We present the case of a 16 year old girl who developed an aggressive colitis in the context of a prior biopsy proven autoimmune pancreatitis, which presented with obstructive jaundice at the age of 13 year. This history prompted prospective investigation and the discovery of compelling evidence to make a diagnosis of IgG4-related sclerosing disease with extra-pancreatic colonic involvement on the basis of raised serum IgG4 levels and a florid colonic IgG4 plasma cell infiltrate with over 20 IgG4 positive plasma cells/hpf. The colitis was resistant to conventional therapy but responded dramatically to treatment with the anti-TNFα monoclonal antibody, adalimumab. This is the first case to report both the effectiveness of adalimumab in treating IgG4 positive colitis in a patient with IgG4-related sclerosing disease, and to prospectively record resolution of an IgG4 positive colonic infiltrate with immunosuppression.
There is accumulating evidence that autoimmune pancreatitis (AIP) is one clinical manifestation of a wider multisystem inflammatory disorder that has been termed IgG4-related sclerosing disease.1 Patients typically present with jaundice or a mass in the pancreas in association with variable extra-pancreatic involvement, although pancreatic involvement is not universal and is not required in order to make a diagnosis of IgG4-related sclerosing disease. The biliary tract, liver, retroperitoneum, and salivary glands are the most classically affected extrapancreatic organs, though IgG4 positive infiltrates have now been found in many other organs including the kidney, eye, lungs, and colon.2 AIP usually responds quickly to steroid treatment, although less is known about extrapancreatic disease.
An association between pancreatitis and inflammatory bowel disease (IBD) is widely accepted in the literature and this has predominantly been attributed to drugs or gallstones with rare cases that have been termed idiopathic pancreatitis.3 However, there is now increasing evidence for IgG4-related sclerosing disease as a potential link between AIP and IBD.3–7 In a recent study from the Mayo clinic 4/71 (5.6%) patients with AIP had concurrent IBD (3 Ulcerative Colitis, 1 Crohn's Disease).4 In two of these cases colonic tissue was available for retrospective IgG4 staining, one of which revealed over 10 IgG4-positive plasma cells/hpf, which is considered diagnostic of IgG4-related sclerosing disease. This raises the strong possibility that in some cases of colitis with concurrent AIP, the colitis is an extra-pancreatic manifestation of IgG4-related sclerosing disease rather than classical IBD.
We report a unique case of IgG4-positive pancolitis developing in a patient with IgG4-related sclerosing disease that did not respond to conventional maintenance treatment, though ultimately responded dramatically to adalimumab with resolution of the colonic inflammatory cell infiltrate.
A 16 year old girl was referred to our unit with a six week history of new onset bloody diarrhoea. Stool cultures were negative and endoscopy demonstrated severe continuous pancolitis. She had a past medical history of an acute presentation at the age of 13 with obstructive jaundice due to a mass in the head of the pancreas (Fig. 1). The mass was biopsied revealing a benign inflammatory infiltrate, and she went on to have her common bile duct stented at endoscopic retrograde cholangio-pancreatography (ERCP) at which time mild changes of cholangiopathy were also noted. A diagnosis of inflammatory pseudotumour was made, and she was treated with oral prednisolone, with prompt and complete resolution of the mass. The biliary stent was removed three months later.
The new presentation of colitis taken in conjunction with her past medical history of a pancreatic pseudo-tumour prompted us to investigate the possibility of IgG4-related sclerosing disease as a unifying diagnosis. Serum IgG4 levels at the time of her presentation with colitis which were found to be elevated at 210 mg/dl (normal < 140 mg/dl), and immunohistochemical staining of her colonic biopsies revealed a florid IgG4-positive plasma cell infiltrate with 20–30 IgG4 + vecells/hpf in all samples taken from throughout the colon (Fig. 2). We subsequently obtained and stained the pancreatic biopsy tissue which again contained numerous IgG4-positive plasma cells consistent with IgG4 sclerosing disease.
She initially responded well to oral prednisolone (0.5 mg/kg/day) and Pentasa 2 g BD though her symptoms recurred on steroid tapering. Azathioprine was therefore started at a dose of 2.5 mg/kg/day and her prednisolone increased with initial response. However on steroid tapering her disease again flared and she was admitted for further treatment of acute severe colitis. After failing to respond adequately to three days of IV hydrocortisone she was commenced on intravenous infliximab 5 mg/kg as rescue therapy. Following this there was an initial rapid clinical improvement and she was discharged from hospital 48 hrs later.
She was in clinical remission at the time of her second infusion two weeks later, but following this her symptoms gradually started to recur. She received her third infusion at six weeks, with no demonstrable benefit. Following considerable discussion she was then treated with adalimumab at an induction dose of 160/80 mg followed by 40 mg weekly with a dramatic and sustained response. At three months her flexible sigmoidoscopy was repeated which revealed complete mucosal healing with histological resolution of the IgG4 infiltrate. Her adalimumab was reduced to 40 mg alternate weeks, and twenty months later she remains in complete clinical and endoscopic remission.
IgG4-related sclerosing disease is now recognised as a multisystem inflammatory disorder characterised by an IgG4-positive plasma cell infiltrate in affected organs.1 AIP is the most widely recognised clinical manifestation of IgG4-related sclerosing disease and has been subdivided into two major subtypes depending on histology.5,6 Type I, is associated with lymphoplasmacytic sclerosing pancreatitis (LPSP) with raised serum IgG4 levels, and commonly affects other organs including the bile duct, retroperitoneum, kidney, lymph nodes, and salivary glands. Type II is associated with idiopathic duct-centric pancreatitis (IDCP), characterised by granulocytic epithelial lesions (GELs) and is associated with a florid neutrophilic infiltrate, fewer IgG4-positive cells and rarely demonstrates raised serum IgG4 levels. Type I/LPSP typically presents in elderly men and is associated with obstructive jaundice, whereas type II/IDCP presents in a younger age group, without a male preponderance, and is more likely to be associated with inflammatory bowel disease (16% vs 1%). Although this classification is currently in use, it remains controversial. At the 2010 Honolulu consensus on histopathological and clinical subtypes of AIP, it has been suggested that type II may not be a true IgG4-related disease due to the paucity of IgG4 infiltrates in pancreatic histology and the limited rise in serum IgG4 levels.5
This case may be considered type I due to the suggestive pancreatic biopsy and the raised serum IgG4 levels, but is demographically atypical due to the age and sex of the patient. Inflammatory bowel disease (IBD) as an associated condition is also usually reported with type II rather than type I AIP. However, in this case we feel a compelling argument can be made to consider the IgG4 colitis as a specific extra-intestinal manifestation of the disease, rather than an associated autoimmune condition.
The occurrence of IBD in association with AIP has most commonly been reported in the Western literature. In a retrospective series of 53 cases of AIP, Zamboni et al. found 6 (11.3%) cases of IBD, a significantly higher incidence than the general population.7 In addition in a large series from the Mayo clinic 4/71 (5.6%) patients had concurrent IBD (3 Ulcerative Colitis, 1 Crohn's Disease).4 Importantly, they were also retrospectively able to demonstrate a florid colonic IgG4 infiltrate in one patient. IBD in association with AIP appears less commonly in the Japanese literature, though in a study from Tokyo 1/6 patients with AIP under the age of 40 years had co-existing UC in contrast to 0/58 aged over 40 years.1 A further case from Japan has reported AIP occurring in a young man 18 months after he underwent a total colectomy for acute severe colitis.8 Ulcerative colitis has also been reported in association with IgG4 sclerosing cholangitis in two HLA identical siblings.9
The specificity and pathological significance of both raised serum IgG4 levels and an IgG4 plasma cell infiltrate in the colon remains unclear. Though serum immunoglobulin subclasses in inflammatory bowel disease have not been the subject of recent research, previous studies have shown that serum levels of IgG1 are significantly higher in UC than in normal subjects, whereas CD patients have normal levels of IgG1. In contrast serum IgG2 levels are elevated in patients with CD, while UC patients show similar levels to normal controls. Serum IgG3 and IgG4 levels are not altered in UC or CD compared with normal controls.10,11 Likewise, the relative frequency of IgG subclass in inflamed colonic tissue is not well characterised and its relevance and specificity is unknown. In this case the frequency of IgG4 cells in the inflammatory infiltrate of 20-30/hpf are considerably more than we have identified in staining of other UC cases (unpublished) and are comfortably above the diagnostic threshold suggested for IgG4 sclerosing disease. However, there is some evidence than an IgG4 infiltrate may be found in IBD as a non-specific consequence of the inflammatory response. Though, the current literature in this area is sparse, in one small study of patients with IBD published in abstract form, the number of IgG4 cells per high powered field has been used as a tool to differentiate UC from Crohn's colitis, with a higher yield of IgG4 + ve cells found in UC than in CD (10.6 vs. 2.1/hpf). In this study there also appeared to be a correlation between the presence of IgG4 positive cells and the histological degree of inflammation,12 though levels were considerably less than found in this case, or usually reported in cases of type I AIP. The presence of an IgG4 infiltrate has also been recently been evaluated in patients with AIP and patients with IBD.13 As would be expected IgG4 cells were more numerous in the colon of IBD patients than patients with type I AIP without colonic inflammation. In the four patients in the study with type II AIP and associated IBD, there was no significant difference between IgG4 infiltrates and those with IBD alone. However, it should be noted these were patients with type II AIP and as such may well be a different pathological entity to our case, which is more in keeping with type I AIP.
Overall, we feel the current balance of evidence suggests that the raised serum IgG4 levels and the florid colonic IgG4 infiltrate in this case are a consequence of systemic IgG4 sclerosing disease rather than a non-specific inflammatory response, and therefore the colitis in this case reflects an extrapancreatic manifestation of IgG4 sclerosing disease rather than a separate associated autoimmune condition.
The possible pathological role of IgG4-positive cells in the colon of patients with biopsy proven AIP remains speculative and controversial. In the only current published mechanistic study, Akitake et al. reported a case of IgG4-related sclerosing disease in which the colon revealed a marked infiltrate of IgG4 positive plasma cells in the absence of inflammation.14 Peripheral blood mononuclear cells (PBMCs) isolated from the patient produced large quantities of IL-10 and IgG4 in response to TL4 and TLR 5 stimulation. In contrast production of the Th1 cytokines IFNγ and TNFα were impaired. This provides a potential mechanistic pathway whereby an excessive Th2 response to microbial antigens causes lymphocytic infiltration as in IBD, and the production of an enhanced IgG4 response through IL-10 driven immunoglobulin class switching.
There is some evidence that, in addition to the immunological differences, the clinical course of IgG4 associated colitis may be more aggressive than classical ulcerative colitis. It is of particular interest that in three out of the four reported cases of UC in association with AIP the outcome has been Colectomy.4 Our case would also have followed this pattern with the exception of the sustained response to adalimumab that has prevented her from undergoing colectomy to date. This colectomy rate is considerably higher than would be expected with classical IBD colitis and suggests that colitis in association with AIP may run a more aggressive. We therefore propose a high index of suspicion for IgG4-related disease in any patient with colitis in association with a history of pancreatitis, and if conventional therapy fails, anti-TNFα therapy may be an effective rescue treatment.
Conflict of Interest Statement
There are no financial conflicts of interests.