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© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

ObjectivesThe endoplasmic reticulum aminopeptidase (ERAP1) haplotypeHap10encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet’s diseases (BD) currently known, but only in carriers ofHLA-B*51, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact.MethodsWe genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9ERAP1KOs fromHLA-B*51+LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems.ResultsAllele frequencies ofERAP1-Hap10were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers ofERAP1-Hap10in anHLA-B*51background.ERAP1KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells.ConclusionsWe demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance ofERAP1-Hap10/HLA-B*51at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.

W E designed and optimized an inter-convertible flow cytometry panel for the analysis and sorting of human CD4+ regulatory T cells (Treg) utilizing all of the major, currently accepted marker combinations for Treg identification. The panel is optimized for use with peripheral blood mononuclear cells (PBMC). In addition, the panel allows for the identification, classification, and isolation of activated, antigen-experienced Treg, and provides estimates of proliferation and suppressive capacity. To this end we created two, easily inter-convertible sub-panels: ATREG—which includes intra-nuclear markers, and BTREG—using surface markers only. Both sub-panels have been tested on cryopreserved PBMC from healthy donors and those with human autoimmune diseases, as well as on long-term cultured human Treg and non-Treg cell lines and clones.

Human regulatory T cells (Treg) are notoriously difficult to isolate in high purity given the current methods of Treg enrichment. These methods are based on the identification of Treg through several activation-dependent cellular surface markers with varying expression levels in different physiologic and pathologic conditions. Populations isolated as “Treg” therefore often contain considerable numbers of non-Treg effector cells (i.e., Teff) which hamper the precise phenotypic and functional characterization of these cells, their genomic and proteomic characterization, their reliable enumeration in different states of health and disease, as well as their isolation and expansion for therapeutic purposes. The latter, in particular, remains a major hurdle, as the inadvertent expansion of effector cells homing in Treg-relevant cellular compartments (e.g., CD4(+)CD25(+) T cells) may render Treg-based immunotherapy ineffective, or even harmful. This work presents a method that circumvents the problems associated with population-based isolation and expansion of Treg and shows that the generation of Treg candidate clones with the subsequent selection, culture, and expansion of only carefully vetted, monoclonal cells, enables the generation of an ultrapure Treg cell product that can be kept in culture for many months, enabling downstream investigation of these cells, including for possible therapeutic applications.

Background:HLA-B51 is a definite risk factor for Behçet’s disease (BD). A coding variant of ERAP1, Hap10 – with low peptide-trimming activity – vastly potentiates this risk, but is mechanistically unclear1,2).Objectives:To test the hypothesis that low or absent ERAP1 activity alters CD8 T cell immunogenicity through changes in the HLA-B51 peptidome and shapes the CD8 T cell immune response in affected subjects.Methods:We generated HLA-B51+ERAP1 KO LCL clones using CRISPR-Cas9, performed mass spectrometry of the immunoprecipitated MHC-class I peptidome with subsequent computational deconvolution for HLA-B51-binding peptides. We then assessed single cell (ICS), bulk (ELISA) and proliferative (CFSE) CD8 effector (IFNg, granzyme B, perforin) T cell responses through stimulation of allogeneic donor cells with WT vs KO LCL and determined ERAP1 haplotypes in 49 untreated Turkish BD subjects with ocular and/ or major vascular involvement as well as healthy donors (HD) whose PBMC were profiled using 6 multicolour flow cytometry panels.Results:WT and KO peptidomes differed significantly (p+CD8 T cells. Analysis of 133 T, B, NK and monocyte cell populations revealed predominance of CD8 T and NKT cell subset in HLA-B51+/Hap10+ BD vs HLA-B51+/Hap10- BD and HD, accounting for 80% of all populations reaching significance (p0.8) or very large (>1.2).Conclusion:We show that absence of functional ERAP1 alters human CD8 T cell immunogenicity. This is mediated by an HLA-class I peptidome with propensity for longer peptides above 9mer and suggests loss or de-novo presentation of peptide-HLA-B51 complexes to cognate CD8 TCR. The reciprocal changes in antigen- experienced vs naive CD8 T cell subsets in affected subjects point to biologic significance of HLA-B51/Hap10 in BD. Collectively, our findings suggest that an altered HLA-B51 peptidome modulates immunogenicity of CD8 effector T cells in ERAP1-Hap10 carriers with BD and identify targets for future drug development.References:[1]Kirino, Y., G. Bertsias, Y. Ishigatsubo, N. Mizuki, I. Tugal-Tutkun, E. Seyahi, Y. Ozyazgan, F. S. Sacli, B. Erer, H. Inoko, Z. Emrence, A. Cakar, N. Abaci, D. Ustek, C. Satorius, A. Ueda, M. Takeno, Y. Kim, G. M. Wood, M. J. Ombrello, A. Meguro, A. Gul, E. F. Remmers, and D. L. Kastner. 2013. ‘Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B*51 and ERAP1’,Nat Genet, 45: 202-7.[2]Takeuchi, M., M. J. Ombrello, Y. Kirino, B. Erer, I. Tugal-Tutkun, E. Seyahi, Y. Ozyazgan, N. R. Watts, A. Gul, D. L. Kastner, and E. F. Remmers. 2016. ‘A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behcet’s disease in HLA-B*51 carriers’,Ann Rheum Dis, 75: 2208-11.Disclosure of Interests:Arshed F. Al-Obeidi: None declared, Ann Cavers: None declared, Yesim Ozguler: None declared, Olivier Manches: None declared, Hua Zhong: None declared, Berna Yurttas: None declared, Beatrix Ueberheide: None declared, Gulen Hatemi Grant/research support from: BMS, Celgene Corporation, Silk Road Therapeutics – grant/research support, Consultant of: Bayer, Eli Lilly – consultant, Speakers bureau: AbbVie, Mustafa Nevzat, Novartis, UCB – speaker, Matthias Kugler: None declared, Johannes Nowatzky: None declared

Objective Apoptotic cell receptors contribute to the induction of tolerance by modulating dendritic cell function following the uptake of apoptotic cells or microparticles. Dendritic cells that have bound or ingested apoptotic cells produce only low amounts of pro-inflammatory cytokines and fail to prime effector T cell responses. Specifically, ligation of the apoptotic cell receptor CR3 (CD11 b/CD18) on human monocyte-derived dendritic cells (moDC) down-modates proinflammatory cytokine secretion, but the consequences for human Th17 cell homeostasis and effector responses remain unknown. Here, we aimed to establish whether CD11b-ligated moDC modulate Th17 cell effector reponses to assess their potential for future use in moDC-based suppressive immunotherapy. Methods We generated a bead-based surrogate system to target CD11b on monocyte-derived human dendritic cells and examined the effects of CD11b ligation on Th17-skewing cytokine secretion, priming, expansion and functional plasticity in DC/T cell co-culture systems at the poly- and monoclonal level. Results We show that Th17 cell expansion within the human memory CD4+ T cell compartment was efficiently constricted by targeting the CD11b receptor on moDC. This tolerogenic capacity was primarily dependent on cytokine skewing. Furthermore, ligation of CD11b on healthy homozygous carriers of the rs11143679 (ITGAM) variant – a strong genetic susceptibility marker for human systemic lupus erythematosus – also down-modulated the secretion of Th17-skewing cytokines. Conclusion Overall, our findings underline the potential of targeted CD11b ligation on human dendritic cells for the engineering of suppressive immunotherapy for Th17-related autoimmune disorders.

A 46-year-old Hispanic man presented with fever, genital ulcers, left eye redness and chest pain. Physical examination was notable for a healed oral ulcer and scrotal ulcers, and bilateral superficial thrombophlebitis. He was found to have new-onset pancytopenia. CT of the chest showed pericardial and pleural effusions and rapidly progressing inflammation of the aortic arch and ascending vessels. Although the patient had Behcet’s disease (BD)-like symptoms, pancytopenia could not be explained by the diagnosis, prompting a bone marrow biopsy which showed myelodysplastic syndrome. This report highlights the importance of excluding alternate disorders before making a diagnosis of Behcet’s disease if atypical, BD-incompatible or incomplete constellations of symptoms and findings are present.

A 58-year-old man with a history of recurrent aphthous ulcers since childhood was admitted to the hospital with acute neurological decline characterised by loss of motor dexterity, dysarthria, dysphagia and unsteady gait. MRI brain was significant for symmetrical hyperintense T2 fluid attenuated inversion recovery (FLAIR) in the corticospinal tracts, including parts of the pons and the mesodiencephalic junction. Though initial concern was for neuro-Behçet’s disease, brain biopsy ultimately revealed a diagnosis of astrocytoma. This report demonstrates a mimic of neuro-Behçet’s disease and the importance of confirming the correct diagnosis prior to initiating therapy.

Behcet's syndrome (BS), or Behcet's disease (BD), is a multisystem inflammatory disorder that mainly affects population clusters along the Old Silk Road; however, it has been reported worldwide. The disease is currently classified as a vasculitis, characterized by sporadic outbreaks. The hallmarks of BS are recurrent, painful oral ulcers. Skin, eyes, central nervous system (CNS), gastrointestinal tract (GI) tract, and other organs may also be involved. CNS, GI, and major vascular involvement can be life-threatening, and uveitis may lead to blindness. Immunosuppressive and immunomodulatory treatment is the mainstay of therapy for this inflammatory disease. Whereas the most frequently used agents for the treatment of BS have been corticosteroids, colchicine, and azathioprine, the introduction of anti-tumor necrosis factor (TNF) agents and interferon-α (IFN-α) has begun to revolutionize the treatment of Behcet's eye disease and the management of other major organ manifestations. Data from randomized controlled trials (RCTs) showing beneficial effects for some of its disease manifestations are available for azathioprine, colchicine, cyclosporine, etanercept, IFN-α depot-methylprednisolone, and others. Currently, an evidence-based approach to the management of BS is possible only for eye, mucocutaneous, and joint involvement, whereas recommendations for the treatment of gastrointestinal, neurological, and vascular disease remain based on expert opinion. Drug Dev Res 72:647–656, 2011. © 2011 Wiley Periodicals, Inc.

Behcet’s disease (BD) is a multisystem inflammatory disorder currently classified as a vasculitis. Its etiopathogenesis is unclear, but environmental, genetic and autoimmune factors have been considered. There are ongoing efforts to elucidate the etiology of BD and numerous attempts have been made to identify biomarkers predictive of the course and severity of the disease. Much of this – mostly cross-sectional – work has yielded some valuable results, but more longitudinal studies are needed. This review provides an overview of some of the biomarkers which have been investigated in BD so far, and aims to evaluate their usefulness in the diagnosis and estimation of disease activity. This is exemplified by certain clinical situations. Clinicians, clinical investigators and basic researchers alike are given a concise database of biomarkers studied in association with BD, as well as a reflection of methods for estimation of disease activity.

Background In ST-elevation MI (STEMI) the culprit artery is usually occluded, whereas non-STEMI (NSTEMI) it is usually patent. The location of the ruptured plaque may influence MI type. We examine whether the distance from the coronary ostium to the culprit lesion is different in STEMI as compared to NSTEMI. Methods We selected patients who presented with an acute MI and underwent coronary angiography during hospitalization. The analysis included 754 patients of whom 514 had STEMI and 240 had NSTEMI. The distance from the coronary ostium to the site of thrombosis was measured. Results For both STEMI and NSTEMI patients the first 60 mm of the coronary artery contained 75% of the culprit lesions. There were no significant differences in median distances from the vessel ostium to the site of thrombosis as well. Conclusions The distance from coronary ostium to culprit lesion is similar in STEMI and NSTEMI. Culprit lesion location does not appear to influence the development of STEMI as opposed to NSTEMI.

The information content of multi-parametric flow cytometry-based immune-phenotyping experiments is often underexploited given the paucity of adequate tools and strategies for large-scale unbiased data analysis. Here, we developed and applied a data analysis approach taking into account all mathematically possible combinations of markers in a given flow cytometry panel. We analyzed flow cytometry data generated from peripheral blood samples of healthy humans and patients with autoimmune uveitis in the setting of 2 different autoimmune diseases: Behcet’s disease and sarcoidosis. Original FACS data files were mined from Dryad Digital Repository http://dx.doi.org/10.5061/dryad.v6ste with reference to http://dx.doi.org/10.1371/journal.pcbi.1003215, and gated in bivariate plots. We employed combinatory mathematics to generate a matrix quantifying the representation of all possible cell populations using a given set of markers within the respective starting population and coded the algorithm to create a Java-based platform enabling the computation of large numbers of markers. Resulting metadata were visualized in a heat map approach. Our method enabled clustering of healthy vs diseased subjects using only 4 common markers (CD3, C8, CD197, and CD45), and of sarcoid vs Behcet’s patients with minimal error. Our approach demonstrates that multi-dimensional analysis of flow cytometry data allows meaningful large-scale screening of biologically relevant markers enabling classification and characterization of states of health and autoimmune disease. The approach is unbiased and has the potential to facilitate the discovery of cell populations with relevance as potential biomarkers or biological research targets.

A 40-year-old Chinese man was admitted for haemoptysis and progressive deep vein thrombosis involving the inferior vena cava (IVC) despite anticoagulation. An IVC filter had been placed earlier at an outside hospital. CT angiography revealed two pulmonary artery aneurysms. The patient was found to have a history of oral and genital ulcers, uveitis and erythema nodosum, thus meeting criteria for Behcet's disease. Other causes of the haemoptysis and thrombophilia were excluded. He underwent successful coil embolisation of the pulmonary artery aneurysms and responded well to immunosuppressive therapy with cyclophosphamide and steroids. Anticoagulation was cautiously continued to limit the long-term risk of secondary thrombosis from his IVC filter. The patient remains well 5 months after initiation of immunosuppressive therapy. Making a diagnosis of Behcet's disease in the setting of thrombosis is crucial, as treatment must include immunosuppression, and, thus, fundamentally differs from the management of most other thrombotic disorders.

The aim of the study is to determine the frequency and functionality of blood conventional dendritic cells (cDCs) in relation to disease activity in systemic lupus erythematosus.Blood cDCs were enumerated for 34 SLE patients, defined as "active" (SLEDAI ≥ 4) or "inactive" (SLEDAI4), 26 RA subjects and 8 healthy subjects by FACS. cDC activation was measured by IL-12p40/70 staining following resiquimod stimulation.The frequency of blood cDCs was significantly lower in active compared to inactive patients, however, with comparable cDC functionality.cDC frequency in active SLE is decreased with no perturbation in cDC function, possibly due to enhanced turnover and/or tissue-specific migration.

The best treatment for patients with Behçet's disease (BD) with major vessel thrombosis has not been fully determined. Our objective was to raise this therapeutic dilemma and to call for controlled studies to help establish guidelines to address this problem.Three patients with BD and major vessel thrombosis whom we recently encountered are described. Their cases were presented to rheumatologists from Turkey, Israel and the USA. The physicians were asked about the kind of treatment they would give each patient at diagnosis of thrombosis and if they chose to give anticoagulation and for long.Fifty-five Turkish, 33 Israeli and 25 American rheumatologists responded to the questionnaire. More than 87% of the Israeli and American rheumatologists would give anticoagulation at the time of diagnosis for the cases of venous thrombosis compared with only 40-44% of the Turkish physicians. In these cases 56% of the American and 45% of the Israeli rheumatologists would give warfarin for life compared with only 5-18% of the Turkish physicians. Regarding a case with intra-cardiac thrombus, 96% of American, 94% of Israeli, and 60% of Turkish rheumatologists would start anticoagulation at diagnosis while 70%, 39% and 33%, respectively would give this treatment for life.The therapeutic approach towards thrombosis in Behçet's disease differs significantly among rheumatologists from different countries. The different prevalence of the disease in these countries may explain this difference. A randomised controlled prospective trial is needed in order to determine the exact role of anticoagulant treatment in BD.

Clinicians have long assumed that an association exists between crystal arthropathies and the presence of osteoarthritis (OA). However, studies establishing an independent association between calcium pyrophosphate or uric acid crystal disease and OA are sparse. Even less is known about a possible pathogenic relationship. Whereas some studies suggest that the relationships between crystals and OA may not be incidental and that crystal deposition may contribute to the onset and/or acceleration of OA joint damage, other authors have challenged this assertion. In this review, we provide an overview of past and current research elucidating the role of crystal deposition, including monosodium urate, calcium pyrophosphate, and other crystals, in OA. Given the clinical frequency of gout and that agents exist to modulate serum UA levels, special attention is given to the role of monosodium urate crystals.

Spontaneous reperfusion (SR) may occur in patients with ST elevation myocardial infarction (STEMI) prior to reperfusion therapy. Hyperglycemia is common on admission in patients with STEMI and is associated with a worse prognosis. Mechanisms remain unclear but may include impairment of coronary flow. The objective of this study was to examine whether acute hyperglycemia influenced the occurrence of SR in patients with STEMI.All patients presenting to our institution with acute STEMI with measurement of glucose levels on presentation were eligible. SR was defined as a combination of significant relief of chest pain associated with an at least 70% resolution of ST segment elevation on follow-up ECG.465 patients were studied of whom 77 patients met criteria for SR. Average glucose levels were not significantly different between the SR and non-SR groups (10.0+/-5.6 mmol/l versus 10.1+/-5.3; P=NS). When patients were divided into normoglycemic and hyperglycemic groups, there was no significant difference in the percentages of such patients in the SR and non-SR groups. (52% versus 54%; P=NS).Acute hyperglycemia on admission does not predict the occurrence of SR in a general population of patients with acute MI.

Spontaneous reperfusion (SR) of the infarct-related artery may occur in patients with ST-segment-elevation myocardial infarctions (STEMIs). Limited data are available on the angiographic characteristics of these patients. The objective of this study was to determine if there are differences in the distance of the culprit lesion from the coronary ostium in patients with STEMIs with and without SR. Patients who presented with acute STEMIs12 hours after pain onset and who underwent coronary angiography were entered into the study. Measurement of the distance from the coronary ostium to the culprit lesion was performed. A total of 469 patients with STEMIs were included in the study, of whom 77 met criteria for SR (significant relief of chest pain associated withor=50% resolution of ST-segment elevation on follow-up electrocardiography) and 392 did not. A highly significant difference was seen in ostial to culprit lesion distance, with the culprit lesions in the SR group being more distal than those in the non-SR group (45+/-22 vs 39+/-20 mm, p0.009). In conclusion, the findings of this study demonstrate that the location of the culprit lesion in patients with STEMIs who undergo SR is more distal in the involved artery than in patients with STEMIs who do not undergo SR.

Adoptive Treg transfer is a promising therapeutic strategy for autoimmune diseases. Most current approaches rely on the enrichment and in vitro expansion of non-clonal, presumably thymus-derived Treg cells. Limitations include low expansion rates, contaminating effector cells, and unstable suppressive activity. Here, we hypothesized that cloning of human CD4+CD127lowCD25highFoxP3+HELIOS+ cells yields a highly pure cellular product with stable suppressor function throughout repeated re-expansion cycles. Cloning was performed through selection for CD4+CD127lowCD25+ cells by magnetic bead isolation and expansion in limiting dilution conditions. Suppressor function was tested in suppression assays of CD3/CD28-stimulated allogeneic Teff cells. Clonality was assessed by Vbeta staining. To demonstrate validity of our approach for a human autoimmune disease we also cloned Treg from a patient with Behcet's disease, a multisystem vasculitis. Cloning efficiency was 2-5/100 seeded cells. Treg clones were homogenously CD4+CD127lowCD25highFoxP3+HELIOS+, and clonality was confirmed by staining for a unique TCR Vbeta chain. Clones maintained at least 80% suppression at a 1:4 Treg:Teff ratio over 8 weeks in in vitro culture. Expansion rate was up to 9.8 billion-fold. Our results indicate that massive expansion of human antigen-specific Treg clones is a feasible approach for the generation of large numbers of functionally stable regulatory T cells for preclinical and clinical testing.

Manipulating monocyte-derived DC (moDC) to alter effector T cell responses is an important strategy for the development of suppressive immunotherapy. We have previously shown that the ligation of CD11b/CD18 on moDC decreases the secretion of the Th17-skewing inflammatory cytokines IL-1β and IL-6, but maintains “immunosuppressive” TGF-β1. Here, we hypothesized that this “tolerogenic” DC-profile would diminish Th17 responses in peripheral human T cell populations. Healthy donor PBMC were differentiated into moDC in IL-4, GM CSF-supplemented media for 5 days. CD11b/CD18 on moDC was targeted via a bead-based surrogate system developed in our lab. Irrelevant IgG, or avb5, and beads without antibodies were used as controls. DC were stimulated with LPS and MDP or PGN or not stimulated, and then co-cultured with enriched CD4+ human T memory cells. IL-17 secretion was monitored per CBA after 24 hours and/or 4 days, and Th17 frequency assessed by ICS following restimulation with PMA/Ionomycin after 2 weeks. LPS/MDP or PGN-stimulated moDC induced significant increases in co-culture supernatant IL-17 levels and CD4+ Th17 cell frequencies (up to15%). Strikingly, these changes were significantly reduced in CD11b/CD18-ligated DC/T cell conditions, showing reversal of this NOD2/TLR4 or TLR2-mediated expansion effect though ligation of CD11b/CD18 on moDC.

Herpes zoster (HZ), caused by reactivation of varicella zoster virus (VZV) from latency in a sensory ganglion, is almost always a condition involving a single dermatome.1 2 Usually it occurs because of an age related decline in cellular immunity or immune compromised conditions. When spreading, it might involve one or two adjacent dermatomes or disseminate systemically (disseminated HZ).3 The simultaneous reactivation of VZV from more than one ganglion is an extremely rare condition.4 A 64-year-old Arab woman was hospitalised with generalised weakness, urinary tract infection and a vesicular eruption on her back and thigh. Four months previously …