Mikulicz Disease in Males: A Comprehensive Review

 

Venkata Triveni Devi Yerra1*, Stephanie Margaret Puvvada1, Vinod Kumar Mugada1,

Srinivasa Rao Yarguntla2

1Department of Pharmacy Practice, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.

2Department of Pharmaceutics, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.

*Corresponding Author E-mail: trivenidevi.yerra@gmail.com

 

ABSTRACT:

IgG4-related disease (IgG4-RD) is an intricate autoimmune disorder that have an effect on multiple organs in the body, including the lachrymal and salivary glands, liver, biliary duct, thyroid, pancreas, gastrointestinal tract, kidney, aorta, prostate and retroperitoneum. Mikulicz disease, a subtype of IgG4-RD, specifically targets the lachrymal and salivary glands, leading to glandular swelling, xerostomia, and xerophthalmia. Diagnosis of Mikulicz disease is established on the presence of proportional and persistent inflammation of at least two pairs of lachrymal, submandibular, and parotid glands, along with exalted serum IgG4 levels and/or marked penetration of IgG4-positive plasmacytes into the affected glandular tissues. Treatment with glucocorticoids has shown to be beneficial in managing IgG4-related MD, but the efficacy of combination therapy in preventing relapse is still a topic of debate. The underlying causes of the disease can vary, but lymphoepithelial sialadenitis is the widespread cause. The disease typically presents in individuals with an average age ranging from 55 to 65 years, and the incidence among individuals under the age of 20 is exceedingly rare. Mikulicz disease is an enigmatic ailment that is still being researched. However, identifying its hallmark symptoms and distinguishing it from other similar conditions is essential for effective diagnosis and treatment. Further research is essential to better comprehend the fundamental causes of the disease and to promote more effective treatment options for patients with Mikulicz disease and other subtypes of IgG4-RD.

 

KEYWORDS: Immunoglobulin G4-Related Disease, Glucocorticoids, Plasma Cells, Autoimmune Diseases, Salivary Gland Diseases.

 

 


INTRODUCTION:

IgG4-related disease, a newly discovered multisystem fibroinflammatory disorder, that is illustrated by a profuse penetration of positive-IgG4 plasma cells and exalted serum concentrations of IgG41,2,3. Due to its resemblance to other illnesses, such as Mikulicz syndrome and Sjogren's syndrome, an accurate diagnosis is required, i.e., a combination of clinical and experimental findings, including imaging and biopsy4.

 

Exalted serum concentrations of IgG45 and significant lymphoplasmacytic penetration with IgG4 are the defining features of IgG4-RD6. The pathogenesis of this condition is yet to be fully comprehended, and further research is required to elucidate optimal management strategies. Corticosteroids have emerged as the primary treatment for IgG4-related disease. These drugs have demonstrated rapid symptom improvement, although some patients may require long-term therapy, and relapses are possible after discontinuing treatment51. In severe cases, other immunosuppressive agents may be necessary6.

 

 

Recent studies have provided valuable insights into IgG4-related disease and its response to corticosteroids. Despite its clinical and pathological similarities to other diseases, IgG4-related disease represents a distinct clinical body with its exclusive diagnostic and therapeutic challenges. A multidisciplinary approach, involving clinicians, pathologists, and radiologists, is necessary to manage this complex disease4. IgG4-RD is a complex and enigmatic ailment that targets multiple organs, which includes the central nervous system, lachrymal and salivating glands, bile duct, liver, pancreas, gastrointestinal tract, kidney, aorta, prostate, thyroid and retroperitoneum2.

 

Mikulicz's syndrome, illustrated by penetration of the lachrymal and salivary glands and brought on by lymphocyte penetration, is linked to fibrosis. Lachrymal and large salivary gland anomalies are sometimes expressed as "Mikulicz's sickness" or "Mikulicz's syndrome"7. IgG4 has been implicated as the cause of systemic disease in Mikulicz's syndrome8. Additionally, it has been posited that Sjögren's syndrome encompasses a subtype that features dacryoadenitis and sialoadenitis caused by IgG-49.

 

IgG4-related sialoadenitis and dacryoadenitis, acknowledged earlier as Mikuliczd disease, is a chronic autoimmune disorder described by the penetration of lymphocytes and positive IgG4 plasma cells into the parotid glands, lachrymal glands, and submandibular glands, resulting in diffuse edema and inflammation of the affected tissues10. The hallmark symptoms of the condition are xerostomia, xerophthalmia, and glandular swelling, which are usually asymptomatic. However, in certain circumstances, the disease can lead to complications such as tubulointerstitial nephritis, retroperitoneal fibrosis, and autoimmune pancreatitis11.

 

Mikulicz's disease has a significant association with autoimmune pancreatitis, which is characterised by generalised pancreatic oedema12. Early detection and treatment of the disease are crucial to prevent further deterioration of symptoms and improve the patient's wellbeing. In spite of significant advances in understanding the pathophysiology of the condition, further research is essential to identify the underlying cause of the disease and advance targeted therapies49.

 

Furthermore, autoimmune pancreatitis can be considered as an indication of IgG4-related disease, which initially presents as asymptomatic lymphadenopathy and shows signs resembling Mikulicz's disease13. It is essential to note that gastrointestinal complications often precede autoimmune pancreatitis among patients with MD14. Additionally, collateral MD and IgG4-related chronic rhinosinusitis (CRS) have been observed, which is characterised by IgG4-positive plasma cell penetration within the nasal mucosa, lachrymal and salivating glands, along with raised blood IgG4 levels. The identification of this association can aid in the differential diagnosis of similar conditions and facilitate prompt treatment15.

 

Mikulicz's disease, also expressed as a benign or harmless lymphoepithelial lesion, is a persistent incendiary disease characterised by persistent proportional amplification of the lachrymal and salivating glands, high IgG4 serum concentrations, and penetration of positive-IgG4 plasma cells within the tissue lymphocytic cells16,17,18. Despite being an uncommon pathology, it is perhaps the second utmost prevalent autoimmune disease, following after rheumatoid arthritis. The disease primarily affects women and usually manifests in the fourth and fifth decades of human life, with manifestations emerging to worsen with people’s age19. However, the diagnosis of Mikulicz's disease can be challenging due to its unknown aetiology. Therefore, multiple tests are required to establish a diagnosis20. Unlike Sjögren's syndrome, which possesses a different pathogenesis, MD is reported as a form of plasmacytic condition associated with IgG421.

 

Mikulicz's disease (MD) is a rare disorder that continues as a subject of contention, with several hypothesized causes7. In 1888, Johann von Mikulicz-Radecki described the first paradigm of painless, bi-lateral, proportional enlargement of the lachrymal, submandibular, and parotid glands. Later, Schaffer connected idiopathic instances with MD and patients exhibiting identical symptoms with evident conditions, such as leukaemia, lymphoma, tuberculosis, sarcoidosis, and LEES. In 1933, Sjogren defined MD as a subgroup of Sjogren's syndrome(SS) based on their shared histological characteristics, particularly lymphocytic penetration9,22,50. Since Morgan's 1953 publication, MD is commonly regarded as a primary component of Sjogren's syndrome22.

 

Recent research has revealed significant insights into the unique characteristics of MD. In comparison to Sjogren's syndrome, MD is physiologically distinguished by rare autoimmune responses and receptivity to glucocorticoid therapy. High blood IgG4 levels and substantial IgG4-bearing plasmacyte penetration in the lachrymal and salivating glands are distinctive features of Mikulicz's syndrome, which are not found in Sjogren's syndrome23. Mikulicz disease also corresponds with an increased rate of bilateral nodal alteration in the submandibular glands compared to Sjogren's syndrome24.

 

Mikulicz's disease has historically been heeded as a sub-type of SS due to the shared histological characteristics among the two diseases. Penetration of positive-IgG4 plasma cells within the salivary glands and lachrymal glands is a distinguishing feature of MD and is indicative of the disease's phenotype as being related to IgG4-related disease. However, recent immunohistochemical studies have discovered a characteristic feature that distinguishes MD from SS. Specifically, these studies have shown that MD patients have higher levels of serum IgG4 than SS patients6. Consequently, distinguishing between MD and SS diagnoses is currently a subject of interest. The typical patient profile for MD consists of males and females above the age of 5025.

 

Analyzing IgG fractions in patients who have MD has been useful in distinguishing Mikulicz's disease from Sjogren's syndrome. According to an evaluation it was found that individuals with MD had exalted IgG4 serum concentrations, while individuals with SS did not48. While the salivating glands and lachrymal glands continue to expand in MD, their functionality is not significantly affected. Additionally, anti-La and anti-Ro antibodies are negative, and only a few positive antinuclear antibodies (ANA) are present. In contrast, most SS patients are females in their mid-50s, and although keratoconjunctivitis sicca is present, gland swellings in SS are sporadic. Most individuals with positive ANA serum testing also have antibodies to Ro, and 30% have antibodies to La. IgG4 levels that are elevated in the serum are typically absent in SS but are specific to MD. Interestingly, while lymphoid follicles in MD surround and protect the duct but they cause lymphoepithelial lesions in SS, and the duct is destroyed. This is why, despite significant gland swellings, keratoconjunctivitis sicca is less common in MD25.

 

Corticosteroids are usually the first-line therapy for MD caused by IgG4. Corticosteroids aid in the regulation of the immune system, inflammatory processes, metabolism, the growth of sexual characteristics, water and salt equilibrium and the body's resistance to disease and damage52. These drugs rapidly alleviate inflammation of the lachrymal and salivating glands, restore their functioning, and slash IgG4 serum concentrations26. In contrast to the female population, Mikulicz's disease (MD) has a lower incidence rate among men. Therefore, the goal of our study was to comprehensively review the clinical characteristics, diagnostic approaches, and outcomes that are more frequently observed in men with MD.

 

SIGNS AND SYMPTOMS:

Mikulicz's disease is an autoimmune disorder of rare incidence that can present a heterogeneous spectrum of symptoms and indications. These manifestations can be taxonomized into four categories based on their prevalence and severity.

a)     The first category comprises very frequent signs that include symmetrical and persistently enlarged submandibular, salivary, and lachrymal glands without any significant loss of function3.

b)    The second category encompasses frequent symptoms such as parotid swelling, allergic rhinitis, and bronchial asthma25.

c)     The third category comprises occasional signs, including abnormalities of the optic nerve, the orbital region and the extraocular muscles, cytoplasmic antineutrophil antibody positivity, antinuclear antibody positivity, facial edema, fatigue, fever, generalized muscle weakness, increased circulating IgA and IgM levels, myositis, keratoconjunctivitis sicca, palpebral edema, periorbital fullness, proptosis, weight loss, and xerostomia.

d)    The fourth category includes rare symptoms such as abnormal lachrymal duct morphology, optic nerve compression, blindness, lymphadenopathy, nodular goiter, retroperitoneal fibrosis, thrombocytopenia27, thyroiditis28, and tubulointerstitial nephritis1.

 

Moreover, Mikulicz disease may rarely present with testicular swelling and severe pancytopenia10. Physical examination findings may include skin and sclera yellow discoloration, swollen, sublingual, sublingual, and lachrymal glands, as well as splenomegaly10. Additionally, mild epigastric tenderness may be observed on deep palpation without rebound29.

 

CAUSES:

Mikulicz disease or syndrome is a medical condition primarily characterized by elevated concentrations of IgG4 antibodies, which target the salivary and lachrymal glands. This autoimmune disorder can arise from various underlying pathologies, such as sarcoidosis, mumps, syphilis, tuberculosis, Graves' disease, malignant lymphoma, and leukemia. Furthermore, lymphocytic penetration and the development of lymphoepithelial lesions may contribute to the onset of Mikulicz disease30.

 

AFFECTED POPULATION:

The incidence of IgG4-related MD among individuals under the age of 20 is exceedingly rare. This condition typically presents in patients with an average age ranging from 55 to 65 years.

 

RELATED DISEASES:

The symptoms of the following conditions can resemble those of Mikulicz disease.

 

Thyroiditis:

When evaluating patients with bilateral inflammation of the lachrymal and salivary glands, as well as nodules in the thyroid, clinicians should be familiar of the possibility of IgG4-related Mikulicz's sickness corresponding with thyroiditis. Unlike nodular goitre, which is typically characterized by soft adenomatous nodules without oppression, thyroiditis is characterized by a goitre with a remarkably hard consistency and no specific clinical symptoms. Ultrasonography is a beneficial tool in differentiating IgG4-related thyroiditis from most malignant nodules, as malignant nodules tend to exhibit considerable vascularization, while IgG4-related thyroiditis presents with hypoechoic nodules and an absence of vascular flow31.

 

It is worth noting that while other types of thyroiditis may be associated with abnormal thyrotropin concentrations, most patients with IgG4-related thyroiditis have normal hormone levels and negative antibody findings in the early stages31. The definitive treatment for Mikulicz's illness associated with thyroiditis is surgical excision of the tumour, which is necessary not only for therapeutic purposes but also to obtain a pathological diagnosis. Therefore, clinicians should be aware of the unique characteristics of the IgG4-related Mikulicz's sickness corresponding with thyroiditis when making a differential diagnosis for patients presenting with these symptoms28.

 

Castleman disease:

In differentiating between IgG4-RD and hyper IL-6 disorders similar to multicentric Castleman's disease, laboratory results play a crucial role. While the latter may occasionally meet the histopathological diagnostic criteria for IgG4-RD and often involve the lymphatic nodes, they also show raised serum IgG4 levels due to high IL-6 levels32.The high IL-6 levels also cause thrombocytosis, anaemia, hypoalbuminemia, and hypocholesterolaemia, as well as primarily raised levels of IgA, IgG and IgM, and also elevated CRP. These markers are useful in distinguishing between the two conditions33.

 

Küttner’s tumour:

Kuttner's tumour is a milder indication of IgG4-RD in the neck area and head, which is characterized by a predominance of the affected salivating glands undergoing fibrosis being confined to the major salivary glands. Küttner's tumour is identified as the submandibular glands that exhibit sclerosing sialadenitis and enlargement13.

 

Mantle cell lymphoma (MCL):

Approximately 3% of malignant lymphomas in Japan are mantle cell lymphomas, which are a moderately rare kind of non-Hodgkin lymphoma. MCL predominantly affects middle-aged to elder individuals, where males are affected preponderantly, and has a less favourable outcome with respect to other non-Hodgkin lymphoma subtypes. Hepatosplenomegaly, lymphadenopathy, involvement of bone marrow, and leukemic spread are more common stage III/IV presentations of MCL. Despite the fact that almost all MCLs affect lymphatic nodes, 25% of MCL cases have extra nodal participation, including the Waldeyer band (6.3%), 5% of the intestine, 2.5% of the stomach, 2.5% of the orbit, and 2.5% of the salivary gland. A conclusive evaluation of MCL may or may not require additional molecular and flow cytometric tests, depending on the appropriate immunohistochemistry staining. MCL is distinguishable from other lymphomas with a similar appearance due to its overexpression of the cyclin D1 protein, which is a defining feature of its clinicopathological characteristics9.

 

DİAGNOSİS:

The Classification criteria of the 2019 ACR/EULAR IgG4-RD were developed with the aim of providing a globally applicable diagnostic framework for IgG4-related MD. These criteria define the disease based on the presence of symmetrical and persistent inflammation of not less than two sets of lachrymal, submandibular glands, and parotid glands, along with raised serum IgG4 (≥1.35 g/L) concentrations and pronounced penetration of positive-IgG4 plasmacytes (≥50% of positive-IgG4 plasmacytes in five high power areas) into the affected glandular tissues34. Lymphadenopathy may also be present, but without accompanying symptoms35.

 

To determine the diagnosis of IgG4-related MD, the criteria require validation of symmetrical and prolonged inflammation in multiple lachrymal glands and major salivary glands, as well as notable penetration of mononuclear cells in glandular tissues. These criteria reflect a rigorous and evidence-based approach to the diagnosis of IgG4-related MD, which will facilitate accurate and consistent diagnosis across different geographic regions. By providing a standardized framework for diagnosis, the criteria will enhance clinical care and research into this disease36.

 

LABORATORY İNVESTİGATİONS:

The laboratory results indicated that the patient’s had raised serum IgG4 levels, hypocomplementemia (CH50 13 U/ml), hypergammaglobulinemia (4859mg/dl)35 and hyperamylasaemia. Furthermore, the patient's enhanced CD4-positive T cells activated innate immune cells and released interleukins and cytokines, which led to a sustained inflammatory response and subsequent fibrosis3. In vitro, the secretion of interleukin (IL)-4, IL-5, and IL-13 by peripheral blood mononuclear cells (PBMC) was significantly increased, while interferon gamma (IFN-) was not. Additionally, the patient showed IgG polyclonal hypergammaglobulinemia with an increased erythrocyte sedimentation rate (SER)37. (However, the ANA, anti-Ro, anti-La, and RF tests for serological markers all yielded negative results.)

 

RADIOLOGICAL INVESTIGATIONS:

For the purpose of diagnostic confirmation, it is highly recommended to undergo both magnetic resonance imaging (MRI) and computerised tomography (CT). The results of the chest CT scans revealed a multitude of abnormalities, including mediastinal lymphadenopathy, diffuse, irregular patchy penetration in both lung fields, consolidation of the bronchial wall, nodule(s), interlobular thickening, pleural thickening, and ground glass opacity and effusion38. Moreover, the CT scan further exhibited an overall enlargement of the pancreas and an expansion in the size of the lachrymal glands on a specific side of the face38.

 

In contrast, the MRI displayed a wide range of lesions that have affected various parts of the body such as the lachrymal glands, bilateral orbits, eyelids, and subcutaneous layers of the temporal areas. Additionally, the MRI scans also detects the presence of hypoechoic lymphatic nodes in the submandibular region and right parotid gland, as well as an increase in the size of both the lachrymal and parotid glands39.

 

TREATMENT:

It is currently unclear what the most effective treatment options are for IgG4-RD, as there are no established recommendations. However, treatment with glucocorticoids has shown to be beneficial in managing IgG4-related MD1. Glucocorticoid treatment can improve glandular processes and reduce IgG4 levels, leading to improvements in both secretion and inflammation of the salivating glands and lachrymal glands. Initially, prednisolone was administered at a dose of 30-40mg/day for MD treatment without causing organ failure. However, it has been determined that corticosteroid medication should be continued at a lower dose of 5-10mg/day or combined with an immunosuppressant to prevent adverse effects35. For IgG4 hypophysitis, steroid treatment has been effective in reversing inflammatory alterations3. Specifically, prednisone at a dosage of 0.5mg/kg per day was administered and gradually tapered by 2.5mg each week after two weeks. Maintenance therapy with prednisolone at a dosage of 10mg daily was initiated after a three-month follow-up, which improved the condition and balanced the Th1/Th2 ratio40. Antibiotics were found to be ineffective in treating this condition10.

 

The efficacy of combination therapy in preventing relapse remains a topic of debate in current research. Multiple studies have demonstrated a correlation between combination therapy and a decreased relapse rate. Our study, specifically, found that individuals receiving GC plus IM therapy exhibited a lower relapse rate compared to those receiving GC monotherapy. Our findings suggest that combination therapy is a safe and effective approach for preventing relapse and may provide patients with added protection against future relapses41.

 

COMPLICATIONS:

Multisystemic IgG4-Related Disease, commonly referred to as MD, is a medical condition that is allied with numerous complications, such as autoimmune hypophysitis, autoimmune pancreatitis, Riedel's thyroiditis retroperitoneal fibrosis, and tubulointerstitial nephritis. These conditions are described by the presence of elevated serum immunoglobulin G4 (IgG4) levels and significant penetration of IgG4-positive plasmacytes35.In comparison to Sjögren's Syndrome, another medical condition, MD has a higher prevalence of allergic rhinitis, bronchial asthma25, olfactory impairment42, and malignant lymphoma43.

 

HISTOPATHOLOGY:

The findings of histological research indicate that the submandibular glands contain plasma cells with a high IgG4-to- IgG ratio of 75%, which corresponds with elevated total IgG4 levels in the serum1.However, the count of plasma cells detected after IgG, CD138, and IgG4 immunohistochemical staining was relatively low1. The salivary glands showed fibrosis and penetration of lymphocytes and plasmacytoid cells, as per the histopathologic analysis35. The left lachrymal gland had a significant penetration of plasma cells, comprising IgG4-positive cells, and lymphocytes based on immunostaining39. Some histological characteristics, such as pronounced neutrophilic infiltrates, markers reliable with an inflammatory myofibroblastic tumour, and necrotizing vasculitis, were identified as exclusion criteria13.

 

The submandibular gland had a significant penetration of positive IgG4 plasma cells and lymphocytes. Similarly, the gall bladder, pancreas lachrymal gland, and submandibular gland had CD4- and CD8-positive T lymphocyte penetration44,45. In the nasal mucosa of MD patients with OD, plasmacytes positive for IgG4 invaded the mucosa42. According to the findings, the cutaneous biopsy that was performed on the right upper eyelid did not provide a definitive diagnosis39. The submandibular gland was observed to have a notable penetration of positive IgG4 plasma cells and lymphocytes. Both glands underwent biopsies, revealing a significant polyclonal proliferation of plasmacytes resulting from chronic dacryoadenitis26. Additionally, a significant lymphocytoplasma cell penetration was recognised in the patient's labial salivating glands. The biopsy also showed a heavy MN cell penetration, obliterate phlebitis, and minor eosinophil penetration29. Sublingual gland biopsy is a useful diagnostic tool when there is swelling of the sublingual glands, as it aids in the identification of the disease46. It is significant to note that patients with IgG4-RS frequently exhibit extra glandular lesions47.Top of Form.

 

 

CONCLUSION:

IgG4-related disease (IgG4-RD) is a complex and multifaceted ailment that impacts multiple organs, leading to a diverse array of symptoms and complications. Although the underlying pathogenesis of IgG4-RD is not copiously comprehended, it is often hypothesised that lymphocytic penetration and the development of lymphoepithelial lesions may contribute to its onset. Diagnostic criteria of IgG4-RD is based on a combination of clinical, experimental, and imaging criteria, with the Classification Criteria – the 2019 ACR/EULAR IgG4-RD, being the most widely accepted. Glucocorticoids have shown to be an effective treatment option in managing IgG4-related Mikulicz's disease, with combination therapy being a potential approach to reducing relapse rates. However, the optimal treatment approach remains uncertain, and more research is needed to demonstrate the pathogenesis of IgG4-RD and to develop more effective therapeutic strategies.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

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Received on 16.06.2023         Modified on 05.08.2023

Accepted on 11.09.2023   ©Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2023; 13(4):318-324.

DOI: 10.52711/2231-5659.2023.00054