IgG4ward! Good Question Series: RPF Fireside Chat Follow-Up – Your Questions Answered

B cell depletion is usually tolerated very well, any many patients tolerate being on these therapies well for years (i.e., indefinitely) if they are managed properly. Many patients with IgG4-RD do not need to be treated every six months with B cell depletion, and certainly every four months is generally too frequent. The MITIGATE trial of inebilizumab used a treatment regimen of every six months.

Even every six months, however, is more than many – and probably most – patients need. Overtreatment with B cell depletion raises the risk of adverse effects, particularly “hypogammaglobulinemia” (low serum antibody levels). It is best, therefore, to time re-treatments for when patients actually need treatment again. Many patients will require re-treatment far less frequently than every six months. Intervals of 9 months, 12 months, 18 months, 24 months, or longer are not uncommon. To some extent, every patient is different with regard to the frequency of B cell depletion required to control their IgG4-RD and retroperitoneal fibrosis.

There are two main ways to gauge the optimal interval for re-treatment with B cell depletion:

Blood tests. The serum IgG4 level is useful in many patients. When the serum IgG4 level is rising consistently, it is likely time to re-treat.

Imaging. For patients in whom IgG4 levels do not seem to rise and fall with disease activity and treatment, imaging studies that show signs of renewed disease activity in affected organs may be the best approach scheduling repeat infusions.

It is wonderful that your disease process is nearly 8 years old and that the condition has been controlled effectively with B cell depletion. It is also wonderful that cancer was excluded early on with a biopsy.

At this point, it is probably neither possible nor necessary to seek a “definitive” diagnosis, which could probably be accomplished in only two ways:

• Re-biopsy of the retroperitoneal mass (if it is even still present).

• Recognition and biopsy of disease is a different organ (which we hope doesn’t happen).

Right now, it seems reasonable to be content with the knowledge that your disease, which is probably IgG4-related retroperitoneal fibrosis, has responded well to treatment and does not need further diagnostic evaluation. But it does need regular follow-up on some schedule and probably periodic re-imaging (CT, MRI, or other) to make sure that the process stays quiet.

The short answer is “no, not right now”. The longer answer is that we already have treatments that are very effective for IgG4-RD and IgG4-related RPF, and one therapy (inebilizumab) that has been approved by regulatory authorities in the U.S., with approvals in other countries likely soon. If these therapies are employed wisely, patients can have long periods of remission during which they are disease free and able to live normal lives.

The diagnostic and management approach that your doctors have taken appears to us to be perfect.

In the overall scenario that you describe, the chance that this is IgG4-related RPF seems quite high. The prednisone dose, which is appropriate, may indeed help ensure that the stent placement is successful by reducing some of the inflammation around the ureter. We typically favor moving directly to B cell depletion once the diagnostic evaluation is as complete as it can be and the diagnosis of IgG4-RD seems certain or likely. Once B cell depletion treatment has been given, we would hope that the prednisone can be discontinued fairly quickly – within a few weeks.

You are right, and this is exactly what we often do. If there is an area of the RPF that can be biopsied with relatively low risk, then it is almost always a good idea to try a biopsy. For reasons that we discussed on the Fireside Chat, though, biopsy is not always possible. In such settings, “empiric” therapy is often required: treatment based on an educated guess that the most likely diagnosis if IgG4-RD.

The serum IgG4 levels are often but not always normal or only mildly elevated in IgG4-related RPF, so sometimes this blood test doesn’t help very much in confirming the diagnosis.

CT scanning can sometimes give a hint of disease activity if there is uptake by the RPF are following the administration of intravenous contrast. But the best way to determine if the RPF is active is frequently through the performance of a PET scan (or a PET/CT scan, i.e., both studies together). A PET scan permits the assessment for increased metabolic activity, which if present usually corresponds to active inflammation.

The pace of the disease is very different from patient to patient. However, we would anticipate being able to see clearcut radiologic changes as early as 2-3 months if the process is active.

The only medication approved by regulatory agencies right now is inebilizumab (Uplizna), which targets CD19, a protein on the surface of the B lymphocyte. By targeting CD19, inebilizumab leads to the depletion of circulating B cells (i.e., it is an approach to “B cell depletion”, a term that you will see in writings about IgG4-RD. Inebilizumab works very well for the treatment of IgG4-RD, as demonstrated by the MITIGATE trial, a worldwide randomized trial.

Rituximab is an older approach to B cell depletion that is not quite a “cutting-edge” in its design. Rituximab targets a different protein – CD20 rather than CD19. In contrast to inebilizumab, rituximab is not a fully “humanized” antibody. Specifically, rituximab is made partly from amino acids derived from mice. For this reason, rituximab is probably more likely to be associated with infusion reactions and other potential side-effects. All other things being equal, inebilizumab is the preferred approach to B cell depletion when treating IgG4-RD.

Limited data suggest to date that RPF, like some other complications of IgG4-RD, is more common in men than in women. The reason for this is not entirely clear at the present time. But it is abundantly clear that women ALSO get IgG4-related RPF, even in numbers that are perhaps a little bit smaller than in men. It is not clear that RPF is any less severe in women than in men, and the same treatment considerations apply to patients of all sexes.

Short answer: NO.

Goodpasture’s syndrome, a dramatic condition that often afflicts both the kidneys and the lungs with inflammation that can lead rapidly to kidney failure and lung hemorrhage, is NOT associated with IgG4-RD. As far as we know, any simultaneous occurrence between these two disorders is likely the product of bad luck more than a sharing of large numbers of the same risk factors.

IgG4-RD RPF affecting the ureters most commonly presents with flank pains going down to the groin. This can also sometimes include testicular pain and even retrograde ejaculation. There is no obvious association with testicular cysts however. The symptoms associated with an enlarged prostate are a little different, usually including urinary frequency, urgency and incomplete bladder voidance, often involving having to go to pee again shortly after having already passed urine. The quickest imaging test to determine if the ureters are blocked is a renal tract ultrasound but for better detail, an abdominal and pelvic MRI or CT scan is required.

TIN does not really have any symptoms to warn the person early, but sometimes inflamed lumps can appear in the kidney in IgG4RD TIN and these can cause flank / back pains. Usually, the earliest sign of tubulointerstitial nephritis (TIN) is a consistent rise in serum creatinine concentration (with a blood test). Urine dipstick analysis is useful to help exclude other kidney problems in tubulointerstitial nephritis; urine dipstick can be sometimes be clear, but more commonly have a little bit of detectable red blood cells and protein. Tubulointerstitial nephritis can only be diagnosed with a kidney biopsy and so if the serum creatinine concentration is rising with no other obvious cause, (a renal tract ultrasound would be necessary to ensure that urine is flowing normally) than your nephrologist would be considering whether to proceed to a kidney biopsy.

SIADH in the context of IgG4 related disease is usually due to the gland in your brain, the pituitary gland, being inflamed. This leads to increased secretion of ADH and your kidneys start to reabsorb too much water causing fluid retention. IgG4 related TIN does not normally associate with SIADH despite directly inflaming the tubules in your kidney. TIN usually presents with elevated serum creatinine concentration often, evidence of blood and small amounts of protein in the urine - a kidney biopsy is required to diagnose TIN. It would be incredibly rare to have both pituitary AND kidney TIN as part of an IgG4RD pattern but still possible nonetheless