IgG4-Related Disease (IgG4-RD)

The disease was recognized first in Japan, when investigators realized that patients with “sclerosing pancreatitis”, now known as autoimmune pancreatitis, had elevated blood levels of IgG4. Many patients with sclerosing pancreatitis also had disease in other organs, such as the bile ducts, orbits (the area surrounding the eyes), the lungs, kidneys, retroperitoneum (abdominal cavity), and others. Following the recognition that autoimmune pancreatitis often has other disease associations, it became clear that the disease now known as IgG4-RD unifies many conditions once regarded as single organ diseases.

Some patients with IgG4-RD have disease in only one organ. Others, however, have disease that affects multiple organs at the same time. It is not unusual for disease to affect anywhere between two and six organs, and sometimes more, in a single patient.

The following organs, listed from head to toe, are often involved in IgG4-RD:

Meninges – The layer of tissues surrounding the brain and spinal cord

Orbits – Also known as the eye sockets, are the muscles that attach to the sides of the eye and move the eye

Lacrimal glands – The glands on the upper outer portion of the eyes that produce tears

Major salivary glands – The parotid, submandibular and sublingual glands produce saliva to aid in the digestion of food

Thyroid gland – The thyroid gland produces a hormone that is important in the regulation of normal body metabolism

Lungs – Tissues of the airways and the lung tissue itself may be involved by a wide array of lesions

Aorta – The aorta, the body’s largest blood vessel, can be affected by IgG4-RD in causing a large-vessel vasculitis (inflammation in the blood vessel wall) or inflammation surrounding the aorta, sometimes involving contiguous structures

Kidneys – Both the kidneys themselves and the ureters–the organs through which they pass urine into the bladder–can be affected

Pancreas – The pancreas has both an endocrine function (makes insulin, which mediates normal blood glucose control) and an exocrine function (produces digestive enzymes, critical for the digestion of some foods, particularly fats and proteins). Both the endocrine and the exocrine roles of the pancreas may be affected by IgG4-RD

Bile ducts – The bile ducts are located both within and outside the liver. They are the channel through which the liver, gallbladder and pancreas provide digestive enzymes and bile to the gastrointestinal tract, aiding in normal metabolism of nutrients.

Because of the many organs that IgG4-RD can affect, the disease can exist in multiple ways associated with many symptoms. A couple of important themes occur, however:

• IgG4-RD often presents as a mass that mimics a cancer. Many patients, unfortunately, have undergone surgery to remove what was thought to be a tumor, only to learn that their true diagnosis is IgG4-RD.
• IgG4-RD is often associated with allergic symptoms (e.g., asthma, allergic rhinitis, eczema, etc.) that are not linked to IgG4-RD for years because these symptoms are so common in the general population.

IgG4-RD typically has a subacute onset, meaning many patients have had active disease with no signs or symptoms for months or even years before the diagnosis is made. The result of this subacute onset is that organ damage often occurs even while the patient is feeling well, long before he or she comes to medical attention.

Patients often feel well for long periods of time despite having disease in multiple organs. Fevers are rare to non-existent in IgG4-RD. Fatigue is often a common symptom, but because fatigue can be a common symptom for many conditions, patients often endure this symptom for long periods of time without a diagnosis. Weight loss can be a prominent component of how IgG4-RD presents. The loss of anywhere between ten and fifty pounds in IgG4-RD is often because of subclinical pancreatic dysfunction. The damaged pancreas is no longer making the appropriate amount of digestive enzymes. As a result, patients do not absorb nutrients and calories from their food and often experience extreme weight loss that defies diagnosis for an extended period of time.

To a large extent, the patient’s symptoms are dictated by the type of organ affected. The most common symptoms below are grouped according to organ:

Meninges – Patients with IgG4-RD affecting the meninges often present with headaches or dysfunction of the cranial nerves, which control eye movements, speech, swallowing, hearing, and other critical functions.

Orbits – Patients with IgG4-RD affecting the orbits, particularly the extraocular muscles (muscles controlling eyeball), frequently develop a prominence (bulging) of one or both eyes known as “proptosis”. Some patients also develop double vision and the inability to move their eyes together in a coordinated fashion because of tethering of the extra-ocular muscles.

Lacrimal glands – The lacrimal glands typically become enlarged. While they are normally not visible in healthy people, in patients with IgG4-related dacryoadenitis (lacrimal gland disease), the glands may bulge noticeably under the eyelids.

Major salivary glands – The parotid, submandibular and sublingual glands, like the lacrimal glands, often expand substantially in size, causing noticeable bulges on the sides of the face or below the chin. The overall production of saliva is also often affected, leading to symptoms of a dry mouth.

Thyroid gland – The main appearance of IgG4-RD in the thyroid gland is a non-cancerous, yet tumorous enlargement of the gland known as Riedel’s thyroiditis (“Ree duls”). Inflammation within the thyroid gland can extend through the thyroid capsule and into surrounding tissues, particularly the airway. This can sometimes lead to airway compromise, requiring major surgery to remove the invasive inflammatory tissue that originated in the thyroid.

Lungs – Patients can have symptoms of allergy and shortness of breath. The radiology features of IgG4-RD in the lung are extremely diverse and can mimic many other disorders. The lining of the chest wall, the pleura, can also be affected by IgG4-RD.

Aorta – Aortic lesions can be silent for long periods of time, until complications develop. In the thoracic aorta (small branches that supply blood to the ribs and chest), the vessel wall grows thick because of internal inflammation. The presence of IgG4-RD is occasionally detected at surgery for an aortic aneurysm. In the abdomen, inflammation caused by IgG4-RD tends to affect around the aorta, rather than involve it directly. A peri-aortic inflammation can trap nearby structures, such as the ureters (the channel urine passes from kidney to bladder), leading to the blockage of urine flow from the kidney, which is a condition known as “hydronephrosis”.

Kidneys – Kidney lesions, like those of the aorta, can also be clinically silent until advanced damage has occurred. Signs of early kidney injury, however, can be detected on routine blood tests. The kidneys often become enlarged when affected by IgG4-RD, and renal cell carcinoma (a primary kidney cancer) is occasionally misdiagnosed.

Pancreas – The classic presentation of IgG4-RD in the pancreas is painless jaundice (yellowing of the skin) that develops because inflammation in the head of the pancreas blocks the flow of bile through the common bile duct. These patients are typically mistaken early on for having pancreatic cancer. Patients with IgG4-related autoimmune pancreatitis often have abdominal pain that ranges from severe (less common) to mild or even barely noticeable. Exocrine failure of the pancreas, as noted, can lead to substantial weight loss. Endocrine failure of the pancreas can lead to diabetes mellitus.

Bile ducts – Patients with bile duct lesions also often present with painless jaundice and are often felt likely to have cholangiocarcinoma: a tumor of the bile ducts.

The diagnosis of IgG4-RD generally requires piecing together clues from several areas:

• Clinical findings
• Serological data
• Radiology studies
• Pathology results

Clinical findings, such as the presence of simultaneous enlargement in the lacrimal, parotid, and submandibular glands, can be a major tip-off to the presence of IgG4-RD. Another major clue to IgG4-RD is the finding of an elevated serum IgG4 concentration. Some patients have levels of IgG4 in their blood that are twenty or thirty times higher than the upper limit of normal. In a significant minority of patients, however, the serum IgG4 concentration is normal. Certain radiology features, such as the finding of a “sausage-shaped pancreas”, also strongly suggest this condition. And biopsies of involved organs are generally required to clinch the diagnosis and also to exclude important disease mimickers such as cancer. It is important for the physician to integrate information from the clinical, serological, radiology, and pathology realms in order to establish the correct diagnosis.

If diagnosed before serious organ damage has occurred, IgG4-RD typically responds well to treatment but chronic therapy and the attempts to avoid side-effects of treatment, particularly glucocorticoids, remain the rule. Glucocorticoids are typically viewed as the initial treatment of IgG4-RD, but the shortcomings of this treatment approach are widely appreciated. Although nearly all patients with IgG4-RD respond to glucocorticoids, approximately 40% of those fail to achieve complete remission or relapse within one year, even if glucocorticoids are continued at a minimum of 5 mg/day. The disease often recurs after prednisone tapering, as well.

The role of conventional DMARDs in IgG4-RD is not clear, and much evidence suggests that the impact of these drugs in the absence of prednisone is small. Rituximab, however, is frequently an excellent treatment for IgG4-RD and it is not typically associated with many of the adverse effects linked to glucocorticoids. Other treatment strategies are now being developed based on the large amount of information learned in recent years about the pathophysiology of IgG4-RD.

Patients with IgG4-RD need to ensure that they have close follow-up with physicians who are knowledgeable about IgG4-RD. They also need to broaden their own knowledge of this condition and be attuned to the kinds of symptoms and complications that can result from disease in the organs that IgG4-RD is known to affect. Finally, they must be aware of potential complications of treatment and be alert to the possibility of disease recurrence.

The rheumatologist should play a leading role in the diagnosis, management and treatment of all patients with IgG4-RD. Rheumatologists are expert in the assessment of multi-organ diseases and often have a broader approach to systemic illnesses than specialists who focus on single organs. Rheumatologists are also comfortable in the integration of information from the clinical, serological, radiological and pathology domains to arrive at diagnoses and to use this information in a longitudinal manner when managing patients. Finally, rheumatologists have the requisite expertise in the use of immunosuppressive medications, particularly prednisone and rituximab, that are essential in the treatment of IgG4-RD.