A Comprehensive Review of IgG4 Related Disease Unraveling the Role of B and T Lymphocytes in the Pathogenesis of the Disease

IgG4-RD is a chronic fibro inflammatory disease characterized by a significant elevation of serum IgG4 concentration and marked infiltration of IgG4-positive plasma cells in the affected organs. A dense lymphoplasmacytic infiltrate and the formation of ectopic lymphoid structures are characteristic histopathological findings in an IgG4-RD lesions. These findings strongly suggest the preferential involvement of T and B lymphocytes in the development of this disease. We want to sum up the last evidences regarding the IgG4-RD with a focus on the role of the involvement of CD4+T-cell subsets and B lymphocytes.

Historical context and nomenclature

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory immune condition characterized by tumour-like forming lesions that can potentially affect any anatomical district, causing a wide range of clinical manifestations that lead to permanent organ injury and death if left untreated [1].

The roots of IgG4-RD, in the medical literature, can be tracked clearly to the nineteenth century, since several conditions characterized by the typical infiltrate of IgG4+ plasma cells, fibrosis in affected organs and, almost always, by an increased level of serum IgG4, previously regarded as unrelated entities, were recognised as different expression of a unique disease. In 2001, Hamano H, et al. [2] made the seminal observation that sclerosing pancreatitis was associated with elevated serum concentrations of IgG4. Within 2 years, the cardinal histopathologic and immunostaining characteristics in tissue had been identified, not only, in the pancreas, but also in extrapancreatic organs of patients with AIP. Kamisawa T, et al. [3] first proposed the existence of a systemic condition occurring in the context of AIP in which pathological features, identical to those in the pancreas, were also observed in extrapancreatic organs. The first decade of the twenty-first century was remarkable for the identification of IgG4-RD in essentially every organ of the body. Many disorders previously believed to exclusively affect single organs were found to be linked by common histopathologic and immuno-histochemical features. Several conditions known by eponyms or acronyms have therefore been renamed over the past few years to reflect the new appreciation for these relationships [4]. In 2010, a group of Japanese investigators chose the consensus name IgG4-RD [5] that was, subsequently, adopted by the First International Symposium on IgG4-RD4. Since then, IgG4-RD has been recognized with increasing frequency by both generalists and specialists worldwide. Histopathology remains key to diagnosis, because reliable biomarkers are lacking. Recently released classification criteria will be invaluable in improving early recognition of the disease. IgG4-RD is highly treatable and responds promptly to glucocorticoids, but it can lead to end stage organ failure and even death if unrecognized. Prolonged courses of corticosteroids are often needed to maintain remission because the disease relapses in most patients. Understanding the pathogenesis of this disease will lead to novel treatment approaches, that would be applicable to this entire spectrum of disorders and will carry out to the identification of novel therapeutic targets and possible personalized approaches to treatment [6].

General epidemiologic and genetic characteristics

The global incidence and prevalence of IgG4-RD remain largely underestimated, the awareness of the diagnostic and therapeutic tools for the management of patients with IgG4-RD remains confined to tertiary care centers and the disease is still, frequently, misdiagnosed as neoplastic, inflammatory, or an infectious conditions. The only disease subset that has been studied in detail with regard to epidemiology is AIP [3,4]. According to the more recent studies, the incidence of AIP is increased from 0.8 to 3.1 cases per 100000 people between 2007 and 2016, suggesting a rapid growth in awareness of IgG4-RD in less than a decade [2,7,8]. AIP, however, represents only one of more than a dozen organs potentially affected by this condition.

IgG4-RD has a predilection for middle-aged to elderly men, whereas most autoimmune disorders develop in younger females1, with a male to female ratio that ranges from 1,6:1 for head and neck manifestations to 4:1 for other sites of organ involvement.

A recent genome-wide association study in 850 Japanese patients identified HLA-DR B1 and FCγ receptor IIb region, as susceptibility loci for the development of IgG4-RD, suggesting a possible genetic predisposition. Potential genetic links to other genes, namely, Fc Receptor–Like 3 (FcRL3), Cytotoxic T-Lymphocyte–Associated antigen 4 (CTLA4), and the potassium voltage-gated channel subfamily A member 3 (KCNA3) loci have been suggested in small studies [9-12].

A proportion of patients have symptoms that overlap with allergic conditions. Whether there is a role for allergens in the pathogenesis of IgG4-RD remains unclear. Some patients have long standing histories of allergy (rhinitis, nasal polyps, asthma, mild eosinophilia) before the full IgG4-RD disease phenotype emerges or is recognized. Mild to moderate peripheral eosinophilia, sometimes involving up to 20% or more of the circulating white blood cells is occasionally observed. Elevations in serum IgE concentration, sometimes higher than 10 times the upper limit of normal, are detected too [13].

In most systematic descriptions IgG4-RD is depicted as a subacute and indolent disorder, with symptoms or signs of organ dysfunction evidence occurring for months or even years before a diagnosis is made. It is also commonly accepted that most patients do not appear constitutionally ill, and that the disorder is typically identified through incidental radiologic findings or on pathological examination of affected organs, after they have been removed to rule out malignancies1-5. However a recent work demonstrates that admission to the Emergency Department represents the most frequent modality by which patients with IgG4-RD seek medical attention at disease onset, indicating that life-threatening manifestations can also represent a modality of disease presentation [14].

Wallace ZS, et al. [15], analysing the distribution of organ involvement with the latent class analysis, have, recently, proposed a categorization of disease in four homogeneous phenotypes: (I) pancreato-hepatobiliary disease, (II) retroperitoneal fibrosis with or without aortitis, (III) head and neck limited disease, and (IV) classic Mikulicz’s syndrome with systemic involvement. Interestingly, patients clustered to each phenotype shared distinctive clinical, epidemiological, and serological features.

Specific organ involvement will be discussed in separate sections.

Head and neck

Salivary gland involvement. The submandibular, parotid, and sublingual glands are often involved, usually bilaterally. Prominent submandibular involvement, formerly known as Kuttner’s tumor, is particularly characteristic of IgG4-RD. IgG4-related sialadenitis must be distinguished from Sjogren’s syndrome, which has a predilection for the parotid glands, is characterized by Th1/Th17 polarization and does not involve the submandibular glands in isolation. Biopsy of the minor salivary glands can be diagnostic of IgG4-RD, even if the oral mucosa has an unremarkable clinical appearance [16].

Orbital and periorbital lesions. Multiple presentations of IgG4-RD involve the orbits and orbital adnexa. The most common is lacrimal gland enlargement (dacryoadenitis) which often occurs in the context of submandibular or parotid gland enlargement (i.e., Mikulicz’s disease) but may occur in isolation. Tumefactive lesions of the orbital or periorbital tissues (orbital pseudotumors), that do not include the lacrimal gland, also occur. These usually lead to some degree of proptosis, which is sometimes dramatic. These mass lesions can extend into the pterygopalatine fossa and infiltrate along the trigeminal nerve, mimicking malignancies on radiologic studies [17]. Mass lesions can also extend into the cavernous sinus or cause thickening of the palpebral fissure. Other ophthalmic manifestations include orbital myositis, a painless thickening of the extraocular muscles, and dacryocystitis.

Thyroid gland. The direct link between IgG4-RD and Riedel’s thyroiditis was not firmly established until 2009 [18]. The thyroid gland enlargement caused by Riedel’s thyroiditis can lead to neck pain, dyspnea, dysphagia, and dysphonia. The thyroid becomes enlarged and sclerotic over time and can extend aggressively into adjacent tissues, threatening vital organs in the anterior neck region. A disorder characterized as a subset of Hashimoto’s thyroiditis, known as fibrosing thyroiditis, also appears to be part of the IgG4-RD spectrum in some cases.

Ear, nose and throat. IgG4-RD can cause diffuse inflammation in the pharynx, hypopharynx, and Waldeyer’s ring and is frequently associated with mass lesions. Tracheal inflammation and vocal cord involvement have also been described. The allergic phenomena that occur in a large subset of patients with IgG4-RD - allergic rhinitis, nasal polyps, chronic sinusitis, nasal obstruction, and rhinorrhoea - often manifest most prominently in the ear, nose, and throat region. The pathophysiologic significance of this anatomic distribution is not well understood, but a pathogenic trigger such as a microbial infection may convert a pre-existing allergic response into IgG4-RD. Studies of the oral and gut microbiome designed to explore potential microbial triggers of IgG4-RD are warranted [19].

Intracranial disease. The two principal intracranial manifestations of IgG4-RD are pachymeningitis and hypophysitis. IgG4-RD generally does not affect the brain parenchyma. Pachymeningitis may involve either the intracranial meninges or the intraspinal meninges; patients with this condition present with headache, radiculopathy, cranial nerve palsies. This disease also tends to form mass lesions in the meninges, consistent with the hypertrophic pachymeningitis, associated with symptoms resulting from spinal cord compression. Clinical features of IgG4-related hypophysitis results by thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or mass formation within the pituitary gland, depending on which hormonal axis is interrupted [20].

Chest

Lung. The lungs are affected by IgG4-RD in diverse ways. Four major clinical pulmonary syndromes have been identified: inflammatory pseudotumor, central airway disease, and diffuse interstitial pneumonia. These different pulmonary syndromes are associated with a range of clinical symptoms, including cough, haemoptysis, dyspnoea, pleural effusion, and chest discomfort. The tendency of IgG4-RD to track along the bronchovascular bundle is particularly characteristic of this condition [21].

Pleura and pericardium. Pleural and pericardium lesions are severe, nodular thickening of the visceral or parietal lining, with diffuse sclerosing inflammation, sometimes associated with effusion [22].

Thoracic aorta. The finding of inflammatory aortitis often comes as a surprise at surgery, when patients undergo repairs of thoracic aortic aneurysms or dissections [23].

Fibrosing mediastinitis. Fibrosing mediastinitis is characterized by an aggressive fibro-inflammatory process occurring within the mediastinum. Progressive fibrosis results from the proliferation of invasive fibrous tissue within the mediastinum. This process can compress vital mediastinal structures, culminating in life threating organ dysfunction. A significant proportion of fibrosing mediastinitis appears to fall within the spectrum of IgG4-RD [24].

Abdomen

2.3.1. Pancreas: Presentations of type 1 (IgG4-related) AIP include mild abdominal pain, weight loss and acute, obstructive jaundice (known as painless jaundice). A significant minority of patients with type 1 AIP present with acute glucose intolerance. A small percentage of patients present with either acute pancreatitis (severe upper abdominal pain, lipase elevation) or chronic pancreatitis with features of exocrine insufficiency and pancreatic calcification, or pseudocysts. Pancreatic atrophy occurs as a complication of longstanding disease. The pancreatic duct is typically diffusely narrowed. The tumefactive lesions often raise suspicions of adenocarcinoma of the pancreas.

Biliary tract: IgG4-related sclerosing cholangitis (IgG4-SC) appears to account for the minority of patients who had previously been considered to have Primary Sclerosing Cholangitis (PSC) but respond well to glucocorticoids. Untreated IgG4-SC can progress to end-stage liver disease and is extremely difficult to differentiate from PSC on the basis of clinical and radiologic findings and sometimes even on the pathological material.

Liver, gallbladder and stomach: Patients may present with mass forming hepatic lesions, that sometimes give rise to obstructive jaundice. Solid-mass lesions may involve the hilar and perihilar bile ducts and may resemble cholangiocarcinoma.

The clinical features of IgG4-RD in the gallbladder and stomach are poorly described. A cholecystectomy is routinely performed during Whipple resection and IgG4-related cholecystitis is generally detected incidentally during surgical resection for AIP. A severe transmural inflammatory infiltrate is typical and a radiologically thickened gallbladder may be observed.

IgG4-related gastropathy represents a unique inflammatory disease of the stomach that may be distinguishable from other causes of gastritis, such as Helicobacter Pylori (HP), and the entity known as autoimmune gastritis. As with the gallbladder, the gastric manifestations have been described only in the context of AIP and identified upon examination of the pathology remnants of Whipple procedures. Whether patients with the histopathological features have clinical symptoms is unclear. The long term consequences of IgG4-related gastropathy are unknown.

Mesentery: The mesentery can be involved in a devastating manner. The fibrosing process can encase vital organ structures, often obviating any attempt at surgical resection. Sclerosing inflammation often originates from the root of the mesentery and can be difficult to differentiate from retroperitoneal fibrosis [25].

Retroperitoneum

Retroperitoneal fibrosis. Idiopathic retroperitoneal fibrosis, known for decades as Ormond’s disease, is known to exist within a larger disease spectrum now referred to as chronic periaortitis. The three major components of chronic periaortitis are IgG4-related retroperitoneal fibrosis, IgG4-related abdominal aortitis, and IgG4-related perianeurysmal fibrosis [26]. Because presentations of IgG4-related chronic periaortitis are often subtle and nonspecific, diagnostic delay may result. Common presentations are: poorly localized pain in the back, flanks, lower abdomen, or thighs, lower extremity oedema, and hydro nephrosis from ureteral involvement [27].

Kidneys. The most common renal manifestation of IgG4-RD is Tubulo-Interstitial Nephritis (TIN). Although this complication is indolent, the nephritic syndrome, advanced renal dysfunction and renal failure can develop [27,28]. Even with the prompt institution of glucocorticoid treatment, renal fibrosis and renal atrophy may occur. Membranous Glomerulonephritis (GN) has also been reported in a minority of IgG4-RD patients who have renal disease. This form of GN is distinct from idiopathic membranous GN, which is associated with antibodies to the phospholipase A2 receptor that, noteworthy, are predominantly of the IgG4 subclass. Either subacute or progressive chronic renal failure can occur. Asymptomatic tumoral lesions, typically multiple and bilateral, are sometimes detected on radiologic studies [28-30].

Other

Lymphadenopathy: Lymphadenopathy IgG4-RD associated is either generalized or localized adjacent to a specific affected organ. The lymph nodes involved are generally 1-3 cm in diameter and not tender. Although lymphadenopathy is often a prominent clinical feature of IgG4-RD, establishing the diagnosis through lymph node biopsy is generally difficult because it is unusual for lymph nodes to undergo the degree of fibrosis observed in other organs [31].

Skin. The literature to date describes only a small number of patients with cutaneous disease associated with IgG4-RD. The typical lesions are erythematous, flesh coloured papules with a predilection for the head and cheeks [32].

Prostate. Symptoms of prostatism are ascribed all too easily to benign prostatic hypertrophy because the typical patient with IgG4-RD is a middle aged to elderly man, however, a biopsy-proven prostatic disease is a recognized complication of IgG4-RD. Some patients have dramatic improvements in their urinary stream after treatment for IgG4-RD [33].

Peripheral nerves. IgG4-RD tends to cause perineural lesions. It can affect the cranial nerves and other peripheral nerves in the head, such as the orbital, optic, spinal, and greater auricular nerves. Peripheral nerve lesions consist of perineural masses, often up to 3 cm in diameter, and are usually detected radiologically - typically by magnetic resonance imaging - in the absence of symptoms. However, the predilection of IgG4-RD to involve nerves in the retroperitoneum may be an explanation for the pain associated with this condition [34].

The diagnosis of IgG4-RD remains challenging. Clinical assessments, laboratory evaluations, and imaging studies often are not sufficient to distinguish IgG4-RD from neoplastic, inflammatory and infectious mimickers. As the IgG4-RD tends to present as a tumefactive indolent lesions, mimics malignancy, infectious or inflammatory disorders like sarcoidosis and vasculitis, it could be considered a great mimicker. In the mean while the early recognition is essential, because, this is a highly treatable condition and diagnostic and treatment delay lead to irreversible organ dysfunction and failure. Blood based diagnostic tests such as serology and flow cytometry are the first step towards the diagnosis, but are neither necessary nor sufficient. The imaging has an important meaning too, in a large retrospective study involving 334 patients the first required exam was CT, with contrast medium (93%), whereas MRI, PET and Gallium scintigraphy were performed in one third of cases, respectively. The imaging can be considered diagnostic for some phenotypes but almost always, because the findings are nonspecific, the biopsy is requested. The histology is the cornerstone for diagnosis yet. But even with definite histopathological diagnosis the clinical pathological correlation is always required [35].

Serological testing for IgG4

Routine laboratory tests are nonspecific but may provide an indication of organ involvement. Sometimes an ethnic differences in protein’s production seem to occur. The C-Reactive Protein (CRP) and the Erythrocyte Sedimentation Rate (ESR) are nonspecific markers of organ inflammation, and usually are not elevated. Typically an elevated CRP could be seen in retroperitoneal fibrosis. Howevwe the CRP levels are in the normal range in the most IgG4-RD patients, even in the setting of multiorgan disease and, when raised are usually less pronounced than the ESR’s changes: in a large cohort of 334 cases the median CRP serum level was 0.1 mg /dL, with a value inferior than 1 mg/dL in 90% of patients. This is an important clue in differentiating IgG4-RD from other pathological mimickers associated with elevated IgG4 levels, such as Castelman’s disease or ANCA associated vasculitis. Hyper-gammaglobulinemia is found in 60% of patients, and an often illusory monoclonal gammopathy can be observed, due to migration of IgG4 between β and ɤ band of serum electrophoresis. According to a recent meta-analysis comprising 6.048 IgG4-RD, a cut off >134mg/dL serum IgG4 had a 93% specificity and 85% sensitivity. The measurement of IgG4 is a useful tool for the diagnosis, but by itself neither specific nor sufficient to make a diagnosis. Although there are only few pathological conditions associated with an IgG4 increase of > 5 five time the upper normal value, elevated levels are found in other rheumatic disease frequently, like in rheumatoid arthritis, in systemic scleroderma and in ANCA-associated vasculitis. A similar increase is often found in pancreatic adenocarcinoma (7-10%), cholangiocarcinoma (>10%), in lymphomas, atopic dermatitis, pemphigus, asthma, allergies, multicentric Castelman’s disease and plasma cell dyscrasia and other malignancy [36]. The IgG4 value, usually, correlates with the numbers of organs involved and tends to be significantly higher in glands involvement: in a large study, Yamamoto M, et al. [37] found that IgG4 concentration was higher in Mickulitz’s disease and Kuttener’s tumor than in dacryoadenitis and AIP. Despite showing the classic histopathological and immune-histochemical findings, nearly 30-40% of patients have normal serum IgG4 concentrations. An occasional finding is an IgG4-seronegative IgG4-RD, also in the course of active disease. The IgG4 serum concentration monitoring might be a useful tool to evaluate the disease activity, but many patients do not achieve normal levels even if they are in clinical remission. Thus IgG4 value is not sufficiently sensitive or specific neither for the diagnosis, nor for monitoring disease activity, and does not seem to correlate with disease response to therapy [36-38]. A notion to bear in mind evaluating IgG4 values is that the nephelometry assay, used to measure the IgG4 concentration is prone to error in the presence of large antigen excess, leading to gross underestimation of the serum IgG4 concentration. This effect, known as the prozone phenomenon can lead to false negative results. An appropriate dilution of the serum sample during the assay process prevents the prozone effect [39]. With these considerations, the monitoring of serum IgG4 concentrations seems useful in the assessment of disease activity in some patients, but this measurement should never be used as the sole determinant in diagnosis as well in treatment decisions. Anecdotal evidence suggests that the ratio of IgG4 to total IgG in serum could be more useful for diagnosis than IgG4 concentration alone [40]. Some experts consider that a concentration of IgG4 greater than the 8% of the total serum IgG concentration is suggestive of the IgG4-RD. The IgG4/IgG total ratio >10% might improve the diagnostic power increasing diagnostic specificity. Elevated serum concentration of IgG4 associated with hypo-complementemia and high inflammatory markers seems to detect a particular subtype characterized by a multiple organ involvement and uncertain response to the treatment. Hypo-complementenemia is probably induced by higher concentration of other immunoglobulin subclasses such as IgG1 or IgG2, witch inversely correlates with C3 levels, or by IgG4 binding to C1q. The complement consumption is inversely correlated to the number of organ lesions, and it is usually founded in 30% of cases, more frequently with lung, pancreas and renal involvement [41]. About 30-40% of IgG4-RD patients present peripheral blood eosinophilia unrelated to an underling atopic condition. A recent retrospective study demonstrates that the prevalence of atopy history is superimposable to the general population and, actually, the major parts of IgG4-RD patients are non-atopic. Elevated peripheral blood eosinophilia and IgE concentration, rather than being expression of atopy, could be deemed as epiphenomenon of impaired immune response [42]. As a nonspecific finding, high ANA titres (>1:160) and rheumatoid factor positivity are found in one third of patients and more frequently in specific phenotypes. Sometimes low titres of the anti-dsDNA can also be detected, the detection of more specific autoantibodies is unusual, and always requires a differential diagnosis [43,44]. In patients with pancreatic involvement the levels of biliary enzymes are increased in 60-80% of cases and are frequently associated with normal, or only mildly elevated, levels of serum amylase and lipase. The autoantibodies against antigens such as carbonic-anhydrase, lactoferrin, amylase alpha-2A, ubiquitin-protein ligase E3 component n-recognition 2, an enzyme expressed by acinar pancreatic cells, against the trypsinogen and annexin A11, pancreatic secretory trypsin inhibitor, have poor specificity for the diagnostic purposes and could be found in AIP mimicker conditions6. Patients with TIN generally present with proteinuria, haematuria, hypo-complementemia and decreased kidney function. Nephrotic range proteinuria occurs in a small minority of IgG4-RD patients with renal disease and, when present, is associated with membranous GN. Decreased renal function with abnormal urine analysis occurs in long standing kidney disease. Patients with renal involvement show elevated IgG4 serum level in almost all cases associated with hypo-complementemia (in one half of cases) and increased serum IgE [28-30].

Pheripheral cellular blood circulating marker

Plasma blasts: The plasma blasts, CD19lowCD38+CD20-CD27+ cells, express high levels of the signalling lymphocytic activation molecule F7 (SLAMF7), a CD2 family receptor on activated human B and T cells. They derive from B cell lineage, and are intermediate between activated B and plasma cells. Both plasma blasts and IgG4 are somatic hyper mutated in IgG4-RD, with a high degree of hyper somatic mutations and an oligo clonal restricted repertoire, with 3 to 5 dominant clones. They express high levels of HLA-DR molecules and play an important role in activation of CTL CD4+ lymphocytes with subsequent production of inflammatory and pro fibrotic cytokines. Plasma blasts, rare in the peripheral blood of healthy individuals, can be expanded after an infectious stimulus or vaccination. They could be also found elevated in other inflammatory conditions, but in IgG4-RD frequently take values more than 2000/mL, with high specificity and sensitivity. Plasma blasts concentration, measured on fresh peripheral blood samples by flow cytometry, is elevated in serum of patients with active disease, independently from serum IgG4 concentration, so if the suspicion is high the measurement of plasma blasts concentration could be useful to settle down any doubt [45]. The plasma blasts count has been reported to coincide with both the active phase and disease relapse, and has been suggested to be a useful biomarker of disease activity in IgG4-RD more sensitive than the serum IgG4 concentrations. A multi-organ involvement has a higher absolute plasma blasts count and is related to IgG4-RI (IgG Responder Index) [45,46]. Thus plasma blasts concentration can be used to follow treatment response, determine its intensity and eventually, to guide time of the maintenance therapy [6,45].

Tfh2: Recent results suggest a potential of activated Tfh2 (T follicular helper 2) cells as a biomarker in IgG4-RD. The number of activated Tfh2 cells correlates with disease activity, and there is a strong correlation between the number of circulating activated Tfh2 cells and the number of affected organs, suggesting that these cells are generated from ectopic germinal centers (i.e. ectopic lymphoid structures, ELSs) in affected organs. Further elucidation of the role of Tfh2 cells as a marker of disease activity would be required for the future [47].

Imaging studies for IgG4-RD

Various and characteristic radiological findings are related with organ involvement but almost always they are not sensitive and not specific. Macroscopically pancreas involvement is characterized by diffuse sausage shape like or localized enlargement with irregular narrowing of pancreatic ducts. This could be founded on CT or US. With more accuracy contrast enhanced CT and MR show a diffuse pancreatic enlargement in 44% of cases, whereas local enlargement, more frequent (56%), goes into differential diagnosis with cancer. The characteristic delayed enhancement pattern and the capsule-like rime sign are related to pancreatic parenchymal replacing fibrosis. The pancreas appears diffusely enlarged during pancreatic phase and uptakes the contrast medium in a reduced and slower manner, giving the typical delayed enhancement. Capsule like rime is a fibrosis band-like structure, that surround all, or part of lesions, and show an increased delayed enhancement than parenchyma, this sign is specific of AIP, whereas nonspecific signs are pseudo-cystic lesions, calcification of parenchyma and atrophy. A recent study, validating the use of perfusion CT in AIP, demonstrates a reduced pancreatic volumetric perfusion in patients with ongoing AIP, and an improvement after steroid therapy. In this regard the perfusion CT would be useful for diagnosis and to evaluate therapeutic response. The absence of typical CT findings does not exclude the AIP. Analogues findings are detected with MR: T2-weighted images show a lower signal in fibrosis organ replacement, and a delayed enhancement pattern, with a capsule rime, is detected in 36% of cases, in the dynamic sequence. More recently the use of Diffusion-Weighted MR imaging (DWI-MR) has been reported as a useful tool in differential diagnoses. Pancreas biopsy can be performed through Endoscopic Ultrasound-guided (EUS) tru-cut, with a high diagnostic value, whereas EUS fine needle aspiration biopsy (FNAB), has a low diagnostic power, unless would be performed with a 22 gauge needle. The needle biopsies could be sufficient to differentiating the diagnosis from other mimickers but not to evaluating characteristic histological features of IgG4-RD [48-51]. The typical findings of PSC are not seen in IgG4-SC. Abdominal US, abdominal CT, abdominal MR can detect the thickening of bile duct, and EUS could show a characteristic circular symmetrical with smooth margin and a homogeneous internal echo thickening, however, the bile ducts narrowing should be assessed with direct cholangiography, such as Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Trans Hepatic Cholangiography (PTC), that allow to perform biopsy that, once again, is a cornerstone of differential diagnosis. The US is the first diagnostic level to detect glandular enlargement in Mikulicz’s disease and Kuttner’s tumor, showing an organ enlargement with diffuse or nodal changes that are considered one of the most characteristic findings, and could be also detected on CT on MR, where the lesions appear iso/hypointense T2, with a homogeneous contrast enhancement [48]. Gallium (Ga) scintigraphy shows a localized accumulation of the radiotraciant in all inflammatory lesions, and can be used either for diagnosis, either to assess the extension of disease, or monitoring the disease activity, although it was positive in 70% of aortic involvement and 20% of salivary-lacrimal glands. PET-CT has been demonstrated as a major diagnostic power to detect the disease and its burden. The maximum Standardized Uptake (SUV) of Fluorodeoxyglucose (FDG), does not differ from tumours, neither in early phase nor in the late phase, whereas the evidence of a multifocal disease (60%) with a concomitant uptake in several organs can be diriment in the differential diagnosis. It is the tool to choose the more safe organ biopsy and it is frequently adopted during the follow up, to optimize steroid therapy or to detect the relapse, however concerning about X-ray and economic expenditure have been raised, so to monitor disease activity the cheaper and more readily available SPECT-CT or Ga scintigraphy could be used [52]. IgG4-related ophthalmic disease can be detected with CT or MR studies, mass lesions appear as well-defined iso-attenuated on pre-contrast CT imaging or iso-intense on T1 and hyper-intense T2 lesion on MR, with a clear margins and a homogeneous internal enhancement associated to bone remodelling, without destruction. The perineuritis of optic nerve and trigeminal nerves, which could be considered a typical feature of IgG4-RD, is showed as an enlargement of infraorbital nerve, and is better seen in coronal sequences on MR [53]. The radiologic features of pulmonary involvement are often striking, even in the setting of mild clinical symptomatology. IgG4-RD in the lung is often easily confused with other entities in its radiologic manifestations, which include: (a) solid nodular lesions, sometimes with spiculations, (b) round-shaped, ground-glass opacities, (c) alveolar interstitial disease, with honeycombing, bronchiectasis, and diffuse ground-glass opacities, and (d) thickening of the bronco-vascular bundle. Pleural effusions or pleural thickening are rare, and a mediastinal lymphadenopathy commonly accompanies the pulmonary involvement [50]. The renal involvement is detected on CT imaging, showing in more than half of cases multiple low density lesions, with progressive contrast enhancement. The second finding, for frequency, is a diffuse bilateral renal swelling, accompanied by a diffuse thickening of renal pelvis, with sparse solitary nodules and renal cysts. The thickening of renal hilum could determine, in one half of the cases, the development of hydro nephrosis, with ureteral obstruction. The kidney lesions evolve toward the organ atrophy. Because of the radioisotope kidney excretion the PET-CT is not useful to detect kidney involvement. The gallium SPECT-TC may be superior to PET-CT, differentiating IgG4R-kidney disease from other renal masses [54]. Retroperitoneal involvement is easily detected on CT. Hydro nephrosis is a common complication and usually there is an intra-abdominal, inguinal, axillary lymphadenopathy, and imaging findings consistent with aortitis, eventually associated with peri-aortic ectasia/aneurysm [49,52,55]. Radiologists sometimes classify this condition into three subtypes defined by their location: (a) periaortic/arterial, involving connective tissue around the abdominal aorta or its first branches; (b) periureteral; and (c) plaque-like, broadly involving the retroperitoneal region [55]. Arterial wall thickening, aortic aneurysms or dissections is detected on cross-sectional imaging studies of the aorta. A homogeneous enhancement is typically present during the late phase of CT scan and appears to correspond to sclerosing inflammation that is located predominantly in the adventitia. Hypophysis involvement is rare, and MR is the gold standard to reveal the enlargement of the anterior part and the thickening of the stalk. Radiologic features of IgG4-related hypophysitis include a thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or mass formation within the pituitary. Destructive lesions of bone has been reported, and in these cases cranial nerves are frequently involved in masses. Localized or diffuse linear thickening or bulging mass of dura mater is an indicator of hypertrophic pachymeningitis [56]. CT as well as EUS can reveal severely swollen prostate gland [57]. The current gold standard for diagnosis is histology with immunohistochemistry [58].

Pathology

Histopathologic features and mechanistic implications: Histopathology is the key to diagnose IgG4-RD. The three major pathological hallmarks of IgG4-RD are a dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis. A dense lymphoplasmacytic infiltrate founded in 100% of cases: lymphocytes and plasma cells are polyclonal. The infiltrate is characteristically eosinophilic, and in the glandular organ it is found around ductal structure, whereas neutrophilic infiltration is rare, it could be still present especially in lesion of upper aerodigestive tract and in bronchoalveolar spaces, or in the case of overlapping disease, but they never form granulomas or necrosis. Storiform fibrosis, cartwheel like, present in 74% of cases, is highly characteristic. Fibrosis is a histological prerequisite for the diagnosis. Storiform fibrosis, characterised by radially arranged collagen fibres, that seem to weave through the tissue, typifies the unique pattern associated with IgG4-RD. Fibrosis commonly predominates over a long disease course, and the histological features can become less specific in patients with longstanding disease. Some fibrosis is present in all cases, even in patients who present shortly after symptoms onset and it has, typically, a patchy distribution, thus en-bloc biopsy is, always, recommended. The characteristic venous lesion, the obliterative phlebitis, could be detected in 40% of cases. Veins appear obliterated by a lymphoplasmacytic cell, infiltrating the wall and the lumen of the affected vessels, which commonly manifest themselves as inflammatory nodules next to a patent artery. Arteritis, with the same characteristic, is frequently observed in the AIP and in pulmonary involvement. The histological appearance is similar for all organs 59. Two of three major characteristics must be present to diagnose IgG4-RD according to the consensus statement on pathology58. A negative biopsy does not rule out the diagnosis. High numbers of IgG4-positive plasma cells at tissue sites are a disease hallmark, even when serum IgG4 concentrations are normal. An international pathology consensus statement proposed, for example, that for sialoadenitis the cut off value should be at least 100 cells per high power field (hpf), but that in the pancreas more than 50 cells per hpf is compatible with a diagnosis of AIP. IgG4-RD cannot be diagnosed on the basis of infiltration by IgG4-positive cells alone, because the plasma cells can be present in other inflammatory and neoplastic disorders, the ratio of IgG4 to IgG-positive plasma cells must be at least 40% (it is typically 70% or higher) [58-60].

The inflammatory infiltrate: The dominant histopathologic feature is the abundance of CD4+ T cells [6]. B cell follicles composed of IgG4+ B cells and extra follicular plasma cells are generally observed within the lymphoplasmacytic infiltrate, as are T cells. In most cases, the B cells are confined to small cohesive lymphoid aggregates or, less commonly, to GCs that are minor histopathological features [6]. The tissue between these GCs is dominated by T lymphocytes, most of which are small, mature-appearing CD4+ T cells. Increased tissue concentrations of IgG4+ plasma cells are a diagnostic hallmark of IgG4-RD [61]. Plasma cells predominate in some cases and they generally appear mature. Binucleate plasma cells and Mott cells are observed only occasionally. Immuno-histochemical and immunoglobulin gene-rearrangement studies confirm that both the plasma cells population and T cells are polyclonal [61,62]. However, a publication suggests that IgG4-RD is associated with lymphoid proliferation that is oligoclonal in nature, composed of a dominant IgG4+ lymphoid cell clones and compatible with an immune response [63]. Extra nodal GCs formation and expansion of somatically mutated clones suggest that the elevated IgG4 serum levels and IgG4 class-switch are caused by an antigen driven, T cell–dependent B cell response. The inflammatory lesions of IgG4-RD are packed not only with IgG4+ plasma cells but also with CD4+ T cells, macrophages, eosinophils, fibroblasts, and myofibroblasts. It has been proposed a model of how the coordinated actions of a range of cell types and cytokines, in the fibro-inflammatory infiltrate, may cause the characteristic storiform fibrosis of IgG4-RD [64]: Th2-derived IL-4 and IL-13, as well as the IL-10, may result in the generation of alternatively activated macrophages, which enhance fibrogenesis by providing additional profibrogenic factors like Tumour Growth Factor β1 (TGF-β1) and Platelet Derived Growth Factor (PDGF). IL-5, produced by Th2 cells, by recruiting eosinophils that, in turn, produce TGF-β1, PDGF, and IL-13 promote fibrosis, as well [64,65]. These profibrotic cytokines can recruit and activate macrophages, fibroblasts, and myofibroblasts and inducing the characteristic fibrosis of IgG4-RD [64]. However, IgG4-RD may be caused by Th1 cells too, in a synergistic way [66].

IgG4-bearing cells: The histopathologic diagnosis is predicated on the documentation of elevated numbers of IgG4+ plasma cells [64-67]. In attempts to codify the histopathologic diagnosis of IgG4-RD, investigators have proposed diagnostic cut offs for the frequency of IgG4+ plasma cells (>40% of all plasma cells) [64]. The presence of positive plasma cells IgG4+ is required but, since there are many other conditions, the presence of IgG4+ plasma cells is not necessary and nor sufficient, their presence ranging from 10 to 50 % for hpf. The ratio between IgG4+ plasma cells and total IgG4 may be a very useful tool, especially in conditions where fibrosis predominate, such as retroperitoneal fibrosis, as well as for differential diagnosis. According to Prisma compliant systematic review, the IgG4/IgG bearing plasma cell >30% is the most reliable marker, with a sensitivity of 59% and specificity of 90% [64-67].

Fibrosis: The storiform fibrosis, that characterizes IgG4-RD, represents an unusual pattern of collagen deposition. In the active phase of IgG4-RD, the collagen deposition is accompanied by an admixture of fibroblasts and myofibroblasts. In cases presumed to be of long duration, such fibroblastic cells dominate the histological picture, creating a resemblance to a mesenchymal neoplasm. These spindle cells are generally positive for smooth muscle actin and negative for desmin. The ratio of IgG4 to total IgG is helpful in such cases. Although the total number of plasma cells, within any hpf, may be small, the finding of an increased ratio of IgG4 to total IgG is nevertheless suggestive of the diagnosis. The key to diagnosis under such circumstances, may be the storiform morphology of the fibrosis. However, the “burnt out” phase of IgG4-RD can be dominated by relatively acellular and patternless fibrosis.

Obliterative vascular disease: A unique feature of IgG4-RD is the presence of obliterated venous and, less commonly, arterial channels. The lumina of these small and medium sized veins are partially or completely occluded by an inflammatory infiltrate composed of lymphocytes and plasma cells. Although there is a strong predilection for venous involvement by the inflammatory infiltrate in IgG4-RD, obliterative arteritis is, sometimes, observed particularly in the lung. When the arterial circulation is affected, there is a preference for small and medium sized arteries, but the disease can also affect large vessels, including the aorta. Rapid destruction of the blood vessel wall is unusual, and has been described in the aorta and other medium to large sized vessels64. The finding of obliterative lesions of blood vessels is of immense diagnostic value because this histologic appearance appears to be unique to IgG4-RD

Eosinophils, germinal centers and macrophages: Eosinophils are absent just in a minority of cases. In some examples of IgG4-RD, such as eosinophilic angiocentric fibrosis, the eosinophils dominate the histological picture [67]. Lymphoid aggregates, composed of small B lymphocytes, are ubiquitous in IgG4-RD, but GCs are observed in only a minority of cases [68-70]. These extra nodal GCs, morphologically resemble nodal GCs, and are composed of centrocytes and centroblasts, as well as a meshwork of CD21+ follicular dendritic cells. Some of these GCs are composed entirely of IgG4-bearing lymphocytes. Macrophages, are usually detectable within the fibro inflammatory infiltrate, if immune-histochemical stains for antigens such as CD68 are performed. However, the finding of diffuse sheets of macrophages, particularly foamy macrophages and multinucleated giant cells, argues strongly against the diagnosis of IgG4-RD [71]. The presence of granulomas, particularly necrotizing granulomatous inflammation, similarly excludes IgG4-RD [58].

Overview on germinal center formations

IgG4-RD may represent the prototype of a T cell–mediated autoimmune disease, wherein the role of autoantibodies is not central to pathogenesis. Clonal expansion of presumably pathogenic B cell and T cell subpopulations in patients’ blood and affected tissues indicates that IgG4-RD is likely sustained by an antigen driven immune response, but the nature of the antigen(s) and the reason for disease targeting of particular organs remain unclear. In response to infection or immunization with a T-dependent antigen, GCs are formed within the B cell follicles of secondary lymphoid tissues. GCs are clusters of rapidly dividing B cells that are undergoing rounds of somatic hyper-mutation of their antigen receptor genes. T-follicular helper (Tfh) cells, a specialized subset of CD4+ helper T cells, that migrate into GC and provide help and survival signals to GC B cells, promoting their differentiation into long-lived plasma or memory B cells. T cell help is essential for the formation and maintenance of the GCs, B cell maturation and differentiation, and immunoglobulin class switch, and the response collapses in the absence of Tfh. Tfh are required for the response to foreign antigens, but in excess they can support autoreactive GCs responses, leading to autoimmunity. The circulating Tfh compartment in human is heterogeneous based on PD1, CCR6, and CXCR3 expression. The CD4+CXCR5+PD1+ Tfh cells are expanded in IgG4-RD [70-72]. In addition to Tfh, there is another subset of CD4+ T cells within the GC, T follicular regulatory (Tfr) cells. Tfr cells share phenotypic characteristics with Tfh, but are derived from suppressive Foxp3+ (forkhead box P3) Tregs. Tfr co-opt aspects of the Tfh differentiation pathway and upregulate B-cell lymphoma-6 (Bcl-6), the transcriptional repressor that is essential for the formation of Tfh. This allows Tfr to enter the GC, and exert a suppressive function: within the GC, Tfr cells control the size of the GC response and restrict the outgrowth of non–antigen specific B cell clones. The formation of Tfh and Tfr is dependent on interactions with B cells, outside the B cell follicle. Extra nodal GCs (i.e. ectopic lymphoid structures, ELSs) are characteristic histopathological findings in an IgG4-RD lesion, indicating aberrant activation of humoral immune responses [72,73]. Recent data suggests that the initial step in the formation of Tfh is upregulation of the achaete-scute homolog 2 (Ascl2). This transcription factor induces upregulation of the chemokine receptor CXCR5, the ligand of which, CXCL13, is expressed in the B cell follicle, enabling pre-Tfh to migrate to the border of the B cell follicle. Ascl2 has also been shown to suppress genes associated with other T cell subsets, priming pre-Tfh differentiation down the follicular pathway. Pre-Tfh cells also express Bcl-6, which is both necessary and sufficient for Tfh differentiation. In contrast with the role for Ascl2 in Tfh cells, Tfr cells require NFAT2 for upregulation of CXCR5 and their subsequent migration. At the T-B border, pre-Tfh encounter antigen primed B cells and receive a second round of antigen presentation, enabling them to stabilize Bcl-6 expression, commit to becoming a Tfh cell, and migrate into the GC. In return, pre-Tfh provide signals to B cells to initiate immunoglobulin isotype class switching and form GCs. In mice, it is clear that the interactions between Tfh, Tfr, and GC B cells are reciprocal. Tfh and Tfr both require ongoing interactions with GC B cells in order to maintain their phenotype and function, and selective lack of GC B cells during an ongoing response leads to a reduction in Tfh numbers. Equally, GC B cell numbers and differentiation depend on support from Tfh, with the GC and response collapse in the absence of Tfh [70-75].

Potential initiating mechanisms

Genetic Risk Factors. Genetic studies of IgG4-RD are in their infancy. Among several of the genetic susceptibility factors for IgG4-RD, the HLA serotypes DRB1*0405 and DQB1*0401 increase the susceptibility to IgG4-RD in Japanese populations, whereas DQβ1-57, without aspartic acid, is associated with disease relapse in Korean populations. Non-HLA genes, in which single nucleotide polymorphisms are involved in disease susceptibility or recurrence, encode proteins that include CTLA4, Tumour Necrosis Factor (TNF) α, and FcRL3 [74,75].

Bacterial Infection and Molecular Mimicry. Substantial homology exists between human carbonic anhydrase II and the α-carbonic anhydrase of HP. The homologous segments contain the binding motif of the HLA molecule DRB1*0405. Homology also exists between the Plasminogen Binding Protein (PBP) of HP and the ubiquitin-protein ligase E3 component n-recognin 2, expressed in pancreatic acinar cells. One study showed that a majority of patients with AIP have antibodies against the PBP of HP [76]. In theory, antibodies directed against these bacterial components could behave as autoantibodies by means of molecular mimicry in genetically predisposed persons. The study, however, appears to have included both type 1 and type 2 cases of AIP and the findings still require confirmation. A study of one patient with IgG4-RD, showed that stimulation of Peripheral Blood Mononuclear Cells (PBMCs), with toll-like receptor ligands induces the production of both IgG4 and IL-10, raising the possibility that various species of bacteria induce production of IgG4 through innate immunity. If this is the scenario the immunologic reactions could be similar among patients, even if the causative factors differ [77].

Autoimmunity. Serum IgG4 from patients with IgG4-RD bind to the normal epithelia of the pancreatic ducts, bile ducts, and salivary gland ducts. Antibodies directed against such antigens, some of which are expressed in various exocrine organs, may be related to systemic manifestations of IgG4-RD. A variety of self-antigens have been identified, including prohibitin, galectin-3, annexin-A11, and laminin-511, suggesting that a breach of immunological tolerance might initiate the disease [78,79]. However, these autoantibodies are neither specific for IgG4-RD, nor known to be, always, of the IgG4 subclass [79]. Thus, their role in IgG4-RD, if any, is unclear. The nuclear protein prohibitin, detected with high frequency in patients with multiorgan IgG4-RD, has not been validated yet. Recently Perugino, et al. [67] have reported an increases expression, in many affected tissues of IgG4-RD patients, of IgG4 autoantibodies, and sometimes IgE serotype autoantibodies too, versus the β-galactoside galectin-3, one of major protein in the fibrogenesis process. The serum AIP 1-7 peptide, show high homology in amino acid sequence with PBP of HP, and, in association with the UBR2, has been recognized as a marker of AIP, however is also present in 5% of patient with pancreatic cancer, missing diagnostic value. The antibodies against truncated form of laminin 511, or its ligand integrin α6β1, are present in more than one half of AIP patients, with very high specificity and, a correlation with disease activity, making them either a good diagnostic, either a valid prognostic marker [76,80].

The role of IgG4 antibodies. There is no evidence to suggest that the IgG4 autoantibodies are directly pathogenic in IgG4-RD [81]. IgG4 antibodies undergo a process, called Fab-arm exchange, within the endosomal compartment of endothelial cells. In this process, the heavy-chain dimers of an IgG4 molecule dissociate and, each hemi-molecule, associates with another, different, hemi-IgG4 protein. Most secreted IgG4 are therefore functionally monovalent and cannot crosslink antigens to form the lattice structure found in immune complexes. As a result, IgG4 antibodies do not directly fix complement, they bind poorly to activating Fc receptors and they are generally thought to be non-inflammatory [81,82]. Compared with other immunoglobulin subclasses, IgG4 antibodies are known to participate in the resolution of tissue inflammation because of intrinsic anti-inflammatory properties. IgG4 concentrations are also known to rise, after IgE concentrations decline, in allergic disorders. In theory, however, IgG4 could be pathogenic and could, perhaps, collaborate with circulating lectins to activate complement in disease lesions. IgG4 bound to FcγRI on the surface of innate immune cells, including dendritic cells, alternatively activated macrophages, and eosinophils, may help in the sampling and presentation of extracellular antigens to T cells. Theoretically, this process could occur within the fibro-inflammatory infiltrate as well as within the lymphoid organs, thereby sustaining the inflammation [82].

Cells involved

Since the establishment of this disease entity, a number of studies have been performed for clarifying the immunological mechanisms of this disease. CD4+ T cells are necessary for support and coordination of IgG switched B cell responses [67,72].

In the early period of IgG4-RD research, Th2 cells and Treg cells were considered the main players in IgG4-RD. After such studies other new CD4+ T cell subsets, including PD-1hiCXCR5- peripheral T helper-like (Tph) cells, Tfr cells, and CD4+ cytotoxic T lymphocytes (CD4+ CTLs) were identified in blood of patients with IgG4-RD and were suggested to play a cardinal role in the immunological settings of IgG4-RD since they are significantly correlated with various clinical parameters [83]. Each cell subtype will be discussed in the following sections.

Th2 cells: Levels of Th2 cells and Th2 cytokines including interleukin IL-4, IL-5 and IL-10 are frequently increased in affected tissues or peripheral blood of patients with IgG4-RD [72,82-84]. However, Mattoo H, et al. [85] reported that circulating memory Th2 cells in IgG4-RD are detected in a limited population of subjects with atopy85. The percentage of tissue Th2 cells in IgG4-RD does not seem to be correlated with clinical parameters, indeed, and the evidences suggest a limited value in the pathological process, mirroring the scarce clinical value. Importantly, Th2-derived cytokines IL-4, IL-5, and IL-13, believed to drive IgG4 (and IgE) class switch, can also be produced by mast cells and Tfh-cell subsets [72].

Treg cells: It is well known that IL-10 and TGF-β are key cytokines for IgG4 class switching and fibrosis, respectively [65-67]. Therefore, regulatory T cells have been regarded as a pathognomonic source of IL10 and TGF-β [86]. Several studies have shown an increased number of Treg cells and increased expression level of their master regulator, Foxp3, in both affected sites and circulating leukocytes in patients with IgG4-RD. Treg cells seem preferentially involved in IgG4 class-switching and fibrosis in lesions of IgG4-RD; however, no direct evidence regarding the function of Treg cells in IgG4-RD was shown and further studies are required.

CD4+ cytotoxic lymphocytes: CD4+ CTLs are characterized by a unique function of secreting perforin, granzyme A (GZMA) and IFN-ɤ for killing target cells in an MHC class II restricted fashion [10,70]. These cells presented SLAMF7, IL-1β, and TGFβ, suggesting a capacity to promote tissue inflammation and fibrosis [87,88]. Recently, there has been an accumulation of experimental evidence suggesting the involvement of CD4+ CTLs in IgG4-RD. Mattoo H, et al. [87] first reported the clonal expansion of CD4+ CTLs in inflamed tissue sites of IgG4-RD. Interestingly, clinical remission, induced by RTX-mediated B cell depletion, is associated with a reduction of CD4+ CTLs. These findings seem to leave to conclusion that CD4+ CTLs could collaborate with activated oligo-clonally expanded plasma blasts and may play an important role in the pathogenesis of IgG4-RD. However, there has been no functional experiment on CD4+ CTLs in IgG4-RD, because of the minor population in CD4+ T-cell subsets and the lack of specific surface markers for live cell sorting. Additional studies are required in the future to obtain direct evidence of cytotoxicity and fibrosis in affected tissues of IgG4-RD by these cells [88].

Tfh cells: A dysregulation of the IgG4 class switch underlies the pathogenesis of IgG4-RD [68]. Tfh cells are postulated as a specialized class of effector helper CD4+ T cells, to assist GCs forming B cells and the class switch recombination, leading to the selection of high-affinity B cells in GC [46],. Importantly, Tfh cells have the capacity to secrete IL-4 and IL-10, which are key cytokines for IgG4 class switching86. Tfh cells have been considered as a potential key player in the development of IgG4-RD [86,89]. Tfh cells are primarily localized in lymphoid organs, but they are also found in tissue lesions and in peripheral blood, as human blood contains CD4+CXCR5+ T cell populations that share some functional properties with Tfh cells [47,86]. Because of the limited access to secondary lymphoid tissues from humans, several groups have examined circulating cells expressing the same surface markers as Tfh, in particular CXCR5, Inducible Costimulator (ICOS), and Programmed cell Death-1 (PD-1), coined the term circulating Tfh-like (cTfh) cells [72-73]. The cTfh-like cells appear to be a population of memory T cells that are generated during Tfh differentiation, cTfh-like cells do not express Bcl-6 protein, but are able to quickly differentiate into cells capable of supporting antibody production [89]. These cTfh cells can be divided into three cTfh subsets based on the expression of CCR6 and CXCR3: CXCR3-CCR6+ cells resemble Th1 cells (termed cTfh1 cells), CXCR3-CCR6-cells resemble Th2 cells (termed cTfh2 cells), and CXCR3+CCR6- cells resemble Th17 cells (termed cTfh17 cells) [90], that can secrete restricted repertories of the cytokines IFN-ɤ, IL-4 and IL-17, respectively, as seen in conventional helper T cell. Of these cTfh subsets, only cTfh2 and cTfh17 could induce naïve B cells to proliferate and differentiate into plasma blasts/plasma cells via the secretion of IL-2 [89-91]. The site where the differentiation and expansion of Tfh occurs is unknown, and no link has been established with IL-1β and TGF-β producing clonal expanded CD4+SLAMF7+ CTLs [72-73]. Major cytokines involved in the early Tfh differentiation process, including IL-12, IL-23, and TGF-β but they are also supported by other STAT3-activating cytokines including IL-6, IL-21, and IL1-β [86,92].

PD-1 is a marker of cell activation in Tfh cells, is essential for B cell selection and survival in the GCs and also induces GC B cell differentiation into high-affinity long-lived plasma cells interacting with PD-L1 and/or PD-L2 expressed on the B cells [92].

ICOS, a member of the CD28 family of costimulatory molecules, is important for the maintenance and function of Tfh cells through cognate interactions with ICOS-L on the B cell surface. According to the expression and intensity of PD-1 and ICOS, each of the cTfh1, cTfh2 and cTfh17 subpopulations could be further divided into 3 subsets: one activated subset (ICOS+PD-1+), and 2 quiescent subsets (ICOS-PD-1+and ICOS+PD-1)93. The activated cTfh1 cell subpopulation, via IL-21 and IL-10, is the most efficient at inducing memory B cells to proliferate and differentiate into plasma cells, with an increase in antibody titers [90-93]. The cTfh2 and cTfh17 cells, activated subpopulation, have increased functional capacity to help both naïve and memory B cells, whereas the ICOS-PD-1+ quiescent populations more efficiently promote help for memory B cells, than the ICOS+PD-1- population, although the latter as more efficient in helping naïve B cells to produce Ig [93]. cTfh numbers are elevated in patients with autoimmune diseases and correlate with increased antibody levels and disease severity [90].

Expansion of Tfh-cell subsets have recently been demonstrated in patients with systemic IgG4-RD. All of the cTfh cell subsets from patients with IgG4-RD exhibited augmented function when compared to those from Healthy Controls (HCs). The frequencies of activated and quiescent cTfh cells were much higher in the circulating blood of patients with IgG4-RD than in HCs and expansion of mature Tfh cell subsets was even greater in the involved organ tissue of patients [93].

The expression of PD-1 on Tfh cells might play an important role in the pathogenesis of IgG4-RD, especially in the process of inducing GC B cell differentiation into IgG4-secreting plasma cells. The PD1+ Tfh population is required for T cells to migrate into B cell follicles. The activation marker PD-1 is essential for B cell selection, survival, and maturation. PD-1+ Tfh cells can support B cells to produce IgG4 antibody, favouring the hypothesis that the expanded population of circulating PD1+ Tfh cells support B cell differentiation toward IgG4+ plasma cells. Tfh cells, in patients with IgG4-RD, have been shown to be more efficient in inducing naïve B cells to differentiate into switched memory B cells and plasma blasts with increased IgG4 secretion, to facilitate B cell proliferation and to inhibit B cell apoptosis compared to HCs, suggesting a functional role of these cells in the disease. Notably, in patients with IgG4-RD, the frequency of PD-1+ in cTfh cells showed a significant positive correlation with the serum levels of IgG, serum levels of IgG4, and IgG4:IgG ratio and the number of organs involved. Interestingly, the frequencies of PD-1+ cTfh cells, also, positively correlated with the frequencies of plasma blasts/plasma cells [93,94]. In rheumatoid arthritis, has been shown that PD1+ cTfh are maintained by plasma blasts, by an IL-6-dependent positive feedback loop, an observation that should be investigated in IgG4-RD42, considering its potential in therapeutical setting. Interestingly, a study showed that PD1+ Tfh cells were significantly decreased in patients with IgG4-RD treated with either steroids alone, steroids plus azathioprine, or steroids plus RTX and that the decrease in PD1+ Tfh cells was always associated with clinical improvement of the disease.

Both PD1+ Tfh2 and Tfh17 subsets have been shown to be prone to migrate into B cell follicles and/or at inflammatory sites and could therefore contribute to B cell activation and IgG4 class switch in IgG4-RD tissues [91-93]. Tfh2 cells have been reported to best mirror disease activity in IgG4-RD: circulating PD-1+ Tfh2 cells correlate with serum levels of IgG4 and IgE, the IgG4-RI disease activity score and plasma blasts and are reduced after treatment in line with clinical remission of disease. PD1+ Tfh2 cells provide added value to the other clinical markers of active disease and perform better than circulating plasma blasts expansion on multiple regression analysis in a large cohort [73]. This supports a role for activated circulating PD-1+ Tfh2 cells as a biomarker of disease activity, complementary to other clinical markers, and highlights a role for the Tfh2-plasmablas axis in active IgG4-RD [72,84,90-94].

Taken together, the results indicate that activated Tfh cells possessing unique functions, abundantly infiltrate affected lesions of IgG4-RD and play an important role in the pathogenesis of IgG4-RD. Fundamental questions that remain to be answered are whether circulating Tfh cells and resident Tfh cells in affected tissues have the same origin and, if so, how circulating Tfh cells migrate from or into the affected tissues. Further studies on Tfh cells in IgG4-RD are needed to answer these questions [86].

Tfr cells: Interestingly, the PD1+ Tfh subset also comprises Tfr cells co-expressing Foxp3 and, an imbalance of Tfh/Tfh Foxp3+ reg could also be implicated in the disease’s pathophysiology and should be further explored [95]. Tfr cells have been characterized as a unique CD4+ T cell subset that participates in the control of germinal center formation and class switch recombination of B cells in collaboration with Tfh cells95. Tfr cells express CXCR5, which is also shared by B cells and Tfh cells. Tfr cells are regulated by Bcl-6, PD-1, and ICOS as well as Foxp3, as observed in Treg cells [96]. To exert germinal center responses, Tfr cells produce IL-10 and TGF-β, for the direct regulation of B cells and Tfh cells. Because most of the studies regarding Tfr cells in disease have mainly been performed in mouse models [97], functional roles of Tfr cells in human diseases are not fully understood [82]. Tfr cells have a critical function to control the magnitude of GC responses, by modulating Tfh cells and B cells [67]. Other studies showed that Tfr cells have the capacity to control the proliferation of Tfh cells [92,98] and that the proliferative activity of GC B cells depends on IL-10 secreted by Tfr cells. Moreover, IL-10 facilitates class-switch recombination of IgG4 in B cells. Moreover, recent studies have revealed that IL-10 produced from Tfr cells promotes the germinal center response [21]. Recent results showed that the number of Tfr cells was increased in blood and inflamed submandibular glands from patients with IgG4-RD [90]. In addition, the absolute number of IL-10 producing Tfr cells in IgG4-RD patients was significantly increased compared to that in age-matched HCs. An increased number of Tfr cells might lead to the activation of Tfh and B cells, and an increased number of IL-10 producing Tfr cells is potentially involved in IgG4-specific class-switch recombination in IgG4-RD lesions. The precise mechanisms by which Tfr cells induce proliferation of activated Tfh cells and the mechanism of IgG4-specific class-switch recombination in IgG4-RD lesions are still unclear but warrant examination. Moreover, although the reason why Tfr cells in blood from patients with IgG4-RD were increased compared to those in age-matched healthy volunteers is not known, it is possible that the increased numbers of circulating and lesional Tfr cells in IgG4-RD reflect a compensatory change, as a way to suppress abnormal immune responses. The percentage of Tfr cells was positively correlated with clinical parameters including serum level of IgG4 and number of involved organs in patients with IgG4-RD [90]. Further studies are needed in order to clarify the mechanisms of accumulation of Tfr cells in IgG4-RD. Collectively, the results support the unique immunological environment in IgG4-RD, in which there is an increased number of Tfr cells and activated Tfh cells, probably underlying the pathogenesis of IgG4-RD.

Tph cells (PD-1hiCXCR5-CD4+ cells)97 present Tfh cell-like features to produce factors associated with B cell help, including IL-21 and CXCL13. Unlike Tfh cells, Tph cells do not express high levels of Bcl-6 and, instead, show elevated levels of Blimp-1, which opposes the actions of Bcl-6, as a counter regulator98. Tph cells also have a unique expression profile of chemokine receptors, such as CCR2, CCR5, and CX3CR1 (a fractalkine receptor), that ignite their migration to inflamed sites [99]. Tph cells frequently expressed GZMA, which is related to a cytotoxic property. Thus, Tph cells show substantial differences from Tfh cells in their surface phenotypes, migratory capacity, and transcriptional regulation [97]. The first study on possible pathological role of Tph cells in IgG4-RD100 shown that circulating PD-1+CXCR- cells (including PD-1hiCXCR5- Tph-like cells) were significantly increased within CD4+T cells in patients with IgG4-RD compared to those in HCs. Clinical remission achieved by treatment with glucocorticoids clearly led to a numerical reduction of Tph-like cells [100,101]. Together, these findings strongly suggest that circulating Tph-like cells play a pivotal role in the pathogenesis of IgG4-RD. Tph can have a major role in hypermutation, class switch recombination, and differentiation of plasma cells [101], they run a functional interplay accelerating the development of the disease. The appearance of a new player, Tph cells, in the research field of chronic inflammation, might lead to a deeper understanding of the immunological mechanisms of ELSs formation in lesions of chronic inflammation including IgG4-RD. Based on results of previous studies and more recent findings regarding IgG4-RD, a presumed relationship between Tph cells and Tfh cells in the pathogenesis of IgG4-RD could be this: owing to the high expression levels of chemokine receptors including CCR2, CCR5, and CX3CR1, Tph cells are preferentially prone to infiltration of inflamed tissues in patients with IgG4-RD. Production of CXCL13 by Tph cells may subsequently provide early stimuli for the recruitment of CXCR5+ immune cells, including both Tfh cells and B cells, as a result, it is possible that Tfh cells and B cells accumulate to form ELSs in the lesions, and eventually provide an immune micro-environment, in which, the production of IgG4 is further induced. Because fractalkine, which is a ligand of CX3CR1, this unique subset of circulating T peripheral helper, may be able to recruit both Tfh cells and B cells to the sites of inflammation. Once these cells are recruited to affected lesions, it is possible that the interaction of Tfh cells with B cells that subsequently accumulate in the lesions provides an immune microenvironment in which production of IgG4 is induced. Tph-like cells in IgG4-RD would play a pathological role as CD4+ cytotoxic T cells rather than as B cell helpers, such as Tfh cells [102]. The percentage of Tph cells correlates with the serum IgG4 levels and IgG4-RI. Key questions remain in the developmental relationship, origin, and differentiation of such cells in the context of IgG4-RD. Understanding the mechanisms underlying Tfh and Tph cell mediated immunity and pathology may bring potential targets for novel therapies in this disease [100-102].

A biphasic disease progression

IgG4-RD follows a biphasic progression characterized by an “inflammatory” phase that eventually culminates in a “fibrotic” outcome. The first inflammatory phase of IgG4-RD is characterized by the appearance of antigen experienced B and T lymphocytes that accumulate at the disease sites, engaged in mutual activating antigen driven interactions and secrete profibrotic molecules such as IL-1β, IL-6, INF-γ, TGF-β, PDGF and lysyl oxidase homologue [67]. These populations of activated lymphocytes include circulating plasma blasts, effector memory T cells, cytotoxic CD4+ T lymphocytes [77]. Both plasma blasts and effector memory T cells express SLAMF7 molecule. Other T cell subsets involved in the inflammatory phase of IgG4-RD are Tfh, Treg and Th2 cells [73,89,90-94]. Although the precise function of Tfh1 cells remains to be elucidated, they are known to express CXCR5, the transcription factor T-bet, and to produce IFN-γ. Thus, they migrate to the GC that express CXCL13, the ligand for CXCR5, and produce IFN-γ in the locally affected lesions. IFN-γ, the key cytokine associated with Th1 responses, inhibits fibrosis in certain contexts, however it may be linked to fibrotic lesions in tuberculosis and Crohn’s disease [103]. IgG4-RD lesions exhibit significantly higher expression of Th2 cytokines, IL-4, IL-5, and IL-13 than interferon IFN-γ [103]. Although Th2 cytokines are detectable in vivo, other researchers have found a predominance of Th1 cytokines following re-stimulation of T cells in vitro [62,66,85]. One of the factors that could contribute to the increased activated Tfh2 cells in IgG4-RD may be IFN-α. In fact, IFN-α is greatly increased in serum and in the affected tissues in patients with IgG4-RD [103]. As a matter of fact, the transcription factor IFN regulatory factor 9 activated by IFN-α is known to bind to the promoter region of the PD-1 gene, and induce PD-1 mRNA transcription [43,44]. Substantial evidence from other autoimmune diseases attributes autoantibody responses to dysregulated Tfh cells [72,77]. Whether IgG4-RD results from the pathological activation of the Th1 or Th2 arm of the immune system remains to be established. At the same time the role of Foxp3+ Treg cells in IgG4-RD is complex and remains to be fully elucidated as well [104-107]. There is a clear trend toward an increase of circulating CD4+Foxp3+ Treg cells in IgG4-RD patients, suggesting that Treg expansion is not restricted to diseased tissues [18]. Foxp3+ Treg cells are seen in IgG4-RD lesions and may account for the increased levels of IL-10 and TGF-β [86,96,103]. IL-10 has been detected in the involved tissues in IgG4-RD, but the cellular sources of this cytokine have not been defined yet [91,92]. IL-10 can be produced by innate immune cells, including macrophages, dendritic cells, and neutrophils [108,109]. Regulatory B cells also produce IL-10, but these cells have still to be observed in the context of IgG4-RD [86]. IL-10 potentiates the IL-4 mediated IgG4 class-switching and suppresses switching to IgE85. From that perspective, IgG4-RD is different from most autoimmune diseases where Tregs are commonly decreased. IgG4-RD would be unique among autoimmune diseases, because the typical role of Foxp3+ Treg cells is to attenuate the inflammatory process. Under these circumstances, the antibody class-switch to IgG4, in IgG4-RD, may reflect the failed attempt of Treg cells to dampen Th2 inflammation. It is also possible that the fibrosis, characteristic of the advanced stages of IgG4-RD, results from the combined effects of Th2 and Treg cells [86].

The role of innate immunity in the pathogenesis of IgG4-RD is much less studied, although innate immune cells seem to be implicated in the transition from the inflammatory to the fibrotic phase of the disease. Activated eosinophils upregulate class II MHC and costimulatory molecules. As a matter of fact, studies of parasite infection suggest that activated eosinophils within lesions present antigens to CD4+ T cells [42,69,77].

M2 macrophages have been shown to infiltrate the IgG4-RD lesions and to express pro-fibrotic cytokines such as IL-10, IL13, IL-33 and CCL18. Further studies of the role of macrophages in IgG4-RD, particularly with regard to their potential contribution to the process of storiform fibrosis, should be performed [68,71,77]. One plausible model of the pathogenesis is that in genetically susceptible individuals, generally older men, some environmental insult, possibly a non-specific microbe triggers a tissue damage, breaking the immunological tolerance. A self-antigen-driven, polarised T helper response would induce a fibrotic pathological process at one or several sites. The reasons for the targeting of particular organs remain unclear. Within these organs, increased CD4+ T cells would activate innate immune cells that secrete other cytokines and drive the pathology cascade. The same antigen could trigger a parallel Tfh response that would induce the development of germinal centres within lymph nodes and the generation of IgG4-secreting plasma blasts and long lived plasma cells. The memory CD4+ T cells orchestrate the disease and are presumably sustained by antigen presenting B cells, this would explain the clinical improvement after B cell depletion. The existence of these cells can be inferred because RTX does not completely attenuate IgG4 concentrations in treated patients [64,67,77].

The tissue damage associated with IgG4-RD results from a striking expansion of fibroblasts. In the advanced stages, IgG4-RD is characterized by severe fibrosis [101,102]. This fibrosis may be caused by the prolonged induction of IL-13, which is a strong inducer of fibrosis and is a central cytokine in the Th2 differentiation pathway. The plasma blasts/plasma cells from patients with IgG4-RD have been shown to prompt fibroblast activation and collagen production in vitro, thus partially explaining the improvement of fibrotic lesions with B cell depletion [34,41-43]. Th2-derived IL-4 and IL-13, as well as IL-10, may result in the generation of alternatively activated macrophages, which enhance fibrogenesis by providing additional pro-fibrogenic factors, such as TGF-β1 and PDGF [6,67]. IL-5, produced by these cells, may also promote fibrosis by recruiting eosinophils that, in turn, produce TGF-β1, PDGF, and IL-13 [77]. These profibrotic cytokines can recruit and activate macrophages, fibroblasts, and myofibroblasts and promote the characteristic fibrosis of IgG4-RD [65]. During the fibrotic phase of IgG4-RD, lymphocytes and innate immune cells are replaced by a dense stromal reaction that progressively leads to tissue distortion and organ damage [1]. The mechanisms implicated in this second phase of the disease are less characterized, but likely involve an extracellular matrix deposition, by activated fibroblasts, and, a still poorly understood contribution of IgG4 antibodies.

Glucocorticoids

Most clinical manifestations of IgG4-RD respond to glucocorticoids. These agents are the first line, standard of care approach for most patients1,6. However, no randomised treatment trials have been done and few large retrospective examinations have been reported. One treatment approach uses a starting prednisolone dose of 0,6 -1,0 mg/kg daily. After 2-4 weeks, the dose is tapered by 5 mg every 1-2 weeks according to clinical responses (e.g., clinical manifestations, blood tests, and follow-up imaging studies). Practice varies as to whether the prednisolone is discontinued entirely after 2 or 3 months or maintained at a low dose. Clinical improvement after the start of glucocorticoid therapy is rapid and a follow up serological assessment should be done about 2 weeks after treatment initiation. A follow up radiological assessment is also appropriate for some types of organ involvement, such as the pancreas, biliary tree, lungs, and kidneys. PET with fluorodeoxyglucose is useful to assess treatment response. A swift response to glucocorticoids is reassuring and provides further diagnostic confirmation, if a tissue biopsy was not possible before the start of therapy. A poor response to glucocorticoids, however, should raise the possibility of other diagnoses, particularly cancer. The response to glucocorticoids varies according to the affected organs and the degree of fibrosis [104,105]. Both endocrine and exocrine pancreatic function can improve in AIP and salivary secretion in IgG4-related sialoadenitis is more likely to improve after glucocorticoid therapy than sialoadenitis due to Sjögren’s syndrome [104,105]. By contrast, retroperitoneal fibrosis, sclerosing mesenteritis, and fibrosing mediastinitis are less amenable to glucocorticoid therapy, underscoring the importance of early diagnosis and treatment [39]. Treatment with glucocorticoids decreases the number of circulating plasma blasts and serum levels of IgG4 and IL-4, but does not decrease the number of cTfh2 cells. Since IL-4 is produced by Tfh2 cells and glucocorticoid treatment decreases serum IL-4, it is conceivable that glucocorticoid treatment affects the function of Tfh2 cells without affecting their quantity, suggesting a partial resistance of Tfh2 cells to this treatment. Treatment with glucocorticoids is effective for IgG4-RD; however, it often causes side effects and relapse frequently occurs after tapering or discontinuing administration of glucocorticoids [106]. A single-group trial of prednisolone, in Japan, showed complete remissions in only 61% of patients at 1 year, despite continuation of maintenance doses of prednisone in all patients [107].

Conventional steroid-sparing agents

Drugs such as azathioprine, mycophenolate mofetil, and methotrexate, all used widely in gastroenterology, rheumatology, and transplant medicine, as means of achieving additional immunosuppression and sparing the effects of long-term glucocorticoids [104,107,108]. However, none has been tested in prospective, controlled studies and evidence for their efficacy beyond the tapering of concomitant glucocorticoid therapy are scarce. Rigorous assessment of these treatments in IgG4-RD is needed.

In general, patients presenting with multi-organ disease, elevation of serum IgG4 and IgE, and peripheral eosinophilia show the highest risk of relapse and might benefit from maintenance of remission therapy [107]. Patients with organ-threatening manifestations should be also considered for maintenance treatment, in an effort to minimize disease morbidity related to a potential relapse [108]. The steroid-sparing agents in this setting could be appealing. Hart, et al. [109] retrospectively compared the addition of different DMARDs to steroid therapy to glucocorticoid monotherapy and found no differences in terms of relapse free survival at two years. Conversely, two prospective studies conducted by Yunyun, et al. [110] showed a reduced relapse rate at one year when either mycophenolate mofetil (1-1.5 gr/day) or oral cyclophosphamide (50-100 mg/day) was added to low-dose corticosteroids compared to steroid treatment alone (20.5 vs 40%, and 12% vs 38.5%, respectively). Other scant reports, mostly focused on AIP, described positive experiences with tacrolimus, azathioprine, methotrexate, or leflunomide in preventing IgG4-RD relapse but these studies remain retrospective, uncontrolled, and limited in the number of patients analysed [106].

B cell depletion. RTX, was the first biologic agent administered to IgG4-RD patients and, is currently the most widely used targeted therapeutic approach in this condition [84]. It was, initially, used in patients who did not respond to glucocorticoids, conventional steroid-sparing agents, or both, under the assumption that B cell depletion might ameliorate the condition putatively mediated by high serum concentrations of IgG4 [104]. B cell depletion targets the subset of plasma cells that produce IgG4 in IgG4-RD [105]. It seems to achieve this action by depleting all circulating CD20 positive cells (ie, B cells), which interferes in turn with the repletion of short-lived plasma cells making IgG4. In other words, the plasma cells generating IgG4 in IgG4-RD are mainly of the short-lived type that naturally undergo apoptosis within weeks. Once these cells disappear as programmed, they cannot be repleted, after RTX administration, because their precursors - CD20+ B cells - are not available. Later it has been shown that RTX depletes expanded plasma blasts, in the peripheral blood, and decreases CD4+ CTLs, from affected tissues, indicating that B cell depletion likely interferes with chronic activation of CD4+ CTLs by disrupting B-T cell interactions and antigen presentation. More recently RTX is also shown to decrease tissue fibrosis in IgG4-RD by directly targeting a subset of B lymphocytes with pro-fibrotic properties, involved in fibroblast activation and recruitment of inflammatory cells [111].

Data from uncontrolled non randomized prospective and retrospective studies indicate that RTX leads to disease remission in 67% to 83% of cases and allows early tapering of the glucocorticoid therapy [108,111]. The clinical improvement correlates with selective decrease of serum IgG4 in most cases, further supporting the utility of targeting B cells in order to inhibit antibody secretion. Because of our partial knowledge of the pathophysiological mechanisms sustaining IgG4-RD, the use of other biological agents in this condition remains limited to single anecdotal case reports. Abatacept, an anti-CTLA4 antibody interfering with T cell co-stimulation, when administered at a dose of 500 mg intravenously every 4 weeks for 8 months, induced and maintained remission in a Japanese patient with RTX resistant Mikulicz’s disease and AIP [112]. Similarly, infliximab, a chimeric anti-TNFα antibody, was successfully used in a patient with orbital pseudotumor refractory to multiple immunosuppressive agents [113]. More recently, dupilumab, a monoclonal antibody, given subcutaneously, that acts on the IL-4 receptor α, markedly improved IgG4-related retroperitoneal fibrosis and prostate involvement in a patient with severe atopic manifestations who refused conventional immunosuppressive therapies [114]. Interestingly, despite targeting different molecular mechanisms, abatacept, infliximab, and dupilumab all reduced serum IgG4 levels and induced marked clinical responses, supporting the notion of a complex interplay between inflammatory pathways, cellular and humoral immunity at the basis of IgG4-RD pathophysiology [106,114].

Finally, B cell depletion is emerging as a valuable alternative to glucocorticoids and immunosuppressive agents for maintenance therapy but the optimal frequency and duration of treatment have not been defined [108]. Existing retrospective studies, in fact, provide clear evidence that RTX performs better than DMARDs therapies in reducing the rate of relapses, but the interval between RTX doses and the protocols of administration largely differ from patient to patient [106]. Regardless of the strategy chosen, there are insufficient data to define the optimal duration of maintenance treatment for each patient, and, probably, a number of individual specific factors, that we still largely ignore, needs to be considered. A commonly accepted strategy suggests discontinuing maintenance therapy within three years in case of persistent serological and radiological improvement [104,106,108] but biochemical and radiological follow up remains warranted, even after treatment discontinuation.

Enhance our understanding of the pathogenesis of IgG4-mediated diseases will allow to identify promising strategies for a target therapeutic intervention [115].

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