Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

Outcomes of Serum Food-Specific Immunoglobulin G 4 to Guide Elimination Diet in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. METHODS: Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. RESULTS: Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. DISCUSSION: Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZY-IL1 in Three Patients with Cryopyrin-Associated Periodic Syndromes.

We present the first results of the proof-of-concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin-associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50 mg of ZYIL1 twice daily for 7 days. A total of 5 treatment-emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5 µg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post-last dose.

Evaluation of glutamic acid decarboxylase (GAD) 65 antibody detection methods for neurological and diabetic investigation in an Australian diagnostic laboratory.

The role of anti-glutamic acid decarboxylase (GAD) 65 autoantibodies in autoimmune neurological conditions is evolving, but testing recommendations remain unchanged in Australia with GAD enzyme-linked immunosorbent assay (ELISA) and immunoblot as the only two Therapeutic Goods Administration approved testing methods available in Australia. Common practice is for use of ELISA in diagnosis of type 1 diabetes mellitus (T1DM) and use of immunoblot for diagnosis of GAD65-associated neurological disease. We observed a cohort of patients with negative immunoblot results and positive ELISA in the context of GAD-associated neurological disease without T1DM. In the absence of robust consensus guidelines on preferred testing modalities, we sought to determine if ELISA could have a superior role in the diagnosis of GAD-associated neurological disease when compared to immunoblot in this paper. We tested for anti-GAD65 autoantibodies on 55 patient samples, 40 samples requested for neurological disease and 15 type 1 diabetes samples with detectable anti-GAD65, using two testing platforms: Euroimmun anti-GAD enzyme-linked immunosorbent assay (ELISA) and. Euroimmun EuroLine immunoblot for paraneoplastic neurologic syndromes. These results were correlated against the clinical scenario. Positive ELISA results had a sensitivity of 100% and specificity of 91% for GAD65-related neurological disease. Immunoblot showed sensitivity of 43% and specificity of 76% for GAD65-related neurological disease. ELISA proved more sensitive and specific for GAD65-related neurological disease compared to immunoblot, raising questions about the role of this testing modality in neurological disease. We propose that ELISA should be used as a sole diagnostic method for all GAD65 antibody-related neurological disease over immunoblot. The presence of anti-GAD65 antibody on immunoblot is of doubtful clinical significance.

Lenalidomide Desensitization for Delayed Cutaneous Reaction: A Case Series and Review of the Literature.

BACKGROUND: Lenalidomide is commonly used for treatment of multiple myeloma (MM) as well as other hematological disorders. Cutaneous adverse reactions occur frequently and withholding lenalidomide treatment may have implications for prognosis. OBJECTIVE: To evaluate the role of lenalidomide desensitization in patients with cutaneous adverse reactions. METHODS: A retrospective review of patients referred for lenalidomide desensitization between May 2019 and May 2022 at a tertiary hospital. All patients underwent a 6-week outpatient desensitization with premedication. RESULTS: There were 12 patients: 10 males and 2 females with a median age of 65 years. All had MM with autologous stem cell transplantation and lenalidomide 10 mg daily added for maintenance therapy. Most patients (n = 8) had a generalized maculopapular exanthem with or without pruritus. All patients had delayed cutaneous reactions; the median time to onset was 14 days (range 2-28 d). Six patients tolerated desensitization: 5 on the first attempt and 1 after 3 attempts and supplementary oral prednisolone. Four patients underwent multiple (≤3) attempts at desensitization owing to breakthrough symptoms. In patients who failed desensitization, recurrence of symptoms occurred variably, either early (within days), within weeks, or delayed by more than 1 month. CONCLUSIONS: Lenalidomide desensitization is worthwhile and allows continuation of treatment. In our MM cohort, lenalidomide desensitization was successful in only 50% of cases, including some cases in whom ongoing symptoms were mitigated by cotreatment with antihistamine.

Recurrent orbital inflammation associated with VEXAS syndrome.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly recognised adult-onset multisystem autoinflammatory disease caused by a somatic mutation in the UBA1 gene in myeloid or erythroid precursor cells. This report describes an atypical presentation of recurrent dacryoadenitis associated with VEXAS syndrome and provides a review of the literature. A 68-year-old male presented with three episodes of unilateral alternating dacryoadenitis followed by bilateral involvement over a 4-year period. Each episode of orbital inflammation was characterised by upper lid swelling, oedema and enlarged lacrimal glands. In addition, he experienced intermittent flares of angioedema-like lesions involving the face and extremities, recurrent jaw aches, rash, progressive pulmonary fibrosis, and myelodysplastic syndrome. His inflammatory symptoms lessened with prednisolone but were refractory to methotrexate. Mycophenolate was subsequently trialled with a reasonable clinical response. Genetic testing established the diagnosis of VEXAS syndrome and tofacitinib, a JAK inhibitor, was commenced with resolution of inflammatory symptoms.

Australian recommendations on tapering of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in inflammatory arthritis.

Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) have been an important advance in the management of inflammatory arthritis, but are expensive medications, carry a risk of infection and other adverse effects, and are often perceived as a burden by patients. We used GRADE methodology to develop recommendations for dose reduction and discontinuation of b/tsDMARD in people with rheumatoid arthritis (RA), axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) who have achieved a low disease activity state or remission. The recommendations form part of the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis, an NHMRC-endorsed 'living' guideline, in which recommendations are updated in near real-time as new evidence emerges. Conditional recommendations were made in favour of dose reduction in RA and AxSpA but not in PsA. Abrupt discontinuation of b/tsDMARD is not recommended in any of the three diseases.

Diagnosis and management of giant cell arteritis: Major review.

Giant cell arteritis is a medical emergency because of the high risk of irreversible blindness and cerebrovascular accidents. While elevated inflammatory markers, temporal artery biopsy and modern imaging modalities are useful diagnostic aids, thorough history taking and clinical acumen still remain key elements in establishing a timely diagnosis. Glucocorticoids are the cornerstone of treatment but are associated with high relapse rates and side effects. Targeted biologic agents may open up new treatment approaches in the future.

Anakinra desensitisation in patients with cryopyrin-associated periodic syndromes.

Cryopyrin-associated periodic syndrome (CAPS) is rare and patients experience rashes, arthralgias and fevers despite supportive treatment. In these cases, anakinra subcutaneous therapy is indicated which provides symptom control. However, adverse reactions notably injection-site related, are common resulting in treatment cessation in these patients. Ongoing symptoms lead to morbidity and predispose patients to complications such as amyloidosis. We describe our experience with anakinra desensitisation in two cases with CAPS who had injection-site related reactions. We also propose a 34-day outpatient desensitisation protocol.

Validation of phospholipase A2 receptor direct immunofluorescence staining in the diagnosis of primary membranous glomerulonephritis.

Distinguishing between primary and secondary subtypes of membranous glomerulonephritis (MGN) is critical for its clinical management. We prospectively compared direct immunofluorescence (DIF) staining for phospholipase A2 receptor (PLA2R) on frozen renal biopsy with the presence of detectable serum PLA2R antibody assessed by enzyme linked immunosorbent assay (ELISA) in the diagnosis of primary MGN. Forty-six patients with biopsy-proven MGN were enrolled from April 2017 to June 2019 with 31/46 (67.4%) being primary and 15/46 (32.6%) being secondary as determined by comprehensive clinical assessment. This is currently deemed to be the gold standard for distinguishing primary from secondary MGN. Amongst the 31 primary MGN patients, 24/31 were positive on PLA2R DIF staining compared to 18/31 being positive on the PLA2R ELISA (p=0.03). Amongst the 15 secondary MGN patients, 1/15 was positive on PLA2R DIF compared to 0/15 on PLA2R ELISA (p=1.0). In conclusion, the presence of PLA2R staining on DIF demonstrated superior sensitivity and similar specificity compared to the detection of circulating PLA2R antibodies by ELISA in the diagnosis of primary MGN in a cohort of 46 patients with biopsy-proven MGN. We suggest that DIF should be considered as part of routine work-up in all newly diagnosed cases of MGN.

Inclusion-body myositis and primary Sjögren syndrome: mechanisms for shared etiologies.

Herein we report a case of sporadic inclusion-body myositis (sIBM) occurring at an unusually young age in a patient with primary Sjögren syndrome, and use the case to explore possible shared mechanisms for disease susceptibility. Possible factors may include the association of both conditions with the 8.1 ancestral haplotype; the presence of anti-cN1A antibodies, which, although considered specific for sIBM, are also seen in pSS; and the shared association with T-cell large granular lymphocyte leukemia (T-LGLL). Further evaluation of this patient did in fact reveal underlying T-LGLL and mechanisms by which T cells in sIBM may escape immune regulation and contribute to disease phenotype are explored. Despite myofiber infiltration with CD8-positive T cells in sIBM, and, although sIBM is traditionally considered treatment-refractory, we report a significant response to the anti-CD20 monoclonal antibody, rituximab, and discuss possible mechanisms by which this response may be mediated.

A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group.

Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.

Immunoglobulin G4 related disease: a single-centre experience from South Australia.

BACKGROUND: IgG4 related disease (IgG4RD) is a newly described multisystem fibro-inflammatory disorder. There is a paucity of literature describing the Australian experience of this rare condition. AIMS: To characterise the Royal Adelaide Hospital IgG4RD cohort with biopsy-proven disease. METHODS: A search of the Frome Road SA Pathology database was performed for all tissue biopsies containing the phrase 'IgG4 positive'. Case notes were reviewed for clinical details, laboratory and radiology results. Histological features according to the Boston Criteria were used. Patients with available case notes, highly suggestive or probable histology and clinical features to suggest IgG4RD were included. RESULTS: Twenty patients had definite or probable IgG4RD and suggestive clinical features; median age 59 (20-76), male : female 1.5:1. There was considerable delay in diagnosis (median diagnosis at 64 months). Organ involvement included: 11 exocrine gland, seven pancreatobiliary, seven nodal, seven soft tissue, five retro-orbital, three retroperitoneal fibrosis and two renal. Systemic symptoms at diagnosis were seen in eight patients. Seven (35%) had an elevated serum IgG4 (>1.35 g/L) at diagnosis. Only 12 (60%) required immunosuppressive treatment (corticosteroids); of these, four (20%) required a steroid-sparing agent and four (20%) required B-cell depleting therapy (rituximab). The median duration of follow up was 18 months. CONCLUSIONS: This is the first characterised Australian cohort with generalised IgG4RD, a rare, relatively indolent and under-recognised multisystem disorder. Diagnosis is difficult given lack of awareness of this rare condition among physicians, its presentation as a great disease mimic, challenges with histopathological assessment and the absence of a suitable serum biomarker.

Vogt-Koyanagi-Harada syndrome presenting with bilateral optic disc swelling and leptomeningeal enhancement.

Vogt-Koynagi-Harada (VKH) disease is a clinical syndrome with classical ocular and extraocular findings that is not uncommonly described in Asian, Middle-Eastern and South American populations. We describe a case of VKH in an elderly Polish-Australian distinguished by prominent bilateral disc swelling rather than uveitis and marked leptomeningeal enhancement on MRI which led to extensive investigation including brain biopsy. Both disc oedema and MRI abnormalities improved dramatically with systemic steroid therapy. VKH disease is an important differential to consider in older patients with an uveo-meningeal picture and atypical eye findings where other causes have been excluded.

High rates of indeterminate interferon-gamma release assays for the diagnosis of latent tuberculosis infection in liver transplantation candidates.

BACKGROUND AND AIMS: Screening for latent tuberculosis infection (LTBI) is recommended prior to solid organ transplantation. Interferon-gamma release assays (IGRAs) are the most widely used test for LTBI screening; however, assessment of IGRA performance in patients with end-stage liver disease is limited. The purpose of this study was to evaluate the prevalence and predictors of indeterminate (INDT) IGRA results in liver transplantation candidates. METHODS: Between March 2011 and May 2018, we retrospectively analyzed 155 patients undergoing liver transplantation assessment, who underwent IGRA testing (Quantiferon-TB Gold, QFT-G) to exclude LTBI. Characteristics of patients, including age, gender, etiology of liver disease, MELD score, and absolute lymphocyte counts, were compared by QFT-G result (determinate vs INDT). RESULTS: Of the 155 patients screened, the rate of positive, negative, and INDT results were 5.2%, 69.8%, and 25%, respectively. The only variable independently associated with an indeterminate test on multivariate analysis was MELD score (odds ratio = 1.07, 95% CI = 1.01-1.14 per unit increase; P = 0.014). In 95% of INDT tests, both TB antigen tube and the positive control tube were negative and repeat testing gave the same indeterminate result, suggestive of anergy rather than laboratory error. CONCLUSIONS: Our study suggests a high rate of INDT IGRA results during screening of liver transplant candidates for LTBI, associated with severity of liver disease and anergy. Because of the high rate of INDT QFT-G testing in this setting, individualized risk assessment is required including a thorough assessment of clinical risk factors and knowledge of local TB prevalence.

Rare mimic of recurrent anaphylaxis.

The distinction between true anaphylaxis and conditions that mimic it can be challenging. We present the unique case of a 23-year-old woman treated for recurrent episodes of anaphylaxis over the course of 11 years and the subsequent discovery of an unlikely condition. We also discuss our approach in managing cases where an anaphylactic mimic is suspected.

Radiotherapy for parotid IgG4-related disease.

We describe the use of radiotherapy for parotid IgG4-related disease (IgG4-RD), initially misdiagnosed as Kimura's disease, with sustained good partial response in a 37-year-old male. To the best of our knowledge, this is the first reported case of radiation for extra-orbital IgG4-RD, albeit inadvertently.

A case of deadly panniculitis.

While the majority of panniculitides are benign in nature, there are rare instances when panniculitis presents as the initial sign of a complex disease state. We describe a case of panniculitis initially diagnosed as lupus profundus that was challenged when features of haemophagocytic lymphohistiocytosis became apparent. We illustrate how some key clinical features and newer investigations can help differentiate between benign and malignant panniculitis.

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.