Table of Content

Current Issue

Autumn 2020, Vol. 28 No. 3

Hong Kong J. Dermatol. Venereol. (2020) 28, 100-109

Review Article

Spectrum of IgG4-related skin disease and differential diagnoses


Y Tokura 戶倉新樹


Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is characterised by high levels of circulating IgG4 and tissue infiltration of IgG4+ plasma cells. IgG4-RD exhibits a distinctive fibro-inflammatory change involving multiple organs, such as pancreas, and salivary and lacrimal glands. The skin manifestations of IgG4-RD, IgG4-related skin disease (IgG4-RSD) may stem from not only direct infiltration of plasma cells but also IgG4-mediated inflammation and can be categorised into seven subtypes: (1) cutaneous plasmacytosis, (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia, (3) Mikulicz's disease, (4) psoriasis-like eruption, (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura and urticarial vasculitis, and (7) ischaemic digit. It is considered that the subtypes (1)-(3) are induced by direct infiltration of IgG4+ plasma cells, while the other (4)-(7) types are caused by secondary mechanisms.

第四型免疫球蛋白G相關疾病的特徵是高血液水平的第四型免疫球蛋白G和第四型免疫球蛋白G陽性漿細胞的組織浸潤。第四型免疫球蛋白G相關疾病表現出獨特的纖維炎性改變,常涉及的多個器官,包括胰臟、唾液腺和淚腺。第四型免疫球蛋白G相關疾病及第四型免疫球蛋白G相關皮膚病的皮膚表現,不僅源於漿細胞的直接浸潤,還與第四型免疫球蛋白G介導的炎症有關,共可分為七類亞型:(1)皮膚漿細胞增多;(2 )假性淋巴瘤和血管淋巴樣增生伴嗜酸細胞增多症;(3)米庫利茲氏病;(4)銀屑病樣皮疹;(5)未明確的斑丘疹或紅斑性皮疹;(6)高球蛋白血症性紫癜和蕁麻疹性血管炎以及(7)缺血性手指腳趾。認為亞型(1)-(3)是由第四型免疫球蛋白G陽性漿細胞的直接浸潤引致的,而其他(4)-(7)類型則是由繼發機制引起。

Keywords: Cutaneous plasmacytosis, IgG4-related disease, pseudolymphoma

關鍵詞: 皮膚漿細胞增多症、第四型免疫球蛋白G相關疾病、假性淋巴瘤


Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a recently proposed clinical entity characterised by high levels of circulating IgG4 and tissue infiltration of IgG4+ plasma cells.1,2 In IgG4-RD, a distinct fibro-inflammatory change is seen in multiple organs, including pancreas, salivary gland, lacrimal gland, biliary tract, peritoneum, kidney, pituitary gland, thyroid gland, lung, prostate/testes, aorta, lymph node, and orbital region (Table 1). Mass-forming, sclerosing lesions are commonly seen in the affected organs.1,2 Histopathologically, there are dense lymphoplasmacytic infiltrates, storiform fibrosis, and modest to moderate tissue eosinophilia.1,2 Systemic corticosteroids are effective for the conditions. Although IgG4-RD is prevalent in Asian countries and many reports have been reported from Japan, Caucasian cases have also been documented.

Table 1 Multiple organ lesions in IgG4-RD
Organ Disease nomenclature
Pancreas Autoimmune pancreatitis
Salivary gland Chronic sclerosing sialadenitis, Kuttner's tumour, Mikulicz's disease*
Lacrimal gland Mikulicz's disease
Biliary tract Sclerosing cholangitis
Peritoneum Retroperitoneal fibrosis*, sclerosing mesenteritis
Pituitary gland Autoimmune hypophysitis
Thyroid gland Riedel's thyroiditis, Hashimoto's thyroiditis*
Lung IgG4-related lung disease, interstitial pneumonia*
Kidney Tubulointerstitial nephritis
Prostate/testis Epididymo-orchitis*
Aorta lymphoplasmacytic aortitis, inflammatory aneurysm*
Lymph node Rosai-Dorfman disease*
Others Orbital pseudotumor, eosinophilic angiocentric fibrosis
* At least a part of the diseases belong to IgG4-RD.

IgG4-RD may have skin lesions, which are called IgG4-related skin disease (IgG4-RSD).3-5 Patients with IgG4-RSD are usually referred to dermatologists following a diagnosis of pancreatitis, Mikulicz's disease or others. Alternatively, some patients present to dermatologists unaware of the diagnosis of IgG4-RD. It is possible that some cases of IgG4-RSD have been diagnosed as other conditions in the past. In this review, we discuss the skin lesions of IgG4-RSD, focusing on differential diagnoses.

History of IgG4-RD

Two different lines of pancreas- and lacrimal/salivary glands-specific clinical observations initiated the clinical entity of IgG4-RD. Lymphoplasmacytic sclerosing pancreatitis was first described in 1991 for a tumourous lesion of pancreas.6 Subsequently, autoimmune pancreatitis was proposed to represent this condition, and high levels of serum IgG4 were found in patients with autoimmune pancreatitis.7 On the other hand, a disorder of swellings of the lacrimal and salivary glands was first described by Mikulicz in 1892. Since Morgan's report in 1953, Mikulicz's disease has been considered part of Sjögren's syndrome. However, Mikulicz's disease shows a unique persistent swelling of the lacrimal and salivary glands and a good therapeutic response to glucocorticoids. Yamamoto et al found serum IgG4 elevation in patients with Mikulicz's disease.8 It is now accepted that IgG4-related Mikulicz's disease is distinct from Sjögren's syndrome. Following autoimmune pancreatitis and Mikulicz's disease, it was discovered that the same disease also occurred in other organs, with high serum IgG4 levels, and the term IgG4-RD has been coined for this systemic disease.

The diagnostic criteria are comprised of serum IgG4 levels >135 mg/dl and tissue infiltration of IgG4+ plasma cells >40% of total IgG+ plasma cells.1 It is noted that IgG4-RD is different from malignancies such as malignant lymphoma, Sjögren's syndrome, primary biliary cirrhosis, Castleman's disease, secondary retroperitoneal fibrosis, granulomatous polyangitis, and sarcoidosis.

Skin lesions of IgG4-RSD

We classified IgG4-related skin disease into seven types (Table 2).3 We first divided the skin lesions into the primary eruptions with massive plasma cell infiltrates and the secondary eruptions without mass formation by plasma cells. The primary eruptions consist of cutaneous plasmacytosis, pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (ALHE), and Mikulicz's disease. Cutaneous plasmacytosis has a distinct clinical appearance with prominent plasma cell infiltrates. Pseudolymphoma and ALHE exhibit non-specific types of plaques and papulonodules. Mikulicz's disease may be initially present to the dermatologist as an upper eyelid swelling. The secondary eruptions include the four heterogeneous manifestations. Psoriasis-like eruption strikingly mimics the plaque type of psoriasis, but plasma cells infiltrate in the upper dermis. Unspecified maculopapular or erythematous eruption represents other plasma cell-infiltrating lesions without mass formation. There have been reported purpuric eruptions in patients with IgG4-RD. The majority of patients show hypergammaglobulinaemic purpura with leukocytoclastic vasculitis, which may exhibit not only purpura but also urticaria. Finally, ischaemic digit is another secondary manifestation caused by vascular damage.

Table 2 Types of skin lesions of IgG4-RD
Type Symptoms Differential diagnoses
1. Cutaneous plasmacytosis
Multiple circular or ellipsoid patches, or prurigo with pigmentation Multicentric Castleman's disease
2. Pseudolymphoma and ALHE Plaques and papulonodules mainly on the periauricular and facial areas IgG4-unrelated B-cell pseudolymphoma, MALT lymphoma
3. Mikulicz disease or IgG4-related dacryoadenitis and sialoadenitis Palpebral swelling, sicca syndrome, exophthalmos Sjögren's syndrome
4. Psoriasis-like eruption Scaly erythematous plaques Psoriasis vulgaris
5. Unspecified maculopapular or erythematous eruptions Multiple maculopapular or exudative erythematous lesions Drug eruption, toxic erythema
6. Hypergammaglobulinaemic purpura and urticarial vasculitis Bilateral asymmetrical palpable purpuric lesions on the lower limbs
Prolonged urticarial lesions occasionally with purpura
Anaphylactoid purpura, Sjögren's syndrome, Lupus erythematosus
7. Ischaemic digit Raynaud's phenomenon, digital gangrene Systemic sclerosis, thrombosis, anti-phospholipid syndrome
ALHE=angiolymphoid hyperplasia with eosinophilia; MALT=mucosa-associated lymphoid tissue

Considering the comprehensive criteria of IgG4-RD,1 primary IgG4-related skin disease may be defined as marked lymphocyte and plasma cell infiltration with the ratio of IgG4+/IgG+ plasma cells >40% and the number of IgG4+ plasma cells/HPF >10. However, such a high percentage of plasma cell infiltration may not be observed in primary IgG4-related skin disease. Secondary IgG4-related skin disease is defined as dense plasma cell infiltration and/or perivascular IgG4 deposition. Considering that fibrosis is less marked in skin lesions even in primary IgG4-related skin disease, fibrosis is not necessarily required

1. Cutaneous plasmacytosis
Cutaneous plasmacytosis is a prototypic, primary skin eruption of IgG4-RSD. Before the discovery of IgG4-RD, cutaneous plasmacytosis was considered to be a benign reactive proliferation of plasma cells and had been reported especially from Japan. This enigmatic disease usually exhibits multiple red-brown papules/nodules and circular or ellipsoid indurations with prominent pigmentation, distributed over the trunk. It has now recognised as one of the skin lesions of IgG4-RSD (Figure 1a).9-11 An extremely high level of serum IgG4 and a marked skin infiltrate of plasma cells positive for IgG4 (Figure 1b) support the diagnosis of IgG4-RD.

Figure 1 Cutaneous plasmacytosis. (a) Multiple pigmented nodules on the trunk; (b) Immunostaining for IgG4. Infiltration of IgG4+ cells in the dermis.

It should be noted that the cutaneous plasmacytosis of IgG4-RSD may exhibit more pruriginous appearance than non-IgG4-RSD cutaneous plasmacytosis. Therefore, there have been reported some cases of IgG4-RSD manifest as prurigo lesions.12

In accordance with the high incidence of IgG4-RD in Japan, cutaneous plasmacytosis mainly affects Asian, as reported especially in Japanese middle-aged individuals. The involvement of organs other than the skin sometimes may be unremarkable,11 suggesting that the skin is occasionally the primary affected organ in IgG4-RD.

It is often difficult to distinguish IgG4-RD from multicentric Castleman's disease.13 While multicentric Castleman's disease is usually based on hyper IL-6 syndrome, IgG4-RD shows normal or slightly high serum IL-6.14 Lymph node involvement rather than pancreas and salivary/lacrimal glands prefers the diagnosis of multicentric Castleman's disease.

2. Pseudolymphoma and ALHE
In addition to cutaneous plasmacytosis, pseudolymphoma is a condition of IgG4-RSD, manifesting as erythematous indurative plaques and papules/nodules on the head and neck (Figure 2a).2,15 Histopathologically, it displays mass-forming infiltration of lymphocytes and plasma cells, containing a high percentage of IgG4+ plasma cells (Figure 2b). There may be germinal centres. Such non-specific plaques and papulonodules can be diagnosed as pseudolymphoma if they lack the monoclonality of infiltrating lymphocytes as assessed by Ig gene rearrangement studies. Generally, tissue-infiltrating plasma cells include IgG4+ cells at 40% or more of total IgG+ cells, is compatible with a diagnosis of IgG4-RD,16 although a lower percentage of IgG4+ cells may be seen in the skin lesions.5 The predilection sites of nodules/plaques of IgG4-RSD include the periauricular, cheek, and mandible regions.2,3 There have been two reported cases of cephalic nodular pseudolymphoma with IgG4+ plasma cell infiltrates.17 Nasal plaques are also a manifestation of IgG4-RSD.18

Figure 2 Pseudolymphoma. (a) Nodular or indurative lesions on the cheeks, palpebrae, neck, and upper limbs. Autoimmune pancreatitis was concomitant. IgG, 2,127 mg/dl and IgG4, 1,270 mg/dl; (b) Immunostaining for IgG4. Focal and massive infiltration of lymphocytes and plasma, containing IgG4+ cells.

Concerning the number of tissue-infiltrating IgG4+ plasma cells, elevated tissue IgG4+ to IgG+ cell ratio is particularly important in the setting of relatively low tissue IgG4+ cell density. However, there is an opinion that the appropriate cutoff point may vary from organ to organ because of the predominant fibrosis at the time of diagnosis. Thus, depending on the biopsied tissue, the number of IgG4 plasma cells per HPF may vary from 10 to more than 200.

The differential diagnosis includes primary cutaneous marginal zone B-cell lymphoma or formerly mucosa-associated lymphoid tissue (MALT) lymphoma. In cutaneous MALT lymphoma, the infiltrate consists of lymphoplasmacytoid cells and monocytoid cells,3 sharing histological features with IgG4-RSD. The tumour cells show monoclonal gene rearrangement of Ig with the CD79a+, CD19+, CD20 +/- and cIg+ (k or l) phenotype.

ALHE or Kimura's disease is characterised clinically by tumoural lesions on the head and neck. The histological features include proliferation of thick-walled blood vessels lined with prominent endothelial cells, infiltration of eosinophils, lymphocytes, histiocytes and plasma cells, and presence of lymphoid follicles with germinal centres. ALHE has been reported to be a skin lesion of IgG4-RD.19,20 Kimura's disease is characterised by eosinophil infiltrates and healing-stage fibrosis, which share the features with IgG4-RD lesions in the other organs. However, not all the cases of ALHE or Kimura's disease are IgG4-RD.

Granuloma faciale has been reported as IgG4-RSD,21 but its association with IgG4-RSD remains unclear.22

3. Mikulicz's disease
Mikulicz's disease is one of the two major disorders of IgG4-RD. In addition to otolaryngologists, patients may also present to the dermatologists with palpebral swelling. This disease entity is different from Sjögren's syndrome in its persistent swelling of lacrimal and salivary glands and the good therapeutic responsiveness to glucocorticoids. It is now recognised that Mikulicz's disease is a subtype of IgG4-RD distinguishable from Sjögren's syndrome and is called IgG4-related dacryoadenitis and sialoadenitis.4

Persistent bilateral swelling in the eyelids and submandibular region is commonly seen in Mikulicz's disease (Figure 3a). The patients may have sicca syndrome with lacrimal and parotid gland swellings. Histopathologically, IgG4+ plasma cells infiltrate the small salivary glands (Figure 3b). Sjögren's syndrome is the most critical differential diagnosis, and laboratory examination including anti-SS-A and anti-SS-B antibodies is helpful for the diagnosis. It is also notable that palpebral swelling and exophthalmos mimic thyroid disease,23 dermatomyositis, and extranodal natural killer/T cell lymphoma.

Figure 3 Mikulicz's disease. (a) Swelling of the bilateral upper eyelids. Sclerotic kidney was concomitant. IgG, 2,470 mg/dl and IgG4, 811 mg/dl; (b) Immunostaining for IgG4. Infiltration of IgG4+ cells in the the vicinity skin of lacrimal gland.

4. Psoriasis-like eruption
Several cases have shown that patients with IgG4-RD develop multiple hyperkeratotic erythematous plaques indistinguishable from psoriasis vulgaris (Figure 4a).3,24,25 There were typical histological findings, but notably, also perivascular plasma cell infiltrates.3,24 Infiltrating plasma cells, part of which contain IgG4, and deposition of IgG4 in the vascular endothelial cells may be found (Figure 4b). Notably, at least three cases developed psoriasis-like eruption after long-standing sclerosing cholangitis and/or sclerosing kidney have been reported.3,24,25 Since the frequency of psoriasis is generally high, it remains to be elucidated whether IgG4-RD and psoriasis are pathologically related or simply coincidental. Interestingly, two cases of generalised pustular psoriasis were documented as a complication with IgG4-RD,26 implying the close association.

The presence of IgG4+ plasma cell infiltrates supports their role in the development of psoriatic lesions. However, as psoriatic lesions are induced by T cells, especially Th17 cells,27 the precise link of IgG4 in the pathogenesis remains elusive. It is well-known that plasma cells infiltrate in the psoriasiform eruptions of secondary syphilis,28 implying their role in acanthosis and hyperkeratosis.

Figure 4 Psoriasis-like eruption. (a) Scaly erythematous eruption on the lower limbs and trunk. Cutaneous plasmacytosis, sclerosing kidney, and bile duct, liver and prostate tumors were concomitant. IgG, 3,525 mg/dl and IgG4, 780 mg/dl); (b) Immunostaining for IgG4. Plasma cells, containing IgG4+ cells, infiltrate as well as lymphocytes perivascularly in the dermal papillae.

5. Unspecified maculopapular or erythematous eruptions
This type of eruption tentatively encompasses non-mass-forming, plasma cell-infiltrating dermatitis. Maculopapular eruptions or multiple erythematous macules (Figure 5a) can be seen usually in association with systemic involvement of the major organs, such as lacrimal and salivary glands, bile duct, lung, and peritoneum.29,30 Histolopathogically, IgG4+ plasma cells, intermingled with lymphocytes, infiltrate in the upper-dermis (Figure 5b), but cases with a IgG4- plasma cell infiltrate have also been reported.29 A characteristic histology of reactive perforating collagenosis was also documented.

Figure 5 Unspecified maculopapular or erythematous eruptions. (a) Erythematous patches and maculopapular eruption on the chest, abdomen, and upper limbs; (b) Immunostaining for IgG4. Lymphocytes and plasma cells, containing IgG4+ cells, infiltrate perivascularly in the upper dermis.

6. Hypergammaglobulinaemic purpura and urticarial vasculitis
Leukocytoclastic vasculitis or urticarial vasculitis with IgG4 deposition has been reported in patients with systemic IgG4-RD.31,32 These cases can be diagnosed as hypergammaglobulinaemic purpura and exhibit bilateral asymmetrical palpable purpuric lesions on the lower extremities (Figure 6a). Urticarial vasculitis shares the histology with hypergammaglobulinaemic purpura. Notably, hypergammaglobulinaemia is also caused by Sjögren's syndrome or lupus erythematosus. In addition, IgA vasculitis, also known previously as Henoch-Schönlein purpura or anaphylactoid purpura, also represents leukocytoclastic vasculitis and resembles IgG4-RD purpura. These diseases should be included in the differential diagnosis.

The tissue-infiltration of IgG4+ plasma cells is one of the crucial diagnostic criteria of IgG4-RD. In the IgG4-related leukocytoclastic vasculitis, while IgG4 deposits are seen in the vascular vessels (Figure 6b), plasma cells do not infiltrate in the purpuric lesions. It has recently been proposed that a subset of localised chronic fibrosing vasculitis may represent cutaneous manifestation of IgG4-RD.33 In IgG4-RD, purpura or petechiae may be induced alternatively by non-vasculitic diseases, represented by idiopathic or thrombotic thrombocytopenic purpura.

Figure 6 Hypergammaglobulinaemic purpura. (a) Purpuric eruption on the lower legs and dorsum of the feet. Autoimmune pancreatitis and Mikulicz's disease were concomitant. IgG, 2,433 mg/dl and IgG4, 1,240 mg/dl; (b) Immunostaining for IgG4. Deposition of IgG4 in the vessels of upper dermis.

7. Ischaemic digit
IgG4-related large-vessel vasculitis is more common than previously recognised, and the inflammation may even affect the thoracic and abdominal aorta, iliac, mesenteric and splenic arteries.34 The luminal changes are mostly dilated but can also be stenotic. Corticosteroid therapy rapidly diminishes the arterial wall thickening.34 IgG4-RD also affects arteries smaller than the aorta and its main branches, leading to ischaemic digits, presenting with symptoms of Raynaud phenomenon and gangrenous fingers35 (Figure 7a). The lesional skin shows deposition of IgG4 in the wall of small vessels (Figure 7b). Stenosis of digital arteries has been found. There has been a report of ischaemic digits and hypergammaglobulinaemic purpura occurring simultaneously in an IgG4-RD patient.35 Differential diagnoses include systemic sclerosis and other autoimmune diseases, antiphospholipid syndrome, and drug use.

Figure 7 Ischaemic digit. (a) Raynaud's phenomenon, cyanosis of digits, and gangrene of her right index finger. Autoimmune pancreatitis and Mikulicz's disease were concomitant; (b) Immunostaining for IgG4. Deposition of IgG4 in the vessels of upper dermis.

8. Other lesions of IgG4-RSD
Cutaneous manifestations of IgG4-RD are various, and there are unclassified or as yet uncharacterised lesions. Alopecia is such a lesion and may be associated with systemic IgG4-RD.36 Skin ulcers mimicking factitial, dermatitis artefacta has also been documented.37

Pathogenesis of IgG4-RD

IgG4 is characterised by a very low ability to activate complements or to bind to Fcg receptor, indicating that IgG4 is less pathogenic than the other subclasses of IgG, such as IgG1 and IgG3. In fact, IgG4 possibly may suppress the inflammatory responses. Thus, antigen binding by IgG4 likely has no or minimally harmful consequences. In pemphigus, binding of IgG to keratinocytes is sufficient to cause intraepidermal blisters without engaging innate immune effectors or complement, and IgG4 autoantibodies seem to mainly mediate acantholysis. It seems that leukocytoclastic vasculitis is attributable to the other subclasses of IgG, such as IgG1 and IgG3, and immunohistochemical IgG4 reactivity in the vessels might indicate prominent deposition of all subclasses of IgG. Ischaemic digit is assumed to be a consequence of both primary and secondary changes. Given that the plasma cell-mediated fibrotic tissue surrounding arteries causes the stenosis of arteries,34 it may be evaluated as the primary lesions.

Similar to IgE, IgG4 production is upregulated by the T helper 2 (Th2) cytokines, interleukin (IL)-4 and IL-13.9 Accordingly, IgG4-RD usually shows elevated Th2 cytokines such as IL-4 and IL-5, leading to blood and tissue eosinophilia. In fact, approximately 40% of IgG4-RD patients have elevated serum IgE and eosinophilia.2 Furthermore, regulatory T cell (Treg) cytokines, IL-10 and transforming growth factor-β (TGF-β), promote the IgG4 expression by B cells.38 In addition to the ability of TGF-β to produce IgG4, its capability to induce fibrosis is well-known, potentially contributing to the pathological change in IgG4-RD.17 More recent studies have suggested that plasmablasts and T follicular helper (Tfh) cells are involved in the pathogenesis.39

In addition to adaptive immune responses, innate immune responses play pathogenic roles in IgG4-RD. Plasmacytoid dendritic cells (pDC), M2 macrophages, and basophils are activated to produce various kinds of cytokines in IgG4-RD.40 Recent studies highlight the importance of type I interferon and IL-33 produced by pDCs in IgG4-RD.

Given the poor functional activity of IgG4, it is tempting to speculate that IgG4 is a biomarker of IgG4-RD rather than a disease mediator. Exploring the roles of Th2, Treg, plasmablasts, Tfh, pDC, M2 macrophages, basophils, and pDC in IgG4-RD and its skin manifestations is a highly promising field of investigation.


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