Use of Rituximab as an off-Label medication in Glomerular Diseases: Clinical Perspective

Objectives: We review rituximab (RTX) use and outcomes in immune-mediated glomerular diseases (GN) and compare it to established literature. Methods: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with literature supporting RTX use. Lupus nephritis (LN), 1o focal segmental glomerulosclerosis (1o FSGS), IgA nephropathy (IgAN), IgG4 related disease, and C3GN had insufficient literature support for RTX use. Clinical Remission was assessed six months after receiving RTX. Results: A total of 61 cases analyzed. RTX was an add on therapy in 87%. Remission rate was 95% in MCD and MN vs. 56 % in off-label group (P=.002). LN patients had a mean initial eGFR of 69mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. Mean initial eGFR for 1o FSGS was 33mL/min and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-related disease cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission achieved in only 2 ANCA vasculitis cases, and none in IgA vasculitis cases. Conclusion: Our data support RTX use in resistant MCD and MN. RTX showed success in LN and IgG4 related disease, but not FSGS or C3GN. The small vasculitis cases number does not allow drawing a conclusion on RTX effectiveness.

Ossifying fibrous epulis as an IgG4-related disease of the oral cavity: a case report and literature review

Background Fibrous sclerosing tumours and hypertrophic lesions in IgG4-related disease (IgG4-RD) are formed in various organs throughout the body, but disease in the oral region is not included among individual organ manifestations. We report a case of ossifying fibrous epulis that developed from the gingiva, as an instance of IgG4-RD. Case presentation A 60-year-old Japanese man visited the Department of Oral and Maxillofacial Surgery, Gunma University Hospital, with a chief complaint of swelling of the left mandibular gingiva. A 65 mm × 45 mm pedunculated tumour was observed. The bilateral submandibular lymph nodes were enlarged. The intraoperative pathological diagnosis of the enlarged cervical lymph nodes was inflammation. Based on this diagnosis, surgical excision was limited to the intraoral tumour, which was subsequently pathologically diagnosed as ossifying fibrous epulis. Histopathologically, the ossifying fibrous epulis exhibited increased levels of fibroblasts and collagen fibres, as well as infiltration by numerous plasma cells. The IgG4/IgG cell ratio was > 40%. Serologic analysis revealed hyper-IgG4-emia (> 135 mg/dL). The patient met the comprehensive clinical diagnosis criteria and the American College of Rheumatology and European League Against Rheumatism classification criteria for IgG4-RD. Based on these criteria, we diagnosed the ossifying fibrous epulis in our patient as an IgG4-related disease. A pathological diagnosis of IgG4-related lymphadenopathy was established for the cervical lymph nodes. Concomitant clinical findings were consistent with type II IgG4-related lymphadenopathy. Conclusions A routine serological test may be needed in cases with marked fibrous changes (such as epulis) in the oral cavity and plasma cells, accompanied by tumour formation, to determine the possibility of individual-organ manifestations of IgG4-related disease.

In-silico phenotype prediction by normal mode variant analysis in TUBB4A-related disease

TUBB4A-associated disorder is a rare condition affecting the central nervous system. It displays a wide phenotypic spectrum, ranging from isolated late-onset torsion dystonia to a severe early-onset disease with developmental delay, neurological deficits, and atrophy of the basal ganglia and cerebellum, therefore complicating variant interpretation and phenotype prediction in patients carrying TUBB4A variants. We applied entropy-based normal mode analysis (NMA) to investigate genotype–phenotype correlations in TUBB4A-releated disease and to develop an in-silico approach to assist in variant interpretation and phenotype prediction in this disorder. Variants included in our analysis were those reported prior to the conclusion of data collection for this study in October 2019. All TUBB4A pathogenic missense variants reported in ClinVar and Pubmed, for which associated clinical information was available, and all benign/likely benign TUBB4A missense variants reported in ClinVar, were included in the analysis. Pathogenic variants were divided into five phenotypic subgroups. In-silico point mutagenesis in the wild-type modeled protein structure was performed for each variant. Wild-type and mutated structures were analyzed by coarse-grained NMA to quantify protein stability as entropy difference value (ΔG) for each variant. Pairwise ΔG differences between all variant pairs in each structural cluster were calculated and clustered into dendrograms. Our search yielded 41 TUBB4A pathogenic variants in 126 patients, divided into 11 partially overlapping structural clusters across the TUBB4A protein. ΔG-based cluster analysis of the NMA results revealed a continuum of genotype–phenotype correlation across each structural cluster, as well as in transition areas of partially overlapping structural clusters. Benign/likely benign variants were integrated into the genotype–phenotype continuum as expected and were clearly separated from pathogenic variants. We conclude that our results support the incorporation of the NMA-based approach used in this study in the interpretation of variant pathogenicity and phenotype prediction in TUBB4A-related disease. Moreover, our results suggest that NMA may be of value in variant interpretation in additional monogenic conditions.

Temporal Artery Vascular Diseases

In the presence of temporal arteritis, clinicians often refer to the diagnosis of giant cell arteritis (GCA). However, differential diagnoses should also be evoked because other types of vascular diseases, vasculitis or not, may affect the temporal artery. Among vasculitis, Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is probably the most common, and typically affects the peri-adventitial small vessel of the temporal artery and sometimes mimics giant cell arteritis, however, other symptoms are frequently associated and more specific of ANCA-associated vasculitis prompt a search for ANCA. The Immunoglobulin G4-related disease (IgG4-RD) can cause temporal arteritis as well. Some infections can also affect the temporal artery, primarily an infection caused by the varicella-zoster virus (VZV), which has an arterial tropism that may play a role in triggering giant cell arteritis. Drugs, mainly checkpoint inhibitors that are used to treat cancer, can also trigger giant cell arteritis. Furthermore, the temporal artery can be affected by diseases other than vasculitis such as atherosclerosis, calcyphilaxis, aneurysm, or arteriovenous fistula. In this review, these different diseases affecting the temporal artery are described.

The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis

Background The relationship between IgG4-related disease (IgG4-RD) and the risk of malignancy is still controversial. This article focused on assessing the risk of cancer in patients with IgG4-RD by meta-analysis. Methods We conducted a systematic review of the literature and meta-analysis characterizing the associated risk of overall malignancy and four site-specific malignancies (pancreas, lung, gastric and lymphoma) in patients with IgG4-RD. A search from 2003 to 2020 was performed using specified terms from PubMed, Embase, Web of Science and SinoMed. Random-effects model analysis was used to pool standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to clarify the heterogeneity of the included studies. Begg’s funnel plot and Egger’s linear regression test were used to evaluate the bias of the meta-analysis. A P value < 0.05 indicated the existence of publication bias. Results A total of 10 studies were included in the article. The overall SIR estimates suggested an increased risk of overall cancer in IgG4-RD patients (SIR 2.57 95% CI 1.72–3.84) compared with the general population. The specific SIRs for pancreas and lymphoma were higher than those of the general population in IgG4-RD patients (SIR 4.07 95% CI 1.04–15.92, SIR 69.17 95% CI 3.91–1223.04, respectively). No significant associations were revealed in respiratory and gastric cancer (SIR 2.14 95% CI 0.97–4.75, SIR 0.95 95% CI 0.24–3.95, respectively). Four studies were found to be the major sources of heterogeneity by sensitivity analysis. There was no evidence of publication bias via Egger’s test. Conclusion Compared with the general population, patients with IgG4-RD appear to have a higher risk of overall cancer, especially pancreatic and lymphoma. The risk of lung and gastric cancer was not different between IgG4-RD patients and the general population.