Clinical manifestations

Presentation and course

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

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.

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:

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

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

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. 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

Pathological findings

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

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:

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

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:

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:

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

Epidemiology

There are no available well-conducted epidemiological studies to date that promote the prevalence and incidence of IgG4-RD worldwide. The Japan Health Ministry has estimated an incidence of 0.28 to 1.08 per 100,000 persons in Japan.

In the different case series available, the incidence of CNS involvement is controversial and ranges from 1% to 35% of the cases.

Prevention

The only modifiable risk factor identified for IgG4-RD is current cigarette smoking, with an odds ratio of 1.79 (25).

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:

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

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:

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

Diagnostic workup

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:

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

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

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-related pachymeningitis and hypophysitis findings

Usual blood and cerebrospinal fluid findings during IgG4-HP.

Blood analysis. IgG4-HP may present with:

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:

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:

Management

Who needs to be treated?

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

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:

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:

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.

Special considerations

Pregnancy

The impact of IgG4-RD on pregnancy is unknown, and the effect of pregnancy on IgG4-RD is also unknown.

The use of steroids during pregnancy is authorized. However, most immunosuppressive agents are forbidden during pregnancy. Therefore, if possible, immunosuppressants should be stopped during pregnancy. If not, azathioprine should be preferred over other drugs.

Anesthesia

There are no particular precautions for general anesthesia reported to date.