Background

The IgG4-related disease is a newly recognized autoimmune condition characterized by chronic inflammation and tissue damage. It is named after IgG4, an immunoglobulin subclass involved in the immune response. The IgG4-related disease can affect multiple organs and tissues throughout the body, leading to various symptoms and clinical presentations.

Epidemiology

IgG4-related disease can occur in individuals of any age, but it predominantly affects middle-aged to older adults, with a higher incidence in males. It is more commonly observed in East Asian populations but has been reported worldwide.

The igG4-related disease has been reported worldwide, but its prevalence and patterns may vary among ethnic groups. It is more prevalent in East Asian populations, including Japanese and Korean individuals, compared to Western populations.

Anatomy

Pathophysiology

The pathophysiology of IgG4-related disease involves a dysregulated immune response, chronic inflammation, and tissue fibrosis. While the exact cause of the disease is still not fully understood, several vital mechanisms have been identified:

IgG4 Antibody Response: IgG4-related disease has an aberrant immune response characterized by increased circulating IgG4 antibodies. These antibodies are thought to play a role in the pathogenesis of the disease.

Tissue Infiltration by IgG4-Positive Plasma Cells: IgG4-related disease is characterized by a significant infiltration of affected tissues by IgG4-positive plasma cells. These plasma cells release cytokines and other inflammatory mediators that promote chronic inflammation and tissue damage. The exact triggers that lead to the recruitment and activation of these plasma cells are not well understood.

Fibrosis and Tissue Remodeling: Chronic inflammation in IgG4-related disease can lead to the activation of fibroblasts and the deposition of extracellular matrix components, resulting in fibrosis and tissue remodeling. This fibrotic process can cause organ dysfunction and architectural distortion. The underlying mechanisms driving the fibrotic response are still being investigated.

Regulatory T Cells (Tregs) and Th2 Response: Evidence suggests that IgG4-related disease is associated with alterations in immune regulatory mechanisms. An imbalance in regulatory T cells (Tregs) has been observed, with a decrease in Tregs and an increase in Th2 cells. This dysregulation of immune response may contribute to chronic inflammation and tissue damage in the disease.

Genetic Factors: While the specific genetic factors contributing to IgG4-related disease have not been fully elucidated, specific human leukocyte antigen (HLA) alleles and gene polymorphisms have been implicated in increased susceptibility to the disease. However, more research is needed to understand the genetic underpinnings of the condition better.

Etiology

The etiology, or underlying causes, of IgG4-related disease, are described as follows-:

• Genetic Factors: Certain genetic predispositions may play a role in developing IgG4-related disease. Studies have identified associations between specific human leukocyte antigen (HLA) alleles and the disease, suggesting a genetic susceptibility. However, the specific genetic factors and their mechanisms of influence are still being investigated.
• Immune Dysregulation: IgG4-related disease is an autoimmune condition characterized by an abnormal immune response. Dysregulation of immune cells, including T and B cells, has been observed in affected individuals. Alterations in regulatory T cells (Tregs) and an increase in Th2 cells have also been reported, indicating an imbalance in immune regulation. These immune dysregulations may contribute to the chronic inflammation and tissue damage seen in the disease.
• Environmental factors: It may cause or aggravate IgG4-related diseases in individuals who are susceptible. However, no specific environmental factors have been clearly identified. Some studies have shown links between specific diseases, allergies, or environmental chemicals, but further study is required to determine a definitive connection.
• IgE-Mediated Reactions: IgG4-related disease may be caused by allergy or IgE-mediated reactions. Individuals who have IgG4-related disease may have elevated blood IgE level. This indicates a possible allergic component.
• Microbiome: The interaction of the gut microbiome to the immune system is connected to the autoimmune disease. While the importance of the microbiome in IgG4-related disease is not yet fully understood. Some research has shown a link.

Genetics

Prognostic Factors

IgG4-related disease prognosis differs and is impacted by many factors. It is necessary to highlight that IgG4-related disease is a heterogeneous disorder with a range of clinical symptoms and organ involvement. This makes it difficult to identify universally useful prognostic markers.

Below are a few factors that have been found to possibly alter the prognosis of IgG4-related disease:

Organ Involvement and Severity: The organs affected by IgG4-related disease and the severity of organ damage can influence the prognosis. A localized disease involving a single organ tends to have a better prognosis than systemic involvement with multiple organs. Severe organ damage, such as advanced fibrosis or organ dysfunction, may indicate a poorer prognosis.

Treatment Response: The response to treatment can be an important prognostic factor. Prompt initiation of appropriate therapy and a favorable response to treatment is associated with better outcomes. Individuals who achieve remission or significant improvement of symptoms and reduction in organ inflammation tend to have a more favorable prognosis.

Relapse: Recurrence or relapse of IgG4-related disease after initial treatment can impact the prognosis. Some individuals experience relapses of symptoms or disease activity despite their initial response to treatment. The frequency and severity of relapses can influence the long-term prognosis and may require adjustments to the treatment approach.

Serum IgG4 Levels: Serum IgG4 levels, although not universally predictive, have been studied as a potential prognostic marker. Some studies suggest that persistently elevated IgG4 levels, despite treatment, may be associated with a higher risk of disease relapse or a more chronic and refractory disease course. However, the utility of IgG4 levels as a prognostic marker is still under investigation.

Presence of Complications: The development of complications, such as organ failure, obstruction, or other serious sequelae, can impact the prognosis. Complications may require additional interventions, surgeries, or specialized management, which can affect the overall outcome.

Delayed Diagnosis and Treatment: Timely diagnosis and initiation of appropriate treatment are crucial for better outcomes in IgG4-related disease. Delayed diagnosis and treatment may lead to more extensive organ damage, irreversible fibrosis, and a potentially poorer prognosis.

Clinical History

Non-specific signs & symptoms

• Fatigue
• Fever
• Weight loss
• Malaise
• Night sweats
• Anemia
• Generalized pain
• Swollen lymph nodes

    Systemic signs & symptoms

• B symptoms
• Fatigue
• Allergic manifestations
• Systemic inflammation
• Organ dysfunction
• Neurological symptoms
• Respiratory symptoms

Age Group:

• Adolescents
• Young adults
• Middle-aged adults
• Elderly people

Physical Examination

The physical exam in the IgG4 related disease will assess and identify the specific results related to the involvement of the organ and systemic symptoms. The results may differ on the basis of affected organ by the disease.

General Appearance: The healthcare provider may assess the overall appearance of the individual, including their general well-being, level of distress, and signs of systemic symptoms such as fever, weight loss, or fatigue.

Organ-Specific Findings: The physical examination will focus on specific organs involved in IgG4-related disease. For example:

Pancreas: Abdominal examination may reveal tenderness, mass-like lesions, or signs of pancreatic dysfunction such as jaundice or steatorrhea (fatty stools).

Salivary Glands: The provider may palpate the salivary glands for enlargement, tenderness, or the presence of masses. They may also assess for dryness of the mouth or difficulty in opening the mouth thoroughly.

Lymph Nodes: Enlarged lymph nodes may be palpable in various body regions, including the neck, axilla, or groin. The characteristics of lymph nodes, such as size, consistency, and tenderness, will be assessed.

Eyes: Ophthalmologic exam may lead to results like bulging eyes, conjunctival injection and limited movement of the eye in the cases of involvement of orbit.

Kidneys: The healthcare provider may perform palpation and percussion of the abdomen to check the enlargement of the kidney or masses. Blood pressure and urinalysis is also performed to check the renal function.

Lungs: In instances with pulmonary involvement, the lungs may be examined for respiratory symptoms like irregular breath sounds or crackles.

Skin Findings: Some individuals with IgG4-related disease may have cutaneous manifestations, such as subcutaneous nodules or plaques. The skin examination may reveal palpable lesions, thickening, or other dermatological changes.

Joint Examination: Joint involvement, although rare, can occur in IgG4-related diseases. The healthcare provider may perform a joint examination to assess for swelling, tenderness, or limited range of motion.

Neurological Examination: In cases where IgG4-related disease affects the central nervous system or peripheral nerves, a neurological examination may be performed to assess for abnormalities in motor or sensory function, cranial nerve deficits, or other neurologic signs.

Age group

Associated comorbidity

Autoimmune disease

Allergic disorder

Sclerosing cholangitis

Lymphadenopathy

Ocular or renal involvement

Exposure to environmental factor

Associated activity

Acuity of presentation

The presentation of IgG4-related diseases varies throughout individuals. It is determined by the specific organs and degrees of inflammation. It may be acute or chronic, with gradual or fast development. Acute symptoms are more prevalent in organ systems like the pancreatic or salivary glands. Inflammation and swelling may lead to significant pain, jaundice, or trouble swallowing. Acute symptoms may occur when there is fast inflammation and edema of the affected organs.

Differential Diagnoses

Autoimmune pancreatitis

Eosinophilia

Hyper eosinophilic syndromes

Lymphadenopathy

Plasma cell neoplasm

Polyclonal hypergammaglobulinemia

Multicentric Castleman disease

Orbital disease

Salivary & lacrimal gland enlargement

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment of IgG4-related disease aims to control inflammation, relieve symptoms, and prevent organ damage or dysfunction. The approach to treatment may vary depending on the organs involved and the severity of the disease.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

the-aspects-of-the-treatment-paradigm-that-involve-modification-of-the-environment-for-igg4-rd

• Avoid triggers that exacerbate the symptoms of IgG4-related disease
Certain environmental factors or triggers may sometimes exacerbate IgG4-RD symptoms. Individuals with IgG4-RD must identify and avoid potential triggers that could worsen inflammation or lead to disease flares. Triggers, including stress, certain foods, or environmental allergens, may vary among individuals.
• Managing stress to subside IgG disease:
Stress can trigger immune responses and worsen inflammatory conditions. Stress management techniques such as mindfulness, meditation, yoga, and relaxation exercises may help cope with stress and potentially reduce disease flares.
• Modification of diet in disease management:
While there are no guidelines for IgG4-RD, some individuals find that specific dietary changes can help manage their symptoms. This could involve avoiding foods that trigger allergic reactions or exacerbate inflammation. However, individual responses to specific foods may vary, so working with a healthcare professional or registered dietitian is essential to develop a personalized diet plan.
• Avoidance of Tobacco and Environmental Toxins:
Smoking and exposure to environmental toxins can worsen inflammation and overall health. Avoiding tobacco and minimizing exposure to environmental toxins is beneficial for individuals with IgG4-RD.
• Regular Exercise:
Regular physical activity can improve overall health and well-being. Exercise can help manage stress, maintain a healthy weight, and promote cardiovascular health, which may positively impact IgG4-RD management.
• Optimize sleep cycle:
Adequate and restful sleep is crucial for immune function and overall health. Creating a sleep-friendly environment and establishing a consistent sleep schedule may help improve disease management.
• Supportive Environment:
A supportive environment and social network can contribute to better emotional well-being, which may positively influence disease management and coping with the challenges of living with a chronic condition.

The other pharmaceutical agents that should be given with therapeutic for bacterial sepsis include corticosteroids, immunosuppressive agents, and other immunomodulatory drugs.

Corticosteroids

Corticosteroids like prednisone or prednisolone are the main treatment of this disease. They are effective to reduce the inflammation and suppress the immune response. It is necessary to manage the symptoms and progression of the disease.

Azathioprine

Azathioprine is an immunosuppressive drug. It interferes with the production of the RNA and DNA in the cells. It is used as steroid sparing agent. It allows to reduce the dosage of corticosteroids. It is taken orally and needs to monitor regularly the blood counts and liver function.

Mycophenolate mofetil

Mycophenolate mofetil is another immunosuppressive agent that inhibits the production of DNA and RNA in cells. It is commonly used in organ transplantation but has also shown efficacy in treating IgG4-related diseases. Like azathioprine, mycophenolate mofetil is taken orally and requires regular monitoring.

Methotrexate

It is an immunosuppressive drug that interferes with the production of DNA and RNA and inhibits certain enzymes involved in the immune response. It is administered orally or by injection and is often used with corticosteroids for maintenance therapy in IgG4-related diseases.

Cyclophosphamide

Cyclophosphamide is a potent immunosuppressive agent that suppresses the immune system by interfering with the replication of cells. It is typically reserved for severe or refractory cases of IgG4-related disease, and its use requires careful monitoring due to potential side effects.

Interventions with procedures may be considered in some cases of IgG4-related disease, mainly when organ involvement, obstruction, or significant tissue damage. The specific procedure depends on the affected organ and the patient’s condition.

Hydronephrosis

In cases where partial obstruction of the urinary tract causes hydronephrosis, placing a ureteral stent can help restore the urine flow. The stent is a flexible tube inserted into the ureter to bypass the obstruction and allow urine to drain from the kidney to the bladder.

Organ compression by sclerosing mesenteritis

Surgical debulking is required in the patient with this kind of mesenteries.

Obstructive jaundice

Managing obstructive jaundice in the context of IgG4-related disease typically involves addressing both the underlying disease and the obstruction in the biliary system. The interventions are biliary stenting, balloon dilatation, medications, and surgery.

Aortic aneurysm & aortitis

In cases where aortic aneurysm and aortitis coexist in IgG4-related disease, the management approach may involve a combination of strategies aimed at both conditions. This may include monitoring aneurysm size, controlling inflammation with medications, and considering surgical intervention if the risk of rupture or dissection is high.

Compression by Riedel thyroiditis

When Riedel thyroiditis causes compression of structures in the neck, the management approach may involve addressing the underlying IgG4-related disease and the complications related to compression.

The management of IgG4-related disease can be divided into different phases involving different approaches and goals. The phases of management include:

• Diagnostic phase
• Induction phase
• Maintenance phase
• Relapse management
• Ongoing Monitoring and Follow-up

Medication

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References

https://www.ncbi.nlm.nih.gov/books/NBK499825/