First, I’ll relate a true story from at least 15 years ago. I was asked to see a middle aged male patient with fibrosing mesenteritis (who ever heard of this?) for slowly worsening renal function. I don’t remember what therapy he had tried. I think it was some combination of steroids and Tamoxifen. Colchicine may have been tried as well. The patient had been to Mayo Clinic (the FM capital of the world) for evaluation. Creatinine was in the mid 3’s. Urinalysis was bland. Urine protein excretion was ~ 1 gm/day. I tried unsuccessfully to get a kidney biopsy. GI said it wasn’t necessary. Insurance said they wouldn’t pay for it. Sigh…… The patient went home with scheduled followup. He didn’t show up. A few weeks later, I was called late Friday afternoon by GI saying his kidney function was much worse. I gave the option of an ER visit or an office visit on Monday. He didn’t show up. Attempted phone contact was unsuccessful. Several weeks after this, I received a frantic call from a nephrologist in a remote place, saying this patient I had seen previously was there needing dialysis. That’s the last I heard of this particular patient. So…. what did this patient have? Fast forward to the ASN National meeting several months later. I was sitting innocently listening to a general session, when the nephrology group from Mayo Clinic described IgG4 interstitial renal disease associated with multiple fibrosing lesions elsewhere in the body. OMG …. talk about an AHA moment. It was clear this patient had IgG4 disease all along, and I had never heard of it. What’s more, I really wondered if the patient’s renal deterioration could have been prevented by appropriate therapy (whatever that is).
IgG4 disease was initially formally described by Kamisawa in a 2003 Journal of Gastroenterology article. Autoimmune pancreatitis had been well recognized in the GI world for at least 2 decades previously This was the first time that severe or moderate infiltration of IgG4-positive plasma cells associated with CD4 or CD8 positive T lymphocytes were seen in multiple other organs in patients with autoimmune pancreatitis. These results suggest that autoimmune pancreatitis is not simply pancreatitis, but that it is a pancreatic lesion involved in IgG4-related systemic disease with extensive organ involvement. They proposed a new clinicopathological entity, of a systemic IgG4-related autoimmune disease in which autoimmune pancreatitis and its associated diseases might be involved. Since that time, innumerable articles have been written about IgG4 disease. Two reasonable references include Stone 2012 NEJM and 2015 Mayo Clinic Proceedings. Formal criteria for diagnosis was given,including immunohistochemical staining. An extensive review of different organ involvement was presented.
The first nephrology reference was written by Raissian in a 2011 JASN article. I included it for your interest.
But wait…… is this really a new disease? I ran into this 1963 NEJM article by Bartholomew describing sclerosing cholangitis, Riedel’s thyroiditis, and fibrous retroperitonitis with ureteral obstruction. Sound familiar? No biopsy results were published.Yep, IgG4 disease was present and described 40 years before the “original” Kamisawa JG article. Even better, there were 2 references in that paper from Hache in 1961-1962 describing fibrous mediastinitis and retroperitontis. Unfortunately, I couldn’t access those old articles. One was a thesis from the University of Minnesota. I’ll bet the professors didn’t appreciate the wisdom of a mere PhD candidate.
A thorough review of sclerosing mesenteritis was reported by Akram (Mayo Clinic) in 2007 Clinical Gastroenterology and Hepatology. Interestingly, there was no mention of IgG4. Sclerosing Mesenteritis was described as a relatively benign condition, but it can lead to a prolonged debilitating course with a fatal outcome. These results suggest that symptomatic patients might benefit from medical therapy, particularly tamoxifen and prednisone combination treatment. However, only about half of the patients had any therapy at all.
The association of sclerosing mesenteritis with IgG4 is now well established. A recent review was authored by Lee in a 2016 Journal of Pathology and Translational Medicine. While not all patients with fibrosing mesenteritis have IgG4 disease, many do. The histologic features of IgG4 sclerosing mesenteritis include more than two of the following: lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The immunologic criterion is IgG4-positive/IgG total plasma cells > 40%, but this ratio is also considered in importance to the histological appearance.
This has been quite a ride for me. I hope you found it intriguing.
References: [1] [2] [3] [4] [5]
Nephrology Fellowship 