Characterization of the peripheral nervous system manifestations in patients with IgG4-related disease: a systematic review

doi:10.21203/rs.3.rs-5183601/v1

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Characterization of the peripheral nervous system manifestations in patients with IgG4-related disease: a systematic review

https://doi.org/10.21203/rs.3.rs-5183601/v1

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Background: Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. While neurological involvement typically presents as pachymeningitis, there have been reports of peripheral nervous system (PNS) manifestations in IgG4-RD patients. Our objective was to review the involvement of the peripheral nerves, neuromuscular junction, and muscles in individuals with IgG4-RD.

Main text: We conducted a systematic review of case reports and case series of patients with IgG4-related disease (IgG4-RD) presenting with peripheral nervous system (PNS) manifestations, using the PubMed/MEDLINE, Embase, and Scopus databases. Articles were analyzed for demographic characteristics, neurological presentations, systemic involvement, and investigative findings (laboratory, electrophysiological, and pathological). A total of 38 articles, encompassing 42 cases of PNS manifestations in patients with IgG4-RD, were included. Peripheral nerve involvement was most frequently reported (25/42, 60%). The most common clinical presentations were mononeuritis multiplex (48%) and polyneuropathy (20%). Systemic involvement was observed in all patients with peripheral neuropathy. Electrodiagnostic studies revealed an axonal pattern in 88% of cases, while nerve biopsies were compatible with vessel and nerve infiltration by IgG4-positive cells in 46% (6/13) of cases. Involvement of the neuromuscular junction was infrequently reported (n = 4), presenting as Lambert-Eaton syndrome (25%) or myasthenia gravis (75%), with all cases being negative for anti-acetylcholinesterase antibodies. Muscle involvement (n = 13) manifested as focal myositis in 53% and a limb-girdle muscle weakness pattern in 47%. Systemic involvement was absent in 61% of muscle cases. Creatine kinase levels were elevated in 53%, and muscle biopsy demonstrated IgG4-positive cell infiltration in all focal myositis cases.

Conclusion: Our review suggests that typical PNS manifestations in patients with IgG4-RD include mononeuritis multiplex, polyneuropathy, and focal myopathy. However, comorbid conditions such as systemic vasculitis, anti-acetylcholinesterase antibody-negative myasthenia gravis, and inflammatory myositis should also be considered as potential contributors to PNS symptoms.

IgG4-Related Disease

Peripheral Nervous System

Peripheral neuropathy

Myositis

Neuromuscular junction

Immunoglobulin-4-related disease (IgG4-RD) is a fibroinflammatory condition resulting from the infiltration of organs by IgG4-positive polyclonal plasma cells and fibroblasts, leading to increased organ size and fibrosis [1]. IgG4-RD is associated with significant morbimortality, increasing the frequency of hypertension, diabetes, osteoporosis, infections, solid organ neoplasms, lymphomas, emergency room and outpatient clinic visits, hospitalization days and death [2, 3]

Little is known about the involvement of the nervous system in IgG4-related disease. In the four largest published cohorts, neurological manifestations consisted mainly of hypophysitis and hypertrophic pachymeningitis [4–7]. Knowledge is particularly scarce regarding the involvement of the peripheral nervous system in IgG4-related disease. The largest published cohort describes seven patients with focal neuropathies identified by magnetic resonance imaging, computed tomography of positron emission tomography scans [8]. Muscle and neuromuscular junction involvement in the disease are limited to case reports [9–11].

Despite the increasing number of publications of PNS manifestations of IgG4-RD throughout the last two decades, we present the first systematic review on this presentation of the disease. Specific questions addressed in this study are: (1) What are the neurological signs and symptoms of PNS manifestations of IgG4-RD, including peripheral nerve, neuromuscular junction, and muscle involvement? (2) What are the systemic characteristics of IgG4-RD in patients with PNS involvement in the disease? and (3) What are the possible mechanisms of PNS involvement in IgG4-RD disease?

This systematic review summarizes the clinical presentation, investigation findings and treatment outcomes of PNS manifestations of IgG4-RD. This study is compliant with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [12] reporting guideline and is registered on PROSPERO (CRD42024496097).

PubMed/MEDLINE, Embase and Scopus were searched for studies reporting PNS manifestations of IgG4-RD. The search did not have a start date limit and was last updated on December 13th, 2023. Search terms were synonyms of IgG4-RD, peripheral neuropathy, neuromuscular junction, and myopathy (Supplementary Data 1).

The inclusion criteria were (1) a diagnosis of IgG4-RD regardless of the diagnostic criteria [1, 13], (2) individual patient data, and (3) signs and symptoms of peripheral nerve, neuromuscular junction, or muscle diseases. Reference lists of the selected articles were screened for additional records. To prevent bias due to duplicated information, only the biggest case series per author/research group (highest number of patients) was included in each analysis. Search and screening were performed by R.F.R. and revised by G.D.S. Disagreements were settled through discussion between the two authors.

We did not perform any formal risk of bias assessment and considered the risk of bias was high for all studies, as we included only case reports and small case series.

Data extracted from selected articles were demographic characteristics, neurological presentation, investigation findings (laboratory, electrophysiological and pathological), extra-neurological involvement, and serum IgG4 levels. PNS involvement was classified as primary or secondary. Primary PNS manifestation of IgG4-RD was considered when a demonstration of IgG4 positive cells was obtained in pathological studies of the PNS or direct compression of adjacent tissues or presumed by neuroimaging. Secondary PNS manifestation of IgG4-RD was defined when neurological presentation was attributed by the effects of treatment, metabolic abnormalities of organ damage, or comorbidity. We complied with the AANEM-IFCN glossary to harmonize terminology of neuromuscular disorders [14]. The data extraction was performed by R.F.R. and revised by G.D.S. Discrepancies were solved through consensus.

We presented median and interquartile ranges for quantitative variables and percentage and total counts from qualitative variables. Summary tables were designed to compare the characteristics of PNS involvement of IgG4-RD.

Database searching retrieved 888 manuscripts, of which 327 were duplicates. After title and abstract screening, 51 manuscripts were eligible for full-text reading. Two manuscripts could not be retrieved. Next, we excluded six cases because IgG4-RD could not be diagnosed after careful revision of the diagnostic criteria, seven manuscripts due to the absence of individual patient data, and one paper to prevent bias due to duplicated information. Screening for the references of the eligible articles yielded another 3 eligible papers. At last, we included 38 articles in our systematic review, yielding a total of 42 cases of PNS disease in IgG4-RD. Figure 1 displays the flow diagram.

Peripheral nerve, neuromuscular junction and muscle involvement of IgG4-RD were summarized in Fig. 2, with a highlight to mononeuritis multiplex and to focal myositis. Kidney and lymph node involvement were the most relevant systemic manifestations in patients with PNS involvement of IgG4-RD (Table 1). Almost half of cases of PNS manifestations in patients with IgG4-RD was attributed to secondary mechanism, particularly autoimmune comorbidities.

Table 1

Systemic involvement in peripheral nervous system manifestations of IgG4-RD.
Affected organ	Total (n = 42)	Nerve (n = 25)	Muscle (n = 13)	NMJ (n = 4)
Kidney	11 (26%)	11 (44%)	0 (0%)	0 (0%)
Lymph Node	11 (26%)	8 (32%)	1 (8%)	2 (50%)
Salivary Glands	8 (19%)	6 (24%)	2 (15%)	0 (0%)
Lung/Pleura	8 (19%)	4 (16%)	3 (23%)	1 (25%)
Aorta	7 (17%)	5 (20%)	0 (0%)	2 (50%)
Retroperitoneum	6 (14%)	4 (16%)	0 (0%)	2 (50%)
Lacrimal Gland	4 (10%)	4 (16%)	0 (0%)	0 (0%)
Liver	3 (7%)	3 (12%)	0 (0%)	0 (0%)
Pancreas	3 (7%)	2 (12%)	1 (8%)	0 (0%)
Eye	2 (5%)	1 (4%)	1 (8%)	0 (0%)
Skin	2 (5%)	1 (4%)	1 (8%)	0 (0%)
Adrenal	1 (2%)	1 (4%)	0 (0%)	0 (0%)
Bone Marrow	1 (2%)	1 (4%)	0 (0%)	0 (0%)
Bowel	1 (2%)	1 (4%)	0 (0%)	0 (0%)
Orbit	1 (2%)	1 (4%)	0 (0%)	0 (0%)
Pacchymeninges	1 (2%)	0 (0%)	1 (8%)	0 (0%)
Paranasal sinus	1 (2%)	1 (4%)	0 (0%)	0 (0%)
NMJ: Neuromuscular Junction.

Peripheral nerve

We included 25 patients with peripheral neuropathy and IgG4-RD of which 76% were male and the median age was 65 (55, 73) years. The most common presentation was mononeuritis multiplex[15–25] (12/25, 48%), followed by polyneuropathy[26–30] (5/25, 20%), radiculopathy/multirradiculopathy[8, 25] (4/25, 16%), polyradiculoneuropathy[31, 32] (2/25, 8%), mononeuropathy[8] (1/25, 4%) and radiculoplexhopathy[33] (1/25. 4%). Median duration of the neurological presentation was 5 (1.5,10) months. All patients presented with electrodiagnostic signs of axonal neuropathy, except for two cases of predominantly demyelinating polyradiculoneuropathy [31, 32]. Nerve biopsy was reported in 13/25 cases and had a normal result in 2/13 (15%) of cases. The most common findings were loss of myelinated fibers (6/13) and axonal degeneration (5/13), epineural vessel occlusion/recanalization (6/13) and nerve inflammatory infiltrates, which most commonly occurred in the epineurum (4/13) and perineurum (4/13). Nerve and vessel infiltrates were abundant in IgG4 positive cells in 6/13 cases. Other classical IgG4-RD findings were fibrosis (3/13 cases), though no cases of storiform fibrosis of the nerve were described, and obliterative phlebitis (1/13). Pathological evidence of vasculitis was observed in 6/13 reported cases. Positive autoantibodies included ANCA, ANA, RF and Anti-SSA, Anti-GQ1b/Anti-VGCC. There were no reports of antibodies associated with IgG4-related autoimmune neuropathy such as contactin or neurofascin.

Systemic involvement occurred in all (25/25, 100%) of reported cases. Organs most commonly involved were the kidney (11/25, 44%), lymph nodes (8/25, 32%), followed by salivary glands (6/25, 24%), aorta (5/25, 20%), lacrimal glands (4/25, 16%), and retroperitoneum (4/25, 16%). There were no reported cases of isolated neuropathy. Serum IgG4 levels were reported in 22/25 (88%) of cases, and were elevated in all patients, with a median value of 762 (257, 1400) mg/dL. Peripheral neuropathy in IgG4-RD was considered primary in 12/25 (48%) cases, with 8/12 cases caused by direct invasion/compression of the affect nerves and 4/12 cases caused by IgG4-related vasculitis. Neuropathy was considered secondary to a comorbid disease in 12/35 (48%) patients. In these cases, the inferred cause was ANCA-associated vasculitis in 7 patients, other vasculidites in 2 patientes, CIDP in 2 patients and diabtes in one patient. The cause of neuropathy could not be determined in 1/25 (4%) patients. The 2019 ACR criteria were met in 18/25 patients (72%).

Neuromuscular junction

We found four case reports with neuromuscular junction disease [10, 34–36], of which two (66%) were female and the median age was 63 (49, 76,5) years. Three patients presented with myasthenia gravis [10, 35, 36] and one patient manifested with Lambert Eaton (syndrome) [34], in a chronic presentation with a median of 70 (38, 101) months. Interestingly, no patient with myasthenia gravis presented with acetylcholine receptor antibodies and two (67%) patients presented with anti-Musk antibodies. Anti-VGCC was reported positive in the Lambert-Eaton myasthenic syndrome patient.

Only two (50%) patients fulfilled the ACR 2019 diagnostic criteria of IgG4-RD and involvement of other organs occurred in all patients, mainly in aorta, retroperitoneum and lymph node. Serum IgG4 levels were elevated in all patients, with a mean value of 264 mg/dL. No case report displayed evidence of direct neuromuscular junction invasion by IgG4-RD cells and, hence, all cases were interpreted as secondary PNS manifestations due to autoimmune comorbidity.

Muscle

We included 13 cases of muscle disease and IgG4-RD ([9, 11, 37–47]), of which seven (53%) were male and the median age was 54 (38.5, 67,5) years. Focal myositis, with localized weakness and muscle pain, was the neurological presentation in seven[9, 39, 41–43, 46, 47] (53%) cases. Proximal symmetric tetraparesis occurred in the remaining six[11, 37, 38, 40, 44, 45] patients (47%). Disease was usually subacute, with a median duration of four months (0.5, 30) at the time of the diagnosis. Creatine kinase (CK) levels were also elevated in most patients (5/7, 83%), with a median value of 1232 (294.5, 1791) mg/dL. MRI imaging was reported in 4/7 cases of focal myositis. The main findings were muscle fascia thickening, scattered contrast enhancement, central T1 hypointensity (presumably due to muscle fibrosis) and muscle edema. In all 3 cases of proximal myopathy for which MRI was described, diffuse muscle edema and fat substitution of affected muscles was reported.

Muscle biopsy was reported in 10/13 (7/7 focal myopathies and 3/6 proximal myopathies) cases. In all cases of focal myositis, muscle biopsy showed infiltration by abundant IgG4 + cells. Fibrosis was reported in 4/7 of such cases but found to have a storiform pattern in only 1/4. In proximal myopathies, muscle biopsy patterns varied, but all cases had mixed inflammatory infiltrates, including plasma cells, with abundant IgG4 + cells. Endomysial fibrosis was reported in 2/3 cases.

Only four (30%) patients fulfilled the ACR-2019 classification criteria for IgG4-RD. Isolated muscle involvement occurred in 8 (61%) cases. When systemic involvement occurred, the most affected organs were the lungs (3/5, 60%), salivary glands (2/5, 40%), and skin (2/5, 40%). Most patients presented with elevated IgG4 serum levels (11/12, 91%) with a median level of 313 (187, 507.5) mg/dL. Two [37, 38] of the cases exhibited muscle infiltration patterns commonly observed in other inflammatory diseases [48] (CD8-rich infiltrate, macrophage-rich infiltrate, histiocytes, and giant cells), yet in both instances, the ratio of IgG+/IgG4 + cells was 40%. A third case showed only nonspecific inflammatory infiltrate with an IgG+/IgG4 + proportion ranging between 20–40% [44]. Figure 1 summarizes the presentation of PNS manifestations of IgG4-related disease.

Our study showed that IgG4-RD predominantly impacts the nerves and muscles of middle-aged men, often presenting as mononeuritis multiplex or focal myositis. PNS symptoms in IgG4-RD patients are likely due to the direct invasion of IgG4-positive plasma cells, although they may also be a manifestation of autoimmune comorbidities such as systemic vasculitis, idiopathic inflammatory myopathies or myasthenia gravis. Most IgG4-RD cases in our study displayed both systemic manifestations and raised IgG4 serum levels.

PNS involvement in IgG4-RD can present as subacute polyneuropathy, mononeuritis multiplex, mononeuropathies, and radiculopathies. Elevated serum inflammation markers, similar to those in PNS involvement in other small-vessel vasculitis ([49–54]) may accompany these manifestations. Our findings suggest that IgG4-RD should be a potential diagnosis in cases of inflammatory PNS disease. However, given the broad differential diagnosis, histological and immunohistochemical confirmation should always be pursued in these cases, as the mechanism appears to be direct PNS invasion by IgG4-positive plasma cells. mononeuritis multiplex and inflammatory polyneuropathies. Nevertheless, neurologists and rheumatologists should carefully exclude other autoimmune conditions when encountering patients with confirmed or suspected IgG4-RD who exhibit symptoms of peripheral neuropathy. In this regard, excluding ANCA associated vasculitis and Sjogren`s disease if of great importance, given the potential clinical and histological similarities between IgG-RD and theses conditions. Chronic inflammatory demyelinating neuropathy must also be excluded.

Neuromuscular junction manifestations in IgG4-RD patients were predominantly linked to comorbidity. It is noteworthy that none of the IgG4-RD patients with myasthenia gravis had anti-AchR antibodies or thymoma [55]. However, two patients had anti-MusK autoantibodies. Interestingly, anti-MusK is an IgG4 subtype antibody [56], suggesting a potential association with IgG4-mediated autoimmunity, which may have implications for treatment responses, thymoma frequency, and prognosis.

Focal myositis cases, especially in the lower limbs, predominantly exhibited direct invasion by IgG4-positive cells and fibrosis. Only one case of focal myopathy exhibited systemic manifestations typical of IgG4-RD, thus not meeting the ACR-2019 criteria [1]. Additionally, our research encountered IgG4-RD in conjunction with proximal myopathies typically associated with inflammatory diseases, indicating that IgG4-RD might be a coexisting condition or an unrecognized cause of polymyositis-like syndromes [48]. Employing immunohistochemical staining for IgG4 in unresolved cases of inflammatory myopathies with lymphoplasmacytic infiltrates could provide greater diagnostic certainty in these cases.

Despite its contributions, our study is not without limitations. The small number of PNS involvement cases mirrors the infrequent nature of this manifestation in IgG4-RD. Moreover, the heterogeneity in case reporting and the varied management approaches across patients may affect the observed frequency of findings. Lastly, while missing data is a common issue in case report reviews, the amalgamated data we've compiled offers more insight than any single report or small series previously published.

In our study, IgG4-RD PNS manifestations predominantly affected middle-aged men, presenting most commonly as mononeuritis multiplex or focal myositis. As the probable mechanism involves nerve/muscle infiltration by the disease, and given the broad differential diagnosis, pursuing histological and immunohistochemical confirmation, whenever possible, is advised. A comprehensive evaluation to exclude other autoimmune diseases is crucial, including systemic vasculitis, Sjogren’s disease, and primary neurological conditions, to confidently attribute the PNS syndromes to IgG4-RD

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Competing interests:

The authors declare that they have no competing interests

Funding:

The authors have received no funding for this research;

Author Contribution

Authors' contributions: Renan Fabri Rosenstein: Article search and screening, draft manuscript preparation. Jose Pedro Baima: manuscript review. Henrique Ayres Mayrink Giardini: manuscript review. Leonardo Henrique Mendonça: manuscript review. Preparation of figures. Guilherme Diogo Silva: Article screening, study conception and design, draft manuscript preparation.

Availability of data and materials:

All data generated or analyzed during this study are included in this published article

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Characterization of the peripheral nervous system manifestations in patients with IgG4-related disease: a systematic review

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Peripheral nerve

Neuromuscular junction

Muscle

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