Treatment and prognosis of IgG4-related disease

INTRODUCTION — Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs [1,2]. Common presentations include type 1 (IgG4-related) autoimmune pancreatitis (AIP); IgG4-related sclerosing cholangitis; major salivary gland enlargement or sclerosing sialadenitis; orbital disease, often with proptosis; and retroperitoneal fibrosis, frequently with chronic periaortitis.

Early recognition and treatment are important because of the indolent nature of the condition and the risk of progression from a typically treatment-responsive proliferative and inflammatory stage to poorly responsive fibrotic disease and serious organ damage. The majority of patients respond to glucocorticoids, particularly in early stages of disease, but the duration of this response treatment is variable [3,4]. Most patients experience disease flares during or after glucocorticoid tapers. Thus, additional therapy, such as rituximab, may also be required.

The treatment and prognosis of IgG4-RD is presented here. The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of IgG4-RD are presented in detail separately, as is the treatment of type 1 AIP and IgG4-related sclerosing cholangitis. (See "Clinical manifestations and diagnosis of IgG4-related disease" and "Autoimmune pancreatitis: Management".)

TREATMENT APPROACH — The goals of therapy are to reduce inflammation and induce disease remission, with the aim of preserving organ function while minimizing the adverse effects of therapy with glucocorticoids and other agents. Major elements of treatment include:

●Pretreatment evaluation – Patients should undergo a thorough pretreatment evaluation to assess the extent and severity of disease once the diagnosis has been established. (See 'Pretreatment evaluation' below and "Clinical manifestations and diagnosis of IgG4-related disease".)

●Initial therapy – Initial therapy with glucocorticoids, and sometimes with an additional immunosuppressive or a biologic agent, particularly rituximab, is required in most patients. The goal of this treatment is to achieve disease remission, defined as the resolution of symptoms of active disease and the normalization or substantial improvement of most biochemical and radiologic abnormalities [4]. (See 'Initial therapy for remission induction' below.)

●Remission maintenance – Further therapy to maintain remission and to re-induce remission in patients with recurrent disease activity is often needed. (See 'Maintenance therapy' below and 'Monitoring' below.)

●Surgery and other interventional procedures – Surgical interventions, including stenting to relieve mechanical obstruction caused by the disease, as well as other procedures, may be indicated in selected patients. (See 'Surgery and interventional procedures' below.)

Our approach to the treatment of IgG4-related disease (IgG4-RD) is generally in agreement with an international consensus guideline statement [3]. The international consensus statement is based largely upon observational data and expert opinion. Much of the literature consists of case series, many of which have focused on autoimmune pancreatitis (AIP). Indirect evidence from the investigation of treatment modalities for type 1 AIP also informs our approach (see 'Initial therapy for remission induction' below and 'Maintenance therapy' below). A growing number of reports support the efficacy of B-cell depletion with rituximab in this condition (see 'Rituximab' below). However, the optimal treatment for IgG4-RD has not been established, and no completed randomized trials have compared approaches to the treatment of either IgG4-RD overall or any organ-specific disease subset. The treatment of type 1 AIP and the evidence supporting the use of these therapies in type 1 AIP are discussed in detail elsewhere. (See "Autoimmune pancreatitis: Management", section on 'Induction of remission'.)

PRETREATMENT EVALUATION — Once the diagnosis of IgG4-related disease (IgG4-RD) has been established, the extent of disease should be evaluated before initiating treatment. (See "Clinical manifestations and diagnosis of IgG4-related disease".)

Baseline testing should include:

●Blood testing:

•Complete blood count with differential white blood cell count, including eosinophil count

•Serum chemistry panels, including renal and liver function tests, amylase, and lipase

•IgG subclass levels

•IgE concentrations

•Serum protein electrophoresis

•Serum C3 and C4 concentrations

•Glycated hemoglobin (hemoglobin A1c)

●Stool testing – Fecal elastase, which we obtain in patients with known or suspected pancreatic involvement, is an indication of exocrine pancreatic reserve. (See "Exocrine pancreatic insufficiency", section on 'Fecal elastase-1'.)

●Urinalysis – Asymptomatic proteinuria may be an indication of subclinical IgG4-related tubulointerstitial nephritis (TIN). However, many patients with significant IgG4-related kidney disease have a completely normal urinalysis.

●Imaging:

•Computed tomography (CT) scan of the chest, abdomen, and pelvis – We generally obtain a CT scan (with contrast) of the chest, abdomen, and pelvis in patients diagnosed with IgG4-RD because of the frequency of subclinical disease. Selected patients require additional imaging studies, particularly if extraocular muscle involvement or other disease in the orbits is suspected.

Magnetic resonance imaging (MRI) is an alternative to CT that is limited to selected patients in whom there is particular concern regarding radiation exposure.

•Positron emission tomographic (PET) scanning – PET scanning can also be highly effective in determining the extent of disease. However, the utility of PET in monitoring disease activity and response to treatment is less clear.

Serum C3 and C4 concentrations are often low, sometimes profoundly so, in IgG4-RD. In patients with hypocomplementemia at baseline, following serum complement concentrations can be a useful means of gauging response to therapy.

In one small study, serum C5a levels were increased substantially in IgG4-RD patients compared with healthy individuals and were reported to correlate with IgG4-RD activity [5]. However, this observation needs further confirmation, and its clinical utility remains to be determined.

Markers of allergic disease, such as serum IgE concentrations and the peripheral eosinophil count, should be tested at baseline and, if abnormal, at follow-up. (See 'Monitoring' below.)

INITIAL THERAPY FOR REMISSION INDUCTION

Treatment indications — All patients with symptomatic, active IgG4-related disease (IgG4-RD) require treatment. Some patients require treatment urgently, particularly subsets of patients with pancreatobiliary or renal disease. A subset of patients with asymptomatic IgG4-RD also requires treatment. Selected patients may benefit from urgent surgical intervention, such as stenting for mechanical obstruction.

We take the following approach, depending upon disease characteristics:

●Symptomatic disease – Patients with active symptomatic disease due to their organ involvement at the time of the diagnosis should be treated (see 'Initial therapy' below). Disease activity requiring treatment may also be identified by biochemical or imaging abnormalities (eg, elevations in the hepatic transaminases, serum bilirubin, or serum creatinine), even if symptoms are not present.

Examples of symptomatic involvement include patients with lacrimal gland swelling or other orbital pseudotumors, who may have significant proptosis; those with submandibular or parotid gland swelling, who may have pain from their glandular enlargement or concern about cosmetic issues; those with renal involvement, who may have kidney dysfunction due to tubulointerstitial nephritis (TIN); and those with type 1 autoimmune pancreatitis (AIP) or retroperitoneal fibrosis, who may have steatorrhea, pain, hydronephrosis, or other manifestations of their organ involvement.

Selected patients require urgent surgical intervention in addition to medical therapy (see 'Surgery and interventional procedures' below). As examples, mechanical obstruction causing hydronephrosis due to retroperitoneal fibrosis or resulting in biliary tract obstruction due to cholangitis may require stenting procedures in addition to medical therapy at the start of treatment.

●Asymptomatic patients with progressive disease – Asymptomatic patients with radiologic or laboratory findings of disease progression in vital organs (eg, patients with asymptomatic IgG4-RD aortitis/periaortitis, IgG4-RD retroperitoneal fibrosis) should be started on therapy. (See 'Initial therapy' below.)

●Asymptomatic, nonprogressive, and limited disease – For patients with asymptomatic lymphadenopathy, mild submandibular gland enlargement, or incidentally detected lung nodules, for example, a policy of "watchful waiting" is appropriate. However, patients with asymptomatic and limited disease that appears to be nonprogressive at early assessments can evolve into disease affecting other organs with or without symptoms that require treatment. These patients therefore require regular monitoring (eg, every six months) to detect changes in symptoms, signs, or laboratory values that may indicate a need for treatment (eg, the development of pancreatic or renal dysfunction).

Initial therapy — For most patients requiring treatment, we suggest prednisone monotherapy, usually at a dose of 0.6 mg/kg (typically 30 to 40 mg) once daily. Nearly all patients demonstrate a response to prednisone 40 mg daily within two to four weeks; many patients respond even earlier. Once a significant response is clinically evident in the affected organ system, we taper the glucocorticoids gradually with a planned reduction over a two-month period and the goal of discontinuing the medication entirely. Practice variations by some experts include the use of twice-daily, divided-dose glucocorticoids in patients who are more acutely ill, and the use of methylprednisolone rather than prednisone or prednisolone in patients in whom liver disease may be present.

The typical response that occurs within several weeks of starting glucocorticoids includes symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and decrease in serum concentrations of IgG4. However, some patients require a few months to respond, and there are some patients who relapse and others who respond less well or not at all initially. American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) classification criteria for IgG4-RD have "failure to respond to an appropriate glucocorticoid dose" as an exclusion criterion for classification purposes [4]. In patients whose disease is largely fibrotic at the start of glucocorticoid therapy (eg, some patients with retroperitoneal fibrosis), responses to treatment are sometimes difficult to detect. Disease worsening while on glucocorticoid therapy, however, certainly implies another diagnosis.

Glucocorticoids are the first-line agent for remission induction in all patients with active, untreated IgG4-RD, unless contraindications to such treatment are present. However, despite initial control of disease with glucocorticoids alone, glucocorticoid monotherapy will often fail to produce sustained disease control. Moreover, long-term glucocorticoid toxicities pose patients to substantial risk. In our experience, patients with multiorgan disease or an extremely high serum IgG4 are likely to require an agent other than glucocorticoids alone. Patients not adequately responsive to glucocorticoids often flare during initial tapering as the dose is reduced below 10 to 15 mg of prednisone or equivalent daily. Thus, in a small number of selected patients with multiorgan disease (eg, three or more organs) or an extremely high serum IgG4 concentration (eg, >5 times the upper limit of normal), starting treatment with the combination of glucocorticoids plus rituximab (see 'Rituximab' below) is beneficial. An early glucocorticoid-sparing approach may be of particular benefit in patients who also have comorbidities such as obesity, diabetes, osteoporosis, hypertension, depression, or other baseline issues predisposing patients to glucocorticoid toxicity. We prefer rituximab for this purpose over azathioprine or mycophenolate mofetil because of the greater evidence for its efficacy than that of the alternative agents. (See 'Alternatives to rituximab' below.)

Combination therapy at treatment onset remains controversial, with experts who developed international consensus guidelines on management of IgG4-RD being divided on this point [3]. This disagreement largely reflected different practice styles between countries, with 80 percent (16 of 20) of experts from Japan disagreeing with early use of a second agent in combination with the glucocorticoid therapy, while 76 percent (13 of 17) of the experts from all other regions (North America, Europe, Korea, and China) agreed with this approach.

Although evidence is somewhat limited, some findings, including observational data and a small randomized trial, support the view that combination therapy has greater benefit than glucocorticoid monotherapy [6-8]:

●In a large cohort, including 215 newly treated patients with IgG4-RD, remission was not successfully reached in 12 percent of patients [6]. Although failure to achieve remission by the study definition was more common in those receiving glucocorticoid monotherapy compared with glucocorticoids plus another immunosuppressive agent (21 versus 7 percent), the treatments were not randomly assigned, so it was not possible to compare the relative efficacy of these approaches.

●In a randomized trial involving 69 patients in China with a new diagnosis of IgG4-RD, patients treated with glucocorticoids (0.6 to 0.8 mg daily with subsequent tapering) combined with mycophenolate mofetil (1 to 1.5 g daily) were more likely to respond, compared with those receiving glucocorticoid treatment alone [7].

●Subsequent to the international consensus guidance [3], a prospective nonrandomized study suggested that combination treatment with glucocorticoids and cyclophosphamide by mouth had comparable short-term efficacy to glucocorticoid monotherapy but better long-term outcomes and lower relapse rates [8]. The toxicity of the combination of glucocorticoids and cyclophosphamide has been demonstrated amply in other diseases, particularly granulomatosis with polyangiitis and systemic lupus erythematosus. Therefore, this drug combination should be used in IgG4-RD only with reluctance and accompanied by Pneumocystis prophylaxis and careful monitoring for toxicity. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

The treatment of AIP and the evidence supporting the use of these therapies in AIP are discussed in detail elsewhere. (See "Autoimmune pancreatitis: Management", section on 'Induction of remission'.)

RESISTANT TO INITIAL THERAPY AND STEROID DEPENDENCE

Rituximab — We suggest rituximab (1 gram intravenously every 15 days for a total of two doses) in patients who are resistant to glucocorticoids alone or unable to reduce their dose sufficiently (usually to below 5 mg/day of prednisone). We also suggest rituximab in patients who have strong relative contraindications to glucocorticoid therapy. In most patients, rituximab is likely to be more effective than low doses of glucocorticoids (prednisone <10 mg daily) and of greater benefit compared with alternative immunosuppressive agents [9]. Information regarding the use and adverse effects of rituximab are described in detail separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Case series suggest that B-cell depletion therapy is an effective treatment in many of the patients with IgG4-related disease (IgG4-RD) that is refractory to glucocorticoids and other medications [10-12]. A retrospective nationwide study in France showed that rituximab was effective as both induction and maintenance treatment. Relapses occurred when rituximab was discontinued. Systematic rituximab infusion (before evidence of relapse) was associated with longer relapse-free survival [13]. In addition, in an open-label trial, 30 patients with IgG4-RD were treated with two doses of rituximab, most without concomitant use of glucocorticoids [14]. The disease responded in 97 percent of the patients, and 40 percent remained at complete remission at 12 months. In a meta-analysis examining efficacy and safety of rituximab in IgG4-RD with pancreato-biliary manifestations, it was found that the pooled rate of complete response at six months was 88.9 percent (95% CI 80.5-93.9), while the relapse rate was 21 percent (95% CI 10.5-40.3) [15]. Relapses were more frequent in patients who had multiorgan disease . However, rituximab has not been evaluated in patients with IgG4-RD in a randomized trial, and its use for this indication is considered off-label by the US Food and Drug Administration (FDA).

B-cell depletion leads to the swift, targeted reduction of serum IgG4 concentrations, with relative preservation of the concentrations of other immunoglobulins and immunoglobulin subclasses. This observation suggests that B-cell depletion achieves its effects at least in part by interfering with the repletion of short-lived plasma cells that are producing IgG4. Once the source of these IgG4-producing cells are eliminated by anti-CD20 antibodies, the serum IgG4 subclass levels rapidly decline and do not immediately rebound owing to the paucity of residual CD20+ B cells. Rituximab also leads even more swiftly to steep declines in blood plasmablast concentrations [16,17].

Normalization of serum IgG4 concentrations following the start of treatment may require many months, presumably because of continued production of IgG4 by long-lived plasma cells that have migrated back to the bone marrow. (Such plasma cells do not have CD20 and are not susceptible to B-cell depleting therapies.)

Alternatives to rituximab — In patients for whom rituximab is not available, either azathioprine (2 mg/kg/day) or mycophenolate mofetil (up to 2.5 g/day as tolerated) are reasonable choices for second-line agents that have potential as glucocorticoid-sparing therapies, especially in studies examining patients with autoimmune pancreatitis (AIP) or with IgG4-related sclerosing cholangitis [9,18,19]. In a study investigating treatment of relapsing AIP, there was no difference in the subsequent relapse-free period between patients who were treated with glucocorticoids or other immunomodulators (azathioprine, mycophenolate mofetil, 6-mercaptopurine) after the first relapse [9]. It should be noted, however, that the effects of these glucocorticoid-sparing medications have not been evaluated adequately in IgG4-RD to clearly define their role relative to other agents. (See "Autoimmune pancreatitis: Management", section on 'Induction of remission'.)

In a case report, a patient with IgG4-RD resistant to rituximab has been described who subsequently responded to abatacept [20]. An open-label trial of abatacept in 10 patients suggested that abatacept had significant efficacy in half of the patients treated, and that the medication might be useful in patients with less severe disease [21]. The efficacy of this agent might be related to the central role of T cells in IgG4-RD, but further studies of abatacept in IgG4-RD are needed before definitive conclusions about its role can be drawn. Case reports also suggest that dupilumab, a monoclonal antibody against interleukin (IL) 4 receptor a (blocking IL-4 and IL-13), may be effective in the treatment of IgG4-RD patients [22,23]. However, further studies are needed to define whether this would gain a position as a therapeutic approach in the setting of IgG4-RD and/or in IgG4-RD patients with specific phenotypes [24]. Finally, in a retrospective study, mizoribine appears to reduce exacerbations in IgG4-RD patients with multiorgan involvement [25].

Refractory to rituximab or other immunosuppressive drugs — There is limited evidence to guide the treatment of patients who are refractory to rituximab and other immunosuppressive drugs. Reasonable options include retreatment with glucocorticoids, the use of maintenance glucocorticoid therapy, or switching to another immunosuppressive drug (eg, azathioprine to mycophenolate mofetil or to rituximab and vice versa) that has not been previously used for the patient [18].

MAINTENANCE THERAPY — Whether patients with IgG4-related disease (IgG4-RD) should receive maintenance therapy is still under debate [4]. It seems that following a successful course of induction therapy, certain patients benefit from maintenance therapy, especially those who are at high risk for disease relapse. As reflected in the international consensus guidance statement for IgG4-RD [3], a glucocorticoid-sparing agent can act as a maintenance therapy; however, there is no evidence addressing the question of how long such agents should be administered. Finally, rheumatologists from Asian countries prefer to continue low-dose glucocorticoids (eg, 2.5 to 10 mg/day) for up to three years [14].

MONITORING — We monitor treated patients, as well as those undergoing "watchful waiting," as follows:

●Patients are educated to report any new symptoms. It is particularly important to be vigilant for recurrences of symptoms previously experienced, but patients should be aware that new organ involvement can occur over time and that this may be associated with new disease manifestations.

●Clinical and laboratory evaluation should be performed every six months, including a complete blood count, blood chemistries, IgG subclass concentrations, IgE levels (if elevated at baseline), and complement C3 and C4 levels.

●Periodic imaging may be useful in patients whose disease is not easily evaluable through history, physical examination, and laboratory testing. In particular, such patients include those with pulmonary disease, retroperitoneal fibrosis, and aortitis/periaortitis. In IgG4-aortitis/periaortitis or IgG4-retroperitoneal fibrosis, CT cannot distinguish between active disease and residual fibrotic changes that might persist after treatment [26,27]. In such cases, the addition of positron emission tomography (PET) imaging to CT might be useful [26,27], but rigorous studies of this approach have not been performed. Thus far, the experience with MRI is limited.

An IgG4-related disease (IgG4-RD) responder index (RI) has been developed and employed in clinical investigations and in laboratory-based biomarker studies using clinical data [28]. Its use has been validated, showing significant correlation between RI and physician's global assessment. Furthermore, significant improvement in the RI score was noticed following treatment [29].

RECURRENT DISEASE — Retreatment with glucocorticoids is indicated in patients who relapse off of treatment following successful remission induction. Following relapse, the introduction of a glucocorticoid-sparing agent for continuation in the remission maintenance period is often beneficial. Patients who flare during or after a glucocorticoid taper are likely to require a glucocorticoid-sparing agent, which should be started promptly to prevent excessive glucocorticoid toxicity [30]. The optimal agent is not established, and treatment should be individualized based in part on comorbidities, patient cost and insurance, and regulatory restrictions. Treatment options include rituximab (1 gram intravenously every 15 days for a total of two doses), azathioprine (2 mg/kg), mycophenolate mofetil (2 to 2.5 grams/day), and other immunomodulatory agents such as calcineurin inhibitors [31]. Future studies are needed to define the duration of therapy with these agents.

SURGERY AND INTERVENTIONAL PROCEDURES — Selected patients may require surgery or other interventional procedures. Indications may include [4]:

●Hydronephrosis – Retroperitoneal fibrosis and periaortitis that is associated with ureteral obstruction requires relief of the obstruction and is unlikely to respond to medication alone, except in mild cases. Ureteral stenting or nephrostomies may be indicated, as well as other procedures including surgical or laparoscopic ureterolysis and omental wrapping. Intermittent medical therapy may be of benefit for recurrences. (See "Treatment of retroperitoneal fibrosis", section on 'Treatment of urinary obstruction'.)

●Vascular and organ compression from sclerosing mesenteritis – Surgical debulking may be required in patients with sclerosing mesenteritis, followed by medical therapy. (See "Sclerosing mesenteritis", section on 'Approach to management'.)

●Obstructive jaundice – Biliary tract obstruction due to IgG4-related sclerosing cholangitis sometimes requires biliary stenting and drainage before instituting medical therapy (eg, with glucocorticoids) [32]. Patients need to be monitored for infection and stent migration.

●Aortic aneurysm and aortitis – Although early treatment of IgG4-related aortitis may reduce the need for surgical repair, patients who develop inflammatory thoracic or abdominal aortic aneurysms may require arterial graft replacement, stent grafting, or endovascular repair [33,34]. (See "Management of thoracic aortic aneurysm in adults" and "Management of asymptomatic abdominal aortic aneurysm".)

●Compressive symptoms of Riedel thyroiditis – Symptoms from Reidel thyroiditis, such as hoarseness, dyspnea, and dysphagia, may require surgical intervention because the response to medical therapy can be inadequate. Patients do sometimes respond to medical therapy if the condition is detected early in the disease process and before extending beyond the thyroid capsule into adjacent tissues. (See "Infiltrative thyroid disease", section on 'Treatment'.)

●Other – Other infrequent indications for surgery include relief of mechanical obstruction that cannot be treated medically and removal of a nonfunctional organ.

PROGNOSIS

General prognosis — The natural history of IgG4-related disease (IgG4-RD) has not been defined in sufficient detail. A minority of patients improve at least temporarily without treatment, but most of these patients relapse. IgG4-RD should generally be regarded as a chronic disease that progresses at variable rates [10,35]. Causes of significant morbidity and mortality in untreated patients include exocrine pancreatic insufficiency; disease- and treatment-induced diabetes mellitus; biliary obstruction; cirrhosis and portal hypertension; retroperitoneal fibrosis; complications from aortic aneurysms, including dissection; damage to extraocular muscles leading to dysconjugate gaze in certain fields of vision; and others [10,36-39]. A subset of patients have subacute constitutional symptoms marked by fatigue and weight loss that may be substantial over months, on the order of 20 or 30 pounds. Significant degrees of weight loss are often a major clue to subclinical pancreatic disease or pancreatic insufficiency. Such patients may benefit from the use of pancreatic enzyme replacement therapies with meals.

Sustained benefit may be observed in treated patients, but relapses are common after discontinuation of therapy. [40]. In a retrospective cohort study, relapse was observed in approximately one-third of patients treated with rituximab [41]. B-cell depletion is not a cure for IgG4-RD, and it is likely that the majority of patients will experience disease recurrences over time. Baseline elevated levels of serum IgG4, IgE, and circulating eosinophils served as markers for relapse prediction. Additional organs and tissues may become involved over time, sometimes despite apparently effective treatment. Additional studies of long-term prognosis are needed.

Risk of malignancy — Some studies have suggested that the presence of IgG4-RD is associated with an increased risk of malignancy, which may involve a variety of organs and tissues, and that the risk may be particularly increased in the year after diagnosis of IgG4-RD. However, other studies have not found such risk, and this issue remains controversial [42,43]. On the other hand, it has been shown that a history of malignancy is associated with subsequent development of IgG4-RD [44].

In a series of 158 patients in Japan with IgG4-RD who were diagnosed between 1992 and 2012, 109 of whom had type 1 autoimmune pancreatitis (AIP; most with extrapancreatic lesions), and who were followed for a mean of six years, there was an increase in the incidence of malignancy compared with the expected rate [45]. The overall malignancy risk and the risk in the first year after diagnosis of IgG4-RD, in particular, were both significantly increased (standardized incidence ratio [SIR] 2.01, 95% CI 1.34-2.69, and SIR 3.53, 95% CI 1.23-5.83, respectively). The total number of malignancies was 34, most often affecting the lung, colon, prostate, stomach, and pancreas. At the time of diagnosis with IgG4-RD, IgG4-RD patients with malignancies had increased levels of several serum markers of disease activity, including IgG, IgG4, and soluble interleukin (IL) 2 receptor. The majority of malignancies occurred in organs other than those affected by the IgG4-RD inflammation.

In one series of 108 Japanese patients with IgG4-related pancreatitis, 18 cancers were found in 15 patients (14 percent); the median follow-up was 3.3 years [46]. At the time of diagnosis of the pancreatitis, the relative risk (RR) of cancer was significantly increased compared with age- and sex-matched controls (RR 4.9, 95% CI 1.7-14.9); the risk was highest in the year following diagnosis. Gastric cancers were the most common; other sites included lung, prostate, colon, non-Hodgkin lymphoma, bile duct, and thyroid. In six of eight patients whose cancer was assessed histologically before treatment with glucocorticoids for the pancreatitis, IgG4-positive plasma cell infiltrates were found in the cancer tissue. Thus, it is of note that the presence of IgG4-positive plasma cell infiltrates does not exclude malignancy, and certain cutoff limits have been defined in order to maximize diagnostic accuracy [47]. None of these patients experienced relapse of their IgG4-related pancreatitis after successful treatment of their cancers, raising the question of whether IgG4-RD may occur as a paraneoplastic syndrome in some patients.

Several sporadic cases of pancreatic cancer and cases of salivary duct carcinoma, pulmonary adenocarcinoma, small cell carcinoma of the lung, and gastrointestinal clear cell sarcoma have also been reported [35]. Large-scale multicenter studies are required to determine the degree, if any, of increased risk for these and other malignancies in affected patients or whether the reported results are due to intensive screening that these patients undergo.

Several types of lymphoma have been reported in patients with IgG4-RD, both in Japan and in North America [35,48-51]. In the study in North America, which involved 111 patients with IgG4-RD (91 percent with AIP), three cases of non-Hodgkin lymphoma were found three to five years after the diagnosis of IgG4-RD [49]. The SIR was 16.0 (95% CI 3.3-45.5), suggesting an increased risk of non-Hodgkin lymphoma among this group of patients referred to an academic medical center with special interest in this disorder. On the other hand, studies have failed to demonstrate a monoclonal plasma cell population in IgG4-RD patients, while it seems that the circulating plasmablasts are most probably derived from oligoclonal expansion of B-cell clones that are somatically hypermutated in germinal centers [47]. Further studies are required to better define the degree of risk and the effect of treatment upon such risk, if present.

A meta-analysis reported that risk for cancer was higher in IgG4-RD patients compared with the general population (SIR 2.57, 95% CI 1.72-3.84) [52]. More specifically, this was observed for pancreatic cancer and lymphoma (SIR 4.07, 95% CI 1.04-15.92; SIR 69.17, 95% CI 3.91-1223.04, respectively), but not for respiratory or gastric malignancies (SIR 2.14, 95% CI 0.97-4.75; SIR 0.95, 95% CI 0.24-3.95, respectively) [52].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: IgG4-related disease".)

SUMMARY AND RECOMMENDATIONS

●Once the diagnosis of immunoglobulin G4-related disease (IgG4-RD) has been established, the extent of disease should be evaluated before initiating treatment. Testing should include a CT scan of the chest, abdomen, and pelvis, and may include other studies; a urinalysis; serum complement levels; and markers of allergic disease, such as serum IgE concentrations and a peripheral blood eosinophil count. (See 'Pretreatment evaluation' above.)

●We suggest beginning treatment with glucocorticoids (Grade 2B). We generally initiate therapy with prednisone (0.6 mg/kg/day), which is then tapered to discontinuation over a two-month period. Responses are characterized by symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and often a decrease in serum levels of IgG4. (See 'Initial therapy' above.)

●In patients who do not respond to up to 40 mg/day of prednisone or cannot be tapered to <5 mg daily, and in patients who have strong relative contraindications to glucocorticoid therapy in these doses, we suggest rituximab rather than a conventional antimetabolite immunosuppressive (eg, azathioprine, methotrexate, or mycophenolate mofetil) (Grade 2C). (See 'Resistant to initial therapy and steroid dependence' above.)

●The natural history and prognosis have not been defined in sufficient detail. Spontaneous improvement can be seen, but disease often recurs without treatment. Most patients respond initially to therapy with glucocorticoids, but relapses are common following discontinuation of therapy. Significant organ dysfunction may arise from uncontrolled and progressive inflammatory and fibrotic changes in affected tissues. The possibility of increased risk of malignancy in patients with IgG4-RD requires further study. (See 'General prognosis' above and 'Risk of malignancy' above.)