Objective IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes. Methods We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis. Results In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, p Conclusion We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

/pdf/clinical-phenotypes-of-igg4-related-disease-an-analysis-of-5bittw9s78.pdf

Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts

IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. The main histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis. The precise pathogenic mechanisms of IgG4-RD are still unclear. CD4+ T and B cells, including IgG4-expressing plasmablasts, constitute the major inflammatory cell populations and are believed to cause organ damage and tissue fibrosis. The diagnosis of the disease may be challenging and should be based on specific histopathological findings, typical laboratory and radiological aspects and an appropriate clinical context. The first-line treatment of IgG4-RD is based on glucocorticoids, which are usually efficacious. However, B cell depletion induced by rituximab has also been found to induce remission in steroid-resistant disease or has been used as steroid-sparing agent for relapsing disease. This review provides an update on clinical and therapeutic aspects of IgG4-RD.

IgG4-related disease: a clinical perspective.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of melanin-positive, dopaminergic neurons in the substantia nigra. Although there is convincing epidemiologic evidence of a negative association between PD and most cancers, a notable exception to this is that melanoma, a malignant tumor of melanin-producing cells in skin, occurs with higher-than-expected frequency among subjects with PD and that melanoma patients are more likely to have PD. A clear biological explanation for this epidemiological observation is lacking. Here, we present a comprehensive review of published literature exploring the association between PD and melanoma. On the basis of published findings, we conclude that (i) changes in pigmentation including melanin synthesis and/or melanin synthesis enzymes, such as tyrosinase and tyrosine hydroxylase, play important roles in altered vulnerability for both PD and melanoma; (ii) changes of PD-related genes such as Parkin, LRRK2 and α-synuclein may increase the risk of melanoma; (iii) changes in some low-penetrance genes such as cytochrome p450 debrisoquine hydroxylase locus, glutathione S-transferase M1 and vitamin D receptor could increase the risk for both PD and melanoma and (iv) impaired autophagy in both PD and melanoma could also explain the association between PD and melanoma. Future studies are required to address whether altered pigmentation, PD- or melanoma-related gene changes and/or changes in autophagy function induce oncogenesis or apoptosis. From a clinical point of view, early diagnosis of melanoma in PD patients is critical and can be enhanced by periodic dermatological surveillance, including skin biopsies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.25912

The association between Parkinson's disease and melanoma.

Idiopathic retroperitoneal fibrosis (RPF), reviewed herein, is a rare fibro-inflammatory disease that develops around the abdominal aorta and the iliac arteries, and spreads into the adjacent retroperitoneum, where it frequently causes ureteral obstruction and renal failure. The clinical phenotype of RPF is complex, because it can be associated with fibro-inflammatory disorders involving other organs, is considered part of the spectrum of IgG4-related disease, and often arises in patients with other autoimmune conditions. Obstructive uropathy is the most common complication, although other types of renal involvement may occur, including stenosis of the renal arteries and veins, renal atrophy, and different types of associated GN. Environmental and genetic factors contribute to disease susceptibility, whereas the immunopathogenesis of RPF is mediated by different immune cell types that eventually promote fibroblast activation. The diagnosis is made on the basis of computed tomography or magnetic resonance imaging, and positron emission tomography is a useful tool in disease staging and follow-up. Treatment of idiopathic RPF aims at relieving ureteral obstruction and inducing disease regression, and includes the use of glucocorticoids, combined or not with other traditional immunosuppressants. However, biologic therapies such as the B cell–depleting agent rituximab are emerging as potentially efficacious agents in difficult-to-treat cases.

Idiopathic Retroperitoneal Fibrosis

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa.

Parkinson's Disease and Melanoma: Co-Occurrence and Mechanisms.

Background Idiopathic retroperitoneal fibrosis (RPF) is a rare disease. Asbestos exposure has been proposed as a risk factor for idiopathic RPF. Objective To investigate the role of asbestos and other occupational agents (such as silica, metals, and organic solvents), as well as environmental agents (such as smoking), and their interactions as potential risk factors for idiopathic RPF. Design Case-control study. Setting National referral hospital for idiopathic RPF. Patients 90 patients with idiopathic RPF and 270 control participants matched for age, sex, and region of residency. Measurements Occupational history was obtained using structured questionnaires administered by blinded specialists in occupational medicine. Exposure to nonoccupational agents and presence of diseases that were potentially predisposing to idiopathic RPF were assessed through patient interviews and examination of medical records. Results A history of asbestos exposure was associated with idiopathic RPF (odds ratio [OR], 4.22 [95% CI, 2.14 to 8.33]). Both current smoking (OR, 3.21 [CI, 1.46 to 7.07]) and former smoking (OR, 2.93 [CI, 1.39 to 6.14]) were more prevalent among patients than among those who never smoked. A multiplicative effect was found between tobacco smoke and both occupational asbestos exposure (OR, 12.04 [CI, 4.32 to 38.28]) and extraoccupational asbestos exposure (OR, 8.42 [CI, 2.77 to 30.58]). Limitation Retrospective, questionnaire-based assessment of occupational exposure. Conclusion Exposure to asbestos and tobacco smoke resulted in strong risk factors for idiopathic RPF. Coexposure to asbestos and smoke had a multiplicative effect on risk compared with single exposure. Primary funding source None.

Asbestos and Smoking as Risk Factors for Idiopathic Retroperitoneal Fibrosis: A Case–Control Study

A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.

A case-control study of Parkinson's disease and tobacco use: Gene-tobacco interactions†

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Asbestos and Smoking as Risk Factors for Idiopathic Retroperitoneal Fibrosis: A Case–Control Study

A case-control study of Parkinson's disease and tobacco use: Gene-tobacco interactions†