Trifecta of CD-19 Receptor, IgG4 Disease and the Mitigate Trials- Feature Article

1. Introduction

IgG4 related disease is a subacute, progressive multisystemic autoinflammatory disorder [1]. This disease involves middle age and elderly age group with higher male predilection [1,2]. Patient presents with symptoms of weight loss, fatigue and myalgia [3]. It is characterized by lymphoplasmacytic infiltrate predominately composed of IgG4 related plasma cells [1,4]. IgG4 activates myofibroblast which produces TGF beta and PDGF. TGF beta is related to storiform fibrosis [5,6].

It involves multiple organs which includes pancreas (type 1 autoimmune pancreatitis – obstructive jaundice, Type 3 diabetes mellitus, exocrine pancreatic failure), bile duct (primary sclerosing cholangitis), thyroid (Riedel’s thyroiditis), salivary and lacrimal glands (Mikulicz’s disease, painless submandibular sialadenitis), mediastinum (mediastinal fibrosis), retroperitoneum (retroperitoneal fibrosis), aorta (peri aortitis, paravertebral mass), veins (obliterative phlebitis), periorbital lesions (inflammatory pseudotumor) and kidneys (tubulointerstitial fibrosis, membranous nephropathy) [1,4,7]. It rarely involves central nervous system (lymphocytic hypophysitis and pachymeningitis) and lung (nonspecific interstitial fibrosis) [1,7]. Other characteristics include the tendency to cause allergic disease (eczema, asthma, sinusitis and nasal polyps and mild eosinophilia) and tumefactive lesions mimicking malignancies [1,2,3,8].

Due to the aggressive nature of the disease, vital organ involvement can cause permanent functional loss [1]. Thus, glucocorticoids are the first line of treatment with excellent and rapid response within 2 weeks [9]. But steroid induced adverse effects and morbidities occur [9,10]. Rituximab, monoclonal antibody targeting CD 20 on B cells is tried as a steroid sparring agent to prevent relapse or in glucocorticoid resistant disease [2,11].

It is now well understood that the B-cell lineage, particularly short-lived plasmablasts, plays a central role in disease activity and tissue pathology [6,12]. IgG4-RD is increasingly considered a fibroinflammatory condition driven by aberrant B–T cell interactions, particularly involving T follicular helper (Tfh) cells, cytotoxic CD4+ T cells, and regulatory cytokines (IL-4, IL-10, IL-21, TGF-β). These cells orchestrate the pathological class switching to IgG4, the recruitment of fibroblasts, and progression to fibrosis [5,6].

The plasmablasts infiltrate target organs (e.g., pancreas, salivary glands, kidneys), releasing IgG4 locally. It may stimulate fibroblast activation via TGF-β and PDGF, promoting storiform fibrosis [5,6,12]. Expressing CD19 (but not CD20), renders them invisible to rituximab yet vulnerable to CD19-directed therapies like inebilizumab [12]. Moreover, these CD19+ plasmablasts likely maintain interactions with Th and CD4+ cytotoxic T cells in affected tissues, perpetuating local inflammation and fibrosis even in the apparent absence of systemic disease [6].

CD20-targeted agents (e.g., rituximab) have demonstrated efficacy in IgG4-RD, but they leave plasmablasts and plasma cells intact due to CD20 downregulation during differentiation [11,12]. This may explain incomplete remission in some patients, early relapses upon B-cell repopulation and persistence of tissue fibrosis despite treatment [6,10]. By targeting CD19, therapies like inebilizumab can achieve: Depletion of both CD20+ B cells and CD20– plasmablasts, more profound and sustained suppression of B-cell–driven autoimmunity, reduction in circulating and tissue-infiltrating IgG4-producing effector cells and likely interruption of fibrogenic signaling pathways, mitigating long-term organ damage [12,13,14].

2. Methods

Databases included PubMed, Cochrane library, Google Scholar, Scopus, and Embase were explored with MeSH terms (“Immunoglobulin G4-Related Disease”[MeSH] OR “IgG4-related disease” OR “IgG4-RD” OR “IgG4 disease”) AND ( “Plasma Cells”[MeSH] OR “B-Lymphocytes”[MeSH] OR “T-Lymphocytes, Helper-Inducer”[MeSH] OR “T-Lymphocytes, Cytotoxic”[MeSH] OR “Transforming Growth Factor beta”[MeSH] OR “Platelet-Derived Growth Factor”[MeSH] OR “Cytokines”[MeSH] OR “Fibrosis”[MeSH]) AND ( “Pancreatitis, Autoimmune”[MeSH] OR “Cholangitis, Sclerosing”[MeSH] OR “Retroperitoneal Fibrosis”[MeSH] OR “Kidney Diseases”[MeSH] OR “Tubulointerstitial Nephritis”[MeSH] OR “Lung Diseases, Interstitial”[MeSH] OR “Orbital Pseudotumor”[MeSH] OR “Hypophysitis”[MeSH] OR “Thyroiditis, Riedel’s”[MeSH] OR “Sialadenitis”[MeSH] OR “Mediastinal Fibrosis” OR “Aortitis”[MeSH] OR “Pachymeningitis”[MeSH]) AND (“Glucocorticoids”[MeSH] OR “Immunosuppressive Agents”[MeSH] OR “Rituximab”[MeSH] OR “CD20 Antigens”[MeSH] OR “CD19 Antigens”[MeSH] OR “Monoclonal Antibodies”[MeSH] OR “Biological Products”[MeSH] OR “Inebilizumab” OR “Mycophenolic Acid”[MeSH] OR “Azathioprine”[MeSH] OR “Methotrexate”[MeSH]). 2 authors independently reviewed results and selected articles used for review. New England Journal of Medicine was used to review MITIGATE trial for narrative review.

3. Discussion

135 participants were involved in the MITIGATE trials with even distribution between Inebilizumab and placebo group.

The average age was 58.2 ±11.8. Most patients were Asians (47%), with 39% are white population and other population include 4 %. Most are selected from Asia and European union with 38 and 34% respectively. About 54% percent of patients reported recurrence while remaining population were newly diagnosed. The average duration of illness was 2.6±3.4. The trial population was representative of moderate to severe disease, with a high disease burden—84% of patients had three or more organs involved, and the median ACR–EULAR classification score was 36.7.

3.1. Inclusion Criterion

The inclusion criteria for the trial included male or female adults who have reached the age of consent in the applicable region (e.g., ≥ 18 years in the US) with clinical diagnosis of immunoglobulin G4 – related disease (IgG4 – RD). The eligibility committee determines whether the candidates fulfill the 2019 classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Participants must meet the classification criteria entry requirements (including involvement of 1 of the following organs: pancreas, bile ducts/ biliary tree, orbits, lungs, kidneys, lacrimal glands, major salivary glands, retroperitoneum, aorta, pachymeninges, or thyroid gland [Riedel’s thyroiditis]). Participants must achieve at least 20 classification criteria inclusion points and must not meet any of the classification criteria exclusions. Participants on glucocorticoid therapy for a recent IgG4-RD flare, with a maximum of 4 weeks of treatment before informed consent, or experiencing active disease about to start GC, must have a total duration of GC treatment of at least 3 weeks during the screening period. The total duration of GC treatment must not exceed 8 weeks with a dosage of no more than 60 mg before randomization. IgG4-RD affecting at least 2 organs/sites at any time during IgG4-RD must meet ACR/EULAR classification criteria

3.2. Exclusion Criteria

Severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disorders were excluded to avoid confounding the interpretation of results. Immunodeficiency, active or prior malignancy or organ transplant were exluded for the same. Some exceptions were made as shown in the table-

Use of B-cell-replacing therapy or any biologic within 6 months or nonbiologic within 4 weeks was another exclusion criterion to avoid affecting the efficacy of CD-19 inhibitors.

Pregnant and lactating women were excluded due to lack of data on teratogenecity.

A positive test for Hepatitis B (HBV) involving the detection of hepatitis B surface antigen or core antibody, or hepatitis B surface antibody in Japan only. If cured after antiviral therapy, the viral load below the limit of detection at least 24 weeks after treatment was warranted. Further exclusion criterion included an evidence of active tuberculosis (TB) or high risk for TB including a history of active or latent TB, recent close contact with someone with active TB, signs or symptoms, positive interferon-gamma release assay test results, chest radiographs, herpes zoster, allergies, or reactions to inebilizumab formulation or human gamma globulin therapy.

The lab exclusion criteria included hemoglobin <7.5 g/dL, neutrophils <1200/mm3, platelets <110 × 109/L, eosinophil count >3000/mm3, prothrombin time >1.2 x upper limit of normal, total immunoglobulins <600 mg/dL, and a cluster of differentiation 19+ B cells at screen <40 cells/μL.

3.3. Endpoints

Some definitions for criteria included in the endpoints is as below in Table 1.

Flare criteria were developed for this trial with the assistance of a global panel of IgG4-RD clinical experts. Flare criteria encompass symptoms, physical exam findings, imaging results, laboratory tests, and pathological findings. Investigators assessed each potential flare according to their clinical acumen and appropriate standards of care. All information collected by the investigator during flare evaluation was provided to the AC in a blinded fashion for central review.

Organs for which specific flare criteria were developed: pachymeninges, pituitary gland, orbits, lacrimal glands, salivary glands, lymph node(s), lungs, including pleura and parenchyma, aorta and large blood vessels, retroperitoneum, mediastinum, and mesentery, pancreas and common bile duct, biliary tree (IgG4-RD sclerosing cholangitis), kidney, skin, other sclerosis/mass formation in the thyroid (Riedel’s thyroiditis), liver, breast, prostate, maxillary sinus, nasal septum, pericardium, peripheral nerves, or other as in Table 2.

3.4. Results of the Trial

The trial’s primary endpoint, time to first adjudicated disease flare, was met with high statistical and clinical significance: only 10.3% of patients receiving Inebilizumab experienced a flare, compared to 59.7% in the placebo group (hazard ratio, 0.13; 95% CI, 0.06–0.28; P<0.001). These results, alongside significant reductions in annualized flare rates and higher rates of glucocorticoid-free complete remission at 52 weeks, demonstrate the biologic’s robust efficacy. Importantly, the clinical benefit of inebilizumab was evident across both relapsing and newly diagnosed disease subgroups, supporting its potential utility at various disease stages. In this clinical trial for IgG4-related disease, patients treated with Inebilizumab experienced far better outcomes than those who received a placebo. Only about 10% of those on Inebilizumab had a disease flare, compared to nearly 60% in the placebo group. The treatment also led to a much lower annual flare rate and significantly higher chances of achieving remission without the need for ongoing treatment or steroids. By week 52, over half of the patients on Inebilizumab were in complete remission—flare-free and either off treatment or off steroids—compared to just over 20% of those on placebo. These findings suggest that Inebilizumab can be a powerful option for helping patients with IgG4-related disease stay in remission and reduce their reliance on long-term medication.

3.5. Adverse Events

The safety profile observed in MITIGATE was consistent with prior experience in B-cell–depleting therapies. Although the incidence of lymphopenia and mild-to-moderate infections was higher in the inebilizumab group, these adverse events were largely manageable and did not significantly offset the benefit-risk balance. Notably, no treatment-limiting hypersensitivity or unexpected serious adverse events were reported. However, continued vigilance for opportunistic infections remains prudent, particularly with prolonged immunosuppression. During the study, side effects were reported in both the Inebilizumab and placebo groups, though some occurred more often in those receiving the actual treatment. The most common issues in the Inebilizumab group were COVID-19 infections (24%), low white blood cell counts (lymphopenia, 16%), and urinary tract infections (12%). While some side effects like headaches and stomach pain were seen in both groups, others—such as fatigue and diarrhea—were slightly more common in the placebo group. However, serious side effects happened more often in the Inebilizumab group (18% vs. 9%), and certain lab-related issues like low blood cell counts (cytopenias) showed up more frequently with the treatment. A few patients on Inebilizumab also experienced more serious infections and rare reactions like infusion-related issues or mild allergic responses. Overall, while there were more side effects with Inebilizumab, most were expected and manageable, given its role in modulating the immune system.

3.6. Limitations

The trial duration of 52 weeks is insufficient to assess long-term outcomes such as organ-specific fibrotic progression, durability of remission, and cumulative organ preservation, which are critical endpoints in a chronic fibrosing condition like IgG4-RD.

Patients previously treated with CD20-targeted agents such as rituximab were excluded, which limits the applicability of findings to rituximab-refractory or biologic-experienced cohorts, a clinically relevant population in tertiary care settings.

Many patients were recruited from Asia (38%) and the European Union (34%), with only 16% from the United States. Given potential ethnic, genetic, and environmental differences in IgG4-RD phenotype and treatment response, this may affect generalizability to the broader global or U.S. population.

The trial excluded individuals with significant comorbidities, including active infections, severe organ dysfunction, and malignancy within the last 10 years, potentially underestimating the real-world risks of immunosuppression, particularly in older or medically complex patients.

The study employed a placebo-controlled design rather than comparing inebilizumab directly to rituximab, the most widely used off-label biologic for IgG4-RD. As a result, it remains unclear whether CD19-targeted therapy offers a clinical advantage over existing CD20-based regimens.

Although flare-free and glucocorticoid-free remission at 52 weeks was a key secondary endpoint, its definition included investigator judgment and lacked central adjudication of all aspects of remission, introducing potential bias or variability in outcome assessment.

With 135 participants, the study was not powered to detect infrequent but serious adverse events, such as opportunistic infections, late onset cytopenias, or secondary autoimmune phenomena, which may emerge with broader post-approval use.

The trial did not systematically assess patient-reported outcomes, functional status, or health-related quality of life—measures increasingly recognized as essential for evaluating therapeutic impact in multisystemic chronic diseases.

3.7. Literature Review

3.7.1. CD19 and Characteristics

The cluster of differentiation 19 (CD19) represents one of the most significant transmembrane proteins in B-cell biology and immunotherapy [15]. This glycoprotein serves as a fundamental marker for B-cell lineage identification and plays crucial roles in cellular development, immune signaling, and therapeutic intervention strategies [16]. Understanding CD19’s multifaceted functions provides essential insights into both normal immune processes and pathological conditions affecting B-cell populations [17].

CD19 functions as a type I transmembrane glycoprotein with a molecular weight of approximately 95 kilodaltons, classifying it within the immunoglobulin superfamily [15]. The encoding gene spans 7.41 kilobases on human chromosome 16p11.2, organized into 15 distinct exons that produce a 556-amino acid protein product [15]. This genetic architecture demonstrates remarkable conservation across mammalian species, indicating evolutionary importance [18].

The protein’s structural organization includes two extracellular immunoglobulin-like domains of the C2 type, separated by a smaller non-immunoglobulin domain that may contain disulfide linkages [18]. The extracellular region also features multiple N-linked glycosylation sites that contribute to proper protein folding and surface presentation [19]. The cytoplasmic domain extends 240 amino acids and contains nine tyrosine residues near the carboxy-terminus, three of which (Y391, Y482, and Y513) are particularly critical for signal transduction [15].

Transcriptional regulation occurs through a unique promoter region lacking a canonical TATA box, with major transcription initiation sites positioned close to the translation start codon [15]. This regulatory arrangement allows for precise control of CD19 expression during B-cell development and maturation [20].

CD19 expression begins during early B-cell development, coinciding with immunoglobulin gene rearrangement and B-lineage commitment from hematopoietic stem cells [20]. The transcription factor PAX5 serves as a master regulator of CD19 expression, with PAX5-deficient mice showing arrested B-cell development at the pro-B cell stage [20]. Throughout B-cell maturation, CD19 surface density undergoes dynamic regulation [15]. Mature B-cells exhibit approximately three-fold higher CD19 expression compared to immature B-cells, with slight elevation in B1 cells relative to conventional B2 cells [15]. This differential expression pattern reflects the protein’s role in modulating activation thresholds at different developmental stages [17]. Importantly, CD19 expression persists throughout most B-cell differentiation stages but becomes dramatically reduced during terminal plasma cell differentiation [15]. This expression pattern makes CD19 an excellent diagnostic marker for distinguishing B-cell lineage malignancies from plasma cell disorders [16].

CD19 operates within a sophisticated multimolecular signaling complex that includes CD21 (complement receptor 2), CD81 (TAPA-1), and CD225 [17]. This complex formation enables CD19 to function as both an adaptor protein for cytoplasmic signaling molecules and a signal amplification component for B-cell receptor (BCR) pathways [21]. The CD19/CD21 complex can engage complement fragment C3d independently of antigen recognition, allowing for enhanced B-cell activation when antigens are opsonized with complement components [15]. This dual recognition mechanism provides critical signal integration for appropriate immune responses [21].

CD19 activation triggers multiple intracellular signaling cascades through phosphorylation of its cytoplasmic tyrosine residues [21]. Key downstream effectors include Src-family kinases (Lyn, Fyn), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and various adaptor proteins such as Vav and Grb2 [15]. The PI3K-Akt pathway represents a particularly important CD19-mediated signaling axis, promoting B-cell survival, proliferation, and differentiation [15]. Additionally, CD19 signaling modulates c-MYC protein stability through the Akt-GSK3β pathway, providing BCR-independent regulation of cell cycle progression and metabolic activity [15].

CD19 serves as a crucial rheostat for B-cell activation, fine-tuning cellular responses to environmental stimuli [17]. In developing B-cells, CD19 signaling influences progression from early pre-B to small resting pre-B cells in bone marrow microenvironments [17]. For mature B-cells, CD19 lowers activation thresholds and promotes survival of naive recirculating populations [16]. The protein also facilitates BCR micro cluster formation during antigen recognition, a process essential for effective signal transduction and cellular activation [21]. This function demonstrates CD19’s importance in translating antigen encounters into appropriate immune responses [21].

Transgenic mice overexpressing CD19 exhibit dramatic reductions in peripheral B-cell numbers due to impaired bone marrow precursor generation and development [20]. However, surviving B-cells show enhanced proliferative responses to mitogens and prolonged survival in culture conditions [20]. These overexpression studies reveal altered immunoglobulin production patterns, with increased IgG2b levels, decreased IgG3 levels, and unchanged IgA concentrations [20]. Such findings suggest that CD19 levels critically influence both B-cell development and functional differentiation [20].

CD19-deficient mice demonstrate normal bone marrow B-cell precursor numbers but exhibit significant defects in peripheral B-cell populations, particularly B1 cells and splenic B-cells [17]. These mice show impaired responses to T-cell-dependent antigens, reduced germinal center formation, and defective memory B-cell generation [17]. Functional analyses reveal that CD19-deficient B-cells exhibit reduced calcium flux responses and compromised BCR signaling, confirming the protein’s essential role in B-cell activation pathways [17].

Human CD19 deficiency, caused by homozygous frameshift mutations, results in hypogammaglobulinemia and increased susceptibility to infections [15]. Affected patients maintain normal total B-cell numbers but show reduced memory B-cell (CD27+) and CD5+ B-cell populations [15]. These patients exhibit normal CD81 and CD225 expression but decreased CD21 levels and undetectable CD19, leading to impaired antigen-induced BCR responses and poor vaccine responses [15].

CD19 dysregulation contributes to autoimmune disease development, with overexpression studies in susceptible mouse strains demonstrating enhanced lupus-like pathology [15]. This suggests that precise CD19 regulation is essential for maintaining immune tolerance and preventing autoimmunity [15].

CD19 expression remains remarkably consistent across B-cell malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and various lymphoma subtypes [16]. This universal expression pattern makes CD19 an invaluable diagnostic marker and therapeutic target [16].

Approximately 85% of non-Hodgkin lymphomas originate from B-cells and maintain CD19 expression, providing extensive opportunities for targeted therapeutic interventions [16].

Early therapeutic strategies employed unconjugated anti-CD19 monoclonal antibodies, achieving transient tumor reductions in progressive B-cell lymphoma patients [22]. Combination approaches with interleukin-2 demonstrated enhanced efficacy in low-grade lymphoma cases [22]. Several antibody-drug conjugates have entered clinical development, including SAR3419 (coltuximab ravtansine), which combines humanized anti-CD19 antibodies with maytansine derivatives [23]. Phase I trials demonstrated tumor responses in 74% of patients with relapsed CD19+ B-cell lymphomas, including rituximab-refractory cases [23]. Loncastuximab tesirine (ADCT-402) represents another promising conjugate, utilizing pyrrolobenzodiazepine dimers for enhanced cytotoxicity [22]. The LOTIS-2 phase 2 trial achieved a 48% overall response rate with 24% complete remissions in relapsed/refractory patients [22]. Blinatumomab, a bispecific T-cell engager connecting CD3+ T-cells with CD19+ B-cells, has shown remarkable efficacy in relapsed/refractory B-precursor acute lymphoblastic leukemia [24]. Clinical trials demonstrate complete remission rates of 43% in adult studies and 39% in pediatric populations [24].

CAR-T cell therapy represents the most revolutionary CD19-targeted approach, with multiple approved products including tisagenlecleucel and axicabtagene ciloleucel [25]. These therapies achieve impressive response rates of 54-82% in heavily pretreated patients with relapsed/refractory B-cell malignancies [26]. Long-term follow-up data indicate that CD19-targeted CAR-T cells can induce prolonged remissions and may be curative for substantial patient subsets [25]. The ZUMA-1 trial demonstrated 82% overall response rates with 54% complete remissions, with responses maintained even after CAR-T cell disappearance [22].

Novel approaches include CAR-NK cell therapies derived from induced pluripotent stem cells, offering potential advantages in manufacturing scalability and reduced toxicity profiles [22]. Dual-target strategies combining CD19 with other antigens like BCMA are under investigation to address antigen escape mechanisms [27].

Despite remarkable therapeutic successes, resistance mechanisms limit long-term efficacy [25]. CD19 antigen loss through gene mutations or splicing variants represents a major escape mechanism, occurring in 15-20% of relapsed patients following CAR-T therapy [24]. Sequential therapy studies suggest that prior blinatumomab exposure may influence subsequent CAR-T cell efficacy, though recent data indicate maintained therapeutic potential when disease burden is adequately controlled [24,28].

Ongoing research focuses on identifying predictive biomarkers for therapeutic response, including genetic signatures, tumor microenvironment characteristics, and patient immune status [25]. These efforts aim to optimize patient selection and treatment sequencing [25]. Combination approaches with checkpoint inhibitors, small molecule therapeutics, and other immunomodulatory agents are under active investigation [22]. These strategies may enhance therapeutic efficacy while addressing resistance mechanisms [22]. Advances in CAR-T cell manufacturing, including point-of-care production and off-the-shelf approaches using allogeneic donors, promise to improve treatment accessibility and reduce costs [22].

CD19 represents a paradigmatic example of successful translation from basic immunology to clinical therapeutics [25]. Its fundamental roles in B-cell development, activation, and survival make it an ideal target for treating B-cell malignancies [16]. The remarkable success of CD19-targeted therapies, particularly CAR-T cells, has revolutionized treatment paradigms for relapsed and refractory B-cell cancers [26]. Continued research into CD19 biology, resistance mechanisms, and novel therapeutic approaches will further enhance our ability to treat B-cell disorders effectively [25]. The integration of precision medicine approaches with advanced cellular therapies promises to extend the benefits of CD19-targeted treatments to broader patient populations while minimizing associated toxicities [22].

3.7.2. CD19 and Characteristics

Immunoglobulin G4 (IgG4) is the least abundant subclass of IgG antibodies, comprising only 3-5% of total circulating IgG antibodies in healthy individuals [29,30]. Unlike other IgG subclasses, IgG4 possesses unique structural and functional properties that distinguish it from IgG1, IgG2, and IgG3.

The normal upper limit for serum IgG4 concentration is 135 mg/dL (1.35 g/L), which has been widely accepted as the diagnostic threshold [1,31,32]. Some laboratories use slightly different reference ranges, with values up to 140 mg/dL considered normal [32]. Elevated serum IgG4 levels (>135 mg/dL) can occur in various conditions, but only approximately 18% of patients with elevated IgG4 levels have IgG4-related disease [32]. Contrary to being pro-inflammatory, IgG4 is predominantly anti-inflammatory and tolerance-inducing due to its unique structural characteristics [33,34,35].

IgG4 antibodies can undergo a unique process called Fab-arm exchange, where they exchange half-molecules with other IgG4 antibodies, creating bispecific antibodies that contribute to their anti-inflammatory activity [4,30]. IgG4 has minimal ability to activate the classical complement pathway and only does so under very specific conditions requiring high antigen and antibody concentrations [36]. This weak complement activation contributes to its anti-inflammatory profile. Due to Fab-arm exchange, IgG4 antibodies often function as monovalent antibodies, preventing the formation of large immune complexes that could trigger inflammatory responses [34,35]. IgG4 functions as a “blocking antibody” that can compete with other antibody subclasses for antigen binding, particularly in allergic responses where it blocks IgE-mediated reactions [33,34].

Although often associated with pancreatic involvement, IgG4-RD frequently affects multiple organs. According to the 2020 revised diagnostic criteria for IgG4-related pancreatitis (AIP), diagnosis involves a combination of (1) characteristic imaging or clinical features (such as diffuse or focal organ swelling or mass lesions), (2) elevated serum IgG4 levels (>135 mg/dL), and (3) histopathological findings. The pathology criteria include dense lymphoplasmacytic infiltration, >10 IgG4-positive plasma cells per high-power field, and storiform fibrosis or obliterative phlebitis. A diagnosis is considered definitive if all three criteria are met, probable if criteria 1 and 3 are met, and possible if only criteria 1 and 2 are fulfilled [1].

When IgG4-RD affects the biliary system, it manifests as IgG4-related sclerosing cholangitis (IgG4-SC). Diagnosis relies on a combination of imaging, serology, histology, coexisting IgG4-related conditions, and in some cases, response to steroid therapy. Based on the location and pattern of bile duct involvement, IgG4-SC is categorized into four types. For instance, Type 1 involves only the distal bile duct and can resemble pancreatic cancer, while Type 2 shows diffuse intrahepatic and proximal bile duct strictures, often mimicking primary sclerosing cholangitis (PSC). Types 3 and 4 can imitate hilar cholangiocarcinoma. Approximately 80–90% of IgG4-SC cases are associated with AIP, but other systemic manifestations like retroperitoneal fibrosis and dacryoadenitis/sialadenitis may also be seen. In contrast to PSC, inflammatory bowel disease is rarely present in IgG4-SC.

Renal involvement typically manifests as tubulointerstitial nephritis. Gastrointestinal ischemia from vascular involvement of mesenteric arteries is another rare but important sign of systemic disease. Lung involvement in IgG4-RD includes a spectrum of findings from parenchymal infiltrates, mediastinal lymphadenopathy, pleural involvement, and airway disease [1,4].

In the retroperitoneum and aorta, disease activity may present as new or progressive retroperitoneal fibrosis, peri-aortic thickening, aneurysmal dilation, or symptoms due to obstructive uropathy. Orbital involvement is characterized by proptosis, diplopia, vision changes, or imaging findings such as an orbital mass or extraocular muscle enlargement. Hypertrophic pachymeningitis presents with new or worsening headaches, focal neurologic deficits, and MRI evidence of dural thickening or enhancement. In the thyroid, specifically Riedel’s thyroiditis, compressive goiter symptoms (e.g., dysphagia or dyspnea), progressive hypothyroidism, and confirmatory imaging or pathology are key features. Skin manifestations include new or worsening plaques, nodules, or rashes with histologic confirmation of IgG4 involvement. Prostatic disease may cause urinary obstruction or lower urinary tract symptoms, with diagnosis supported by biopsy if performed [4].

Treatment usually begins with glucocorticoids, with prednisone 40 mg daily for 4 weeks followed by a gradual taper over 7 weeks [1]. While most patients initially respond well, up to 50% relapse. For those with recurrent or refractory disease especially during tapering second-line immunosuppressants like azathioprine, mycophenolate mofetil, methotrexate, or tacrolimus may be considered, though data from randomized controlled trials is lacking [2].

Rituximab, a B-cell depleting anti-CD20 monoclonal antibody, has shown promise in observational studies, inducing remission and reducing steroid dependence [2]. However, more long-term safety data are needed. Newer targeted therapies are also under investigation. These include Bruton’s tyrosine kinase inhibitors like rilzabrutinib and zanubrutinib. These agents aim to suppress disease activity while minimizing systemic side effects and long-term steroid use.

3.7.3. MITIGATE trials- Integration of CD-19 and IgG4

The MITIGATE trial evaluated inebilizumab, an anti-CD19 monoclonal antibody, as a potential steroid-sparing treatment for IgG4-related disease (IgG4-RD). While rituximab (anti-CD20) has shown success in treating IgG4-RD by depleting mature B cells, inebilizumab targets CD19, a B-cell marker that includes not only mature B cells but also plasmablasts.

By targeting CD19 rather than CD20, inebilizumab offers B-cell depletion, including plasmablasts that often escape CD20-directed therapies like rituximab. This may be especially important given that persistent plasmablast activity is associated with disease relapse and progression in IgG4-RD. Results from MITIGATE suggest that inebilizumab is effective in reducing disease flares hence offering a steroid sparing alternative.