance: IG4-RD: male>female, 2:1
Heredity: No hereditary factors
Population groups selectively affected: No population group selectively affected
Occupation groups selectively affected: No occupation groups selectively affected

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IgG4-related disease: neurologic manifestations

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IgG4-related disease: neurologic manifestations

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

IgG4-related hypertrophic pachymeningitis

Table 1. Main Neurologic Clinical Symptoms During IgG4-HP

IgG4-related hypophysitis

Table 2. Main Neurologic Symptoms During IgG4-H

Prognosis and complications

Biological basis

Etiology and pathogenesis

Pathological findings

Immunology

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

IgG4-related hypertrophic pachymeningitis mimickers

Table 3. Non-Exhaustive List Of Common IgG4-HP Mimics

IgG4-related hypophysitis mimickers

Table 4. Non-Exhaustive List Of Common IgG4-H Mimics

Diagnostic workup

Diagnostic criteria

Table 5. ACR/EULAR Exclusion Criteria for IgG4-RD Diagnostic

Table 6. ACR/EULAR Inclusion Criteria for IgG4-RD Diagnostic

IgG4-related pachymeningitis and hypophysitis findings

Management

Who needs to be treated?

What is the treatment target?

Which treatment should be given?

How to treat IgG4-HP and/or IgG4-H?

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Patient Profile

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