Type 1 AIP
Clinical Features
Since type 1 AIP is the pancreatic manifestation of IgG4-RD, a multiorgan disorder, it has a variety of clinical presentations which can be divided into pancreatic and extrapancreatic manifestations (figure 1). Since AIP has been followed long term, it has become clear that its clinical and imaging profile changes over time. Therefore, pancreatic manifestation of type 1 AIP can be further divided into active and late phase presentations. The most common clinical presentation in the active phase of type 1 AIP is painless obstructive jaundice, whereas features suggestive of acute pancreatitis (abdominal pain and elevation of serum pancreatic enzymes greater than three times upper limit of normal) are more often observed in type 2 AIP. It may also present as a pancreatic mass or less commonly with steatorrhoea. Patients who present late in the course of the disease after multiple relapses or those in whom the initial presentation was undiagnosed or misdiagnosed may show pancreatic parenchymal atrophy associated with stones/calcifications, similar to features of advanced ordinary chronic pancreatitis. Functional impairment with endocrine and exocrine failure leading to diabetes and steatorrhoea, respectively, is also common in late stages of disease.
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Figure 1.
Clinical presentation of type 1 autoimmune pancreatitis (AIP) as IgG4-related disease.
A characteristic feature of type 1 AIP is extrapancreatic OOI, a reflection of it being the pancreatic manifestation of IgG4-RD. IgG4-RD is characterised by an IgG4-rich lymphoplasmacytic infiltrate in the affected organs including the biliary tree, salivary/lacrimal glands, retroperitoneum, kidney, lung, lymph nodes, prostate, aorta, pericardium and pituitary gland (figures 1 and 2). OOI in type 1 AIP may precede the diagnosis of AIP, be present concurrently, or develop metachronously over months to years after diagnosis of AIP.
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Figure 2.
Spectrum of other organ involvement of type 1 autoimmune pancreatitis. (A) Magnetic resonance cholangiopancreatography shows a long-segment stricture (arrowheads) of the main pancreatic duct associated with hilar bile duct strictures. (B) Retroperitoneal fibrosis (arrow). (C) Physical examination reveals bilateral enlargement (circles) of the submandibular salivary glands. (D) Multiple round or wedge-shaped renal mass (arrows).
Diagnosis and Differential Diagnosis: International Consensus Diagnostic Criteria
Many diagnostic criteria for AIP have been published (Table 1). The diversity of diagnostic criteria for AIP from individual countries may reflect differences in practice patterns in the use of various tests and local expertise. Whereas Asian diagnostic criteria have focused on type 1 AIP, American and Italian diagnostic criteria may pertain to both subtypes. Recently, the ICDC for AIP have been proposed because of the need to diagnose AIP regardless of practice patterns in the use of various tests and to incorporate differentiation of the two subtypes of AIP.
The ICDC use the combination of five cardinal features of AIP: pancreatic imaging (parenchyma and duct), serology, OOI, histology and immunostaining, and steroid responsiveness. The first four features are graded into levels 1 and 2 depending on their strength of association with type 1 AIP —for example, serology level 1, IgG4 level >2 times upper limit of normal; serology level 2, ≤2-fold elevation of serum IgG4. Different diagnostic criteria are used for the two AIP subtypes, and even in type 1 AIP the diagnostic criteria differ based on CT features (typical vs indeterminate). In patients with typical CT imaging for AIP, if there is supporting evidence from serology (elevation of serum IgG4 level) or OOI, definitive diagnosis of type 1 AIP can be made without the need for endoscopic retrograde pancreatography (ERP).
In the ICDC, total serum IgG level or autoantibodies such as antinuclear antibody or rheumatoid factor are not included as serological criteria because of their low specificities. Because pancreatic cancer is far more common than AIP, maintaining high specificity of diagnostic criteria is more important than increasing sensitivity. In the ICDC, the performance of diagnostic ERP is not mandatory, and pancreatographic findings assume the role of collateral evidence when CT features are not typical or in seronegative patients without OOI. It is clear that ~30% of patients with AIP cannot be diagnosed simply on the basis of CT features, serology and OOI, and will require a pancreatic core biopsy to look for unique histological and immunohistological characteristics. In this setting, diagnostic ERP is reserved for patients who have inconclusive results on core biopsy or in whom core biopsy is not feasible. The key ERP findings highly suggestive of AIP include (i) a long stricture involving more than one-third of the duct length, (ii) lack of upstream duct dilatation from the stricture, and (iii) multifocal strictures. In the ICDC, endoscopic retrograde cholangiopancreatography has multiple roles in the diagnosis of AIP, such as providing a direct pancreatogram and guiding bile duct/ampulla biopsy with IgG4 immunostaining, in addition to relieving biliary obstruction.
Although type 1 AIP, as a pancreatic manifestation of IgG4-RD, can involve virtually any organ in the body, the ICDC restrict the radiological/physical evidence of OOI only to proximal bile duct stricture (figure 2A), retroperitoneal fibrosis (figure 2B), symmetrically enlarged salivary glands (figure 2C) and renal involvement (figure 2D). This is because the imaging features of extrapancreatic organ involvement (eg, lymph node, lung) may be non-specific and do not permit reliable distinction between AIP and pancreatic cancer.
The use of a steroid trial to 'diagnose' AIP is included in the ICDC. A steroid trial to diagnose AIP involves use of prednisolone with reassessment of imaging after 2 weeks of steroid trial. Subjects with indeterminate CT features should first be investigated for pancreatic cancer, and a steroid trial should be considered only if work-up for cancer including endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is negative.
In patients without collateral evidence, the diagnosis of AIP can be challenging, and pancreatic histology is required for definitive diagnosis. However, histopathology is often not available in the diagnostic workup of a patient with suspected AIP. Transcutaneous core biopsies should be avoided if malignancy cannot be excluded. EUS-guided biopsy is an option, but the more widely available EUS-FNA is usually not suitable for histological diagnosis. EUS-guided core biopsy would be a solution, allowing tissue specimens to be obtained for histological and immunohistochemical analysis of stromal, inflammatory and parenchymal tissue components, but it is not yet widely available, and it may not be feasible to access all areas in the pancreas requiring histological verification. Furthermore, even if EUS-guided core biopsy samples of adequate size were available, a full histopathological evaluation may still not be possible because of the limitations in quantity and quality of biopsy samples. Criteria for diagnosing AIP in core biopsy specimens have been proposed, but need to be validated in larger series. Establishing histopathological diagnosis on minute biopsy specimens such as micro-tissue core fragments aspirated in EUS-FNA, as previously suggested for pancreatic cancer, may be a clue to optimising the diagnosis of AIP. The fact that, after a complete diagnostic workup, a few cases still require a diagnostic steroid trial and the risk of misdiagnosing or delaying the diagnosis of even a single case of the far more common pancreatic cancer underscore the necessity for novel diagnostic approaches.
Future Perspectives. To improve conventional EUS imaging of the pancreas, several techniques of image enhancement such as contrast-enhanced EUS to evaluate vascularisation patterns and EUS plus elastography to estimate the elasticity of hypoechoic masses in the pancreas have been used. It has been suggested that contrast-enhanced EUS shows hypervascularisation of AIP lesions, whereas pancreatic cancer lesions appear to be more hypovascular masses. With elastography, masses caused by AIP in contrast with pancreatic cancer show loss of tissue elasticity not only in the mass but also in the surrounding pancreatic parenchyma. Furthermore, preliminary data from small numbers of patients suggest that AIP lesions show reduced 'apparent diffusion coefficient' values in diffusion-weighted MRI and reduced maximal 'standardised uptake values' (SUVmax) in [F]fluorodeoxyglucose positron emission tomography CT.
In addition, novel serum markers for initial diagnosis, in particular for type 2 AIP and for monitoring of treatment response, are urgently needed. Some efforts have been made in this field and include antibodies in the serum of patients with AIP detecting a peptide with homology to the amino acid sequence shared by the Helicobacter pylori plasminogen-binding protein and ubiquitin protein ligase E3 component n-recognin 2 highly expressed in pancreatic acinar cells, autoantibodies against the trypsinogens, PRSS1, PRSS2 and PSTI, or an autoantibody against amylase α-2A.
However, none of the novel imaging modalities and serum markers has so far been validated in larger independent series or been established in clinical routine.
Treatment
Induction of Remission. The first goal of therapy in type 1 AIP is to induce remission. Response to steroid therapy in patients with AIP is dramatic and consistently leads to clinical improvement regardless of the subtypes. As a result, steroids have become the standard therapy for inducing remission in AIP. In the ICDC the starting dose of steroid for remission induction is defined as 0.6–1 mg/kg per day.
Issues to be Solved in the Induction of Remission: Many issues need to be agreed upon in the initial management of AIP. For example, there is still no consensus on the details of the steroid regimen to be used to induce remission, including the duration of induction therapy and tapering schedule. Also, there is as yet no consensus on the definition of 'clinical remission', how much radiological improvement should be seen before steroid tapering is initiated, or what constitutes 'radiological remission'. Clearly defining remission would be a very important issue in the treatment of AIP because patients who experience relapse during the course of steroid taper or while on steroid maintenance might represent a recrudescence of residual disease which is not yet in remission.
There are some patients, especially those with severe diabetes, who tolerate steroids poorly or have serious adverse effects during steroid therapy (eg, psychosis, infection or avascular necrosis of the hip). In such patients the only drug that has been reported to induce remission is the CD20 antibody, rituximab. On the basis of initial reports of efficacy of this drug in AIP and IgG4-related sclerosing cholangitis, an open label trial is underway in the USA to determine its role in the management of IgG4-RD.
Maintenance of Remission. Disease relapse is common in type 1 AIP, ranging from 30% to 50%. Relapse rates reported in different publications vary and may be caused by inconsistent definitions of disease relapse, study design (retrospective trials, short follow-up, small patient populations), inconsistent separation of subtypes and, most likely, ethnic variability. The issue of whether maintenance therapy should be used on all patients with AIP or restricted to patients who relapse at least once also remains to be resolved.
The primary purpose of maintenance therapy is prevention of relapse; however, the choice of medication (ie, steroid or immunomodulator) and the optimal duration of maintenance therapy have not yet been standardised. Currently there are three options for managing patients with a relapse of type 1 AIP (figure 3). To prevent relapses in type 1 AIP, Japanese groups advocate maintenance therapy with a low dose of prednisone for an extended time period after induction of remission. In contrast, the Mayo group suggests that not all patients receive maintenance therapy since, in their experience, nearly half of patients have not relapsed 3 years after the induction therapy with steroids.
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Figure 3.
Current practice in the treatment of type 1 autoimmune pancreatitis.
In a recent study by the Mayo group in patients with relapsing AIP, immunomodulators such as azathioprine were not shown to be better than an additional course of steroids alone. In the same study, a small case series (n=12) with a high clinical response to rituximab treatment and low risk of disease relapse and treatment-related side effects was reported. Unfortunately, it is at present difficult to set a standard for maintenance treatment since the different studies are usually based on small numbers of patients and use different regimens, different criteria for patient selection and different study designs.
Issues to be Resolved in the Maintenance of Remission: Overall, what is needed most in the field of AIP are prospective studies of novel diagnostic and treatment approaches, since what is known so far is mostly based on uncontrolled and retrospective data. Thus, the degree of evidence is low for virtually all aspects of diagnosis and treatment of AIP. In view of the rareness of the disease, multicentric and multinational concerted actions are needed to create a critical mass of patients to allow performance of clinical trials with sufficient statistical power to develop internationally accepted treatment regimes. Approaches such as the recently published international survey of long-term outcomes of AIP patients point in the right direction and should be the basis for designing and conducting prospective trials.
Natural History
According to a recent international multicentre study, 31% of patients with type 1 AIP experienced at least one disease relapse. More than half of patients who experienced multiple relapses had pancreatic calcifications or stones. With multiple relapses, type 1 AIP may result in irreversible damage with intense fibrosis, and these patients do not show steroid responsiveness. However, the long-term survival of patients with type 1 AIP has been reported to be similar to age- and gender-matched subjects from the general population.
Several cases of pancreatic cancer have been reported in patients with AIP, where most were suspected to have type 1 AIP. Pancreatic cancers were diagnosed synchronously with AIP or detected during the follow-up after the remission of AIP. The lessons learned from these cases are that diagnosis of AIP using pancreatic biopsy alone should be performed carefully and close follow-up examinations are mandatory for AIP even after remission.
Future Perspectives. While sporadic cases of cancer complicating AIP have been reported, no systematic case–control studies have been performed to evaluate the risk of cancer in AIP. Since type 1 AIP is a disease of the elderly, the risk of cancer may be underestimated. It would require long-term follow-up of a relatively young cohort of patients to determine if AIP truly increases the risk of cancer in affected organs.