Polyethylene glycol hypersensitivity, patient outcomes in a 7-year retrospective study.

BACKGROUND: Immediate IgE-mediated hypersensitivity reactions to polyethylene glycol (PEG) are rare. Our understanding of PEG hypersensitivity is limited. OBJECTIVE: To evaluate the clinical characteristics and investigation outcomes of the largest cohort of patients with PEG allergy reported. METHODS: A total of 44 patients investigated for suspected PEG allergy across 4 United Kingdom tertiary allergy centers between October 2013 and December 2020 were studied. Clinical characteristics, index reaction, and approaches to and outcomes of allergy investigations were analyzed. RESULTS: PEG hypersensitivity was confirmed in 42 of 44 cases. Macrogol laxatives were the most common index drugs reported (23%), followed by depo-medroxyprogesterone (19%), oral penicillin V (10%), and depo-methylprednisolone (10%). In general, 61% experienced grade III anaphylaxis. Intradermal testing (IDT) increased the diagnostic sensitivity from 51% to 85%. Five patients experienced systemic reactions during IDT. Of the 5 patients, 2 were skin prick test positive to a high molecular weight PEG. Three patients with negative skin test results had positive drug provocation test results. Seven patients with PEG allergy reported tolerance to H1-antihistamines containing PEG. Administration of messenger RNA COVID-19 or Oxford/AstraZeneca COVID-19 vaccines was tolerated in all 16 patients to whom they were administered. CONCLUSION: PEG hypersensitivity is an uncommon cause of drug-induced anaphylaxis. Four index drugs accounted for two-thirds of the cases, and reactions to these drugs should prompt PEG hypersensitivity investigations. PEG IDT increases diagnostic yield. The role of skin prick test with higher molecular weight PEGs requires further attention. Further studies are required to understand PEG thresholds and PEG equivalent doses of various administration routes. COVID-19 vaccines were tolerated by all exposed.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency.

PURPOSE: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. METHODS: Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. RESULTS: The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. CONCLUSION: Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.

BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Impact of vaccination on hospitalization and mortality from COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience.

Background: Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients. Objectives: To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern. Methods: The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022. Results: 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave. Conclusions: Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts.

Common variable immunodeficiency with coexisting central nervous system sarcoidosis: case report and literature review with implications for diagnosis and pathogenesis.

We describe a patient with a history of longstanding primary generalised epilepsy, on anticonvulsant therapy, who presented with fever, headache, worsening seizures and hallucinations. Among various investigations, the patient had high CSF protein and ACE levels, leptomeningeal nodular enhancement on MRI brain and non-caseating granulomas in the brain and meninges on the biopsy. The patient was diagnosed with neurosarcoidosis. Subsequently, he was found to be panhypogammaglobulinaemic and was diagnosed with probable common variable immunodeficiency (CVID). The coexistence of common variable immunodeficiency and neurosarcoidosis is rare. Typically, non-caseating granulomas in CVID patients are localised in the lymphatic tissue and solid organs. To our knowledge, there are only five reports of the granulomas of the central nervous system (CNS) in CVID. We discuss the diagnostic difficulties in this case and review the literature.

Meta-analysis is no substitute for a comprehensive national registry.

Anti-tumor necrosis factor alpha (TNF-alpha) agents have become an established treatment option for rheumatoid arthritis (RA), but are not without risks. As TNF-alpha has a role in tumour surveillance, anti-TNF-alpha blockade could potentially increase the risk of malignancy. Recent meta-analysis by Bongartz et al. (JAMA 295:2275-2285, 2006) reported an increase in the incidence of malignancy attributed to anti-TNF-alpha antibodies, and the information has quickly and uncritically reached several secondary sources with huge effects on public perception of risks related to anti-TNF-alpha therapy. In contrast, the results from the British Society for Rheumatology Biologics Register show that in clinical practice, anti-TNF-alpha therapy in RA does not appear to increase the risk of malignancy in those patients with low risk of malignancy. We discuss the issues emerging from these published data and suggest caution against giving weight to meta-analysis of short-term drug studies.

Lupus and leg ulcers--a diagnostic quandary.

Leg ulcerations can occur in systemic lupus erythematosus (SLE) patients with antiphospholipid (aPL) antibodies and/or vasculitis, and it has been suggested that aPL antibodies may play a pathogenetic role in skin manifestations of SLE. To our knowledge, there is only one report of an aPL antibody-negative patient who developed pyoderma gangrenosum (PG) several years before the diagnosis of SLE. We describe a case of a young male affected by SLE who developed leg ulcers diagnosed as PG in the absence of aPL antibodies, where the onset of PG was associated with reactivation of SLE. Effective treatment led to significant improvement in skin lesions and SLE activity.

Unusual cause of painful shoulder in an elderly woman with rheumatoid arthritis.

The painful shoulder is a very common condition encountered in the rheumatology clinic with rotator cuff disorders, glenohumeral disorders, acromioclavicular joint disease and referred neck pain being the most common causes. Other rare causes have to be considered in the presence of "red flag" indicators. We describe a case of a patient with mild rheumatoid arthritis and a past medical history of stage 2C epithelial ovarian carcinoma who presented to the rheumatology clinic with a painful shoulder and who was initially diagnosed with rotator cuff tendinopathy. When seen 3 months later she was found to have a 15 x 10-cm firm, non-tender soft tissue mass over the right scapula and X-rays showed a large lytic mass destroying much of the upper border of the scapula, suggestive of metastasis. Bone metastases in patients with ovarian carcinoma are very rare; they occur in about 2% of cases and are invariably predictors of poor prognosis. To our knowledge, this is the first case of ovarian cancer metastasised to the scapula. We suggest that rheumatologists should be aware of the differential diagnosis of painful shoulder and look for "red flag" indicators in patients with known rheumatic conditions.

A still image of a transient rash captured by a mobile phone.

The diagnosis of adult onset Still's disease (AOSD) can be difficult as the differential diagnosis is broad, it is based on clinical criteria and the signs, for example rash, can be transient. Clinical photography has an obvious role, and with modern technology, is now in the hands of physicians. We report a case of AOSD where an image of a transient rash taken with a camera phone allowed the diagnosis to be established. Further, we discuss the controversies around hospital bans on mobile phones (due to potential incompatibility with medical devices) and the reality of their widespread use. We conclude that, providing safeguards of consent and data storage are in place, the camera phone is a useful tool in rheumatology practice.

From scleredema to AL amyloidosis: disease progression or coincidence? Review of the literature.

Scleredema (also called scleredema of Buschke) is a fibromucinous connective tissue disorder of unknown cause that belongs to a group of scleroderma-like disorders. We report the case of a 64-year-old lady with long-standing scleredema, associated with a paraprotein, and progressing to multiple myeloma and AL amyloidosis. The relationship of scleredema with paraprotein and multiple myeloma is well established, but only two cases of scleredema associated with amyloidosis have been reported to date. We suggest that amyloidosis may be underdiagnosed in patients with scleredema and paraproteinaemia. Features attributed to extracutaneous manifestations of scleredema could represent systemic amyloidosis. We review published reports of scleredema associated with paraprotein and discuss the difficulties in the differential diagnosis of scleroderma-like disorders. We discuss the diagnosis of plasma cell dyscrasias and amyloidosis and their relevance in rheumatology practice.

Acute myocarditis associated with adenoviral infection in a patient with scleroderma.

We describe a 40-year-old man with limited scleroderma who presented with acute heart failure following a flu-like illness. He was known to have incomplete left anterior bundle branch block, initial isolated pulmonary hypertension with enlarged right atrium, and no pulmonary fibrosis. He received therapy for acute heart failure and was transferred to a scleroderma centre for specific treatment of scleroderma cardiomyopathy. Investigations showed raised inflammatory markers and diffuse hyperechogenic thickening of the myocardium on echocardiography. Contrast-enhanced (Gd-DOTA) cardiovascular magnetic resonance imaging (CV-MRI) showed multiple areas of non-homogeneous delayed hyperenhancement in the left ventricle, suggestive of myocarditis. Antiadenovirus IgM antibodies were detected with a titer consistent with recent infection. Six weeks later a repeat Gd-DOTA CV-MRI showed an almost complete resolution of the areas of hyperenhancement and there was a significant reduction in the adenovirus antibody titer with serological conversion to IgG. To our knowledge this is the first report of viral myocarditis in scleroderma. Infections are important causes of morbidity and mortality in this disease and should always be included in the differential diagnosis of cardiac symptoms. We propose that contrast-enhanced CV-MRI is valuable in a non-invasive diagnosis of heart disease in patients with scleroderma.

EBV-driven diffuse large B-cell lymphoma confined to the liver in a patient with a history of idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia (ICL) is a rare immunodeficiency disorder. We describe a 49-year-old woman with a history of ICL who developed hepatic Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). ICL was diagnosed at a time of her presentation with varicella-zoster virus (VZV) meningoencephalitis and chorioretinitis. Her CD4 count subsequently improved but remained at the lower limits of the normal range. Five years later she presented with cough, fever and night-sweat. She was found to have multiple liver nodules on MRI, fluorodeoxyglucose (FDG) avid on the positron emission tomography (PET) CT, histologically defined as DLBCL, EBV positive and of non-germinal centre type. To our knowledge this is the first reported case of EBV-positive DLBCL localised to the liver in the context of ICL. EBV-positive DLBCL typically occurs in immunocompromised individuals. The corticosteroid therapy she received for VZV meningoencephalitis may have contributed to the EBV reactivation with subsequent EBV-driven malignant transformation of B-cells.

Normal circulating serum amyloid P component concentration in systemic sclerosis.

OBJECTIVE: The observation of reduced circulating concentrations of the constitutive plasma pentraxin protein, serum amyloid P component (SAP), in serum samples obtained from a small number of patients with systemic sclerosis (SSc) has been reported as confirmation of an antifibrotic role of this protein. Because neither sustained SAP depletion in humans nor SAP deficiency in mice is associated with fibrosis, we sought to establish rigorously the serum SAP concentration in well-characterized patients with SSc. METHODS: Serum concentrations of SAP were measured by electroimmunoassay in a cross-sectional cohort of 20 patients with diffuse cutaneous SSc and 12 patients with limited cutaneous SSc, and in a separate 12-month longitudinal cohort of 13 patients with diffuse disease and 37 patients with limited disease. The extent and severity of disease were characterized in detail at the time of serum sampling. Serum concentrations of the classic acute-phase reactants, C-reactive protein and serum amyloid A protein, were measured by immunonephelometric assays. RESULTS: SAP values were entirely within the normal range, regardless of the extent and severity of disease, apart from a very few isolated raised values associated with acute intercurrent complications causing major acute-phase responses. CONCLUSION: We observed no reduced circulating concentrations of SAP in patients with SSc, nor any evidence of an association between SAP levels and the extent or severity of fibrosis.