Upskilling haematological services for WGS and germline assessments through a regional skin biopsy training programme

NHS England Genomics introduced whole genome sequencing (WGS) with standard-of- care (SoC) genetic testing for haemato-oncology patients who meet eligibility criteria, including patients with acute leukaemia across all ages, and exhausted SoC testing. Alongside, the role of germline mutations in haematological cancers is becoming increasingly recognised. DNA samples are required from the malignant cells (somatic sample) via a bone marrow aspirate, and from non-malignant cells (germline sample) for comparator analysis. Skin biopsy is considered the gold-standard tissue to provide a source of fibroblast DNA for germline analysis. Performing skin punch biopsies is not within the traditional skillset for haematology teams and upskilling is necessary to deliver WGS/germline testing safely, independently and sustainably. A teaching programme was designed and piloted by the dermatology and haematology teams in Sheffield and delivered throughout the NHS trusts in North East & Yorkshire Genomic Laboratory Hub. The training programme consisted of a 90-min session, slides, video and practical biopsy on pork belly or synthetic skin, designed to teach up to six students at one time. To disseminate best practice, the standard operating procedure and patient information used routinely in Sheffield were shared, to be adapted for local service delivery. From January 2021 to December 2022, 136 haematology staff from 11 hospitals, including 34 consultants, 41 registrars, 34 nurses and 8 physician associates, across the NEY GLH region completed the skin biopsy training programme. Feedback from the course was outstanding, with consistently high scores in all categories. Practical components of the course were especially valued;98.6% (71/72) trainees scored the practical element of the programme a top score of 5 out of 5, highlighting that despite the challenges of delivering face-to- face teaching due to COVID-19, teaching of practical skills was highly valued;training in this way could not have been replicated virtually. Costs of the programme have been approximately 16 000, including consultant input and teaching/educational materials. Recent support has been provided by a separately funded Genomic Nurse Practitioner (GNP), with succession planning for the GNP to take over leadership from the consultant dermatologist. Plans are in place to use the remaining budget to disseminate the programme nationally. Our training programme has shown that skin biopsy can be formally embedded into training for haematology consultants, trainees, nursing team, and physician associates. Delivery of training can be effective and affordable across regional GLHs with appropriate leadership and inter-speciality coordination, and ultimately sustainable with specialist nursing staff, including GNPs.

Chilblain lupus erythematosus associated with systemic lupus erythematosus: A classic diagnosis in a current epidemiological context

Objectives: Chilblain lupus erythematosus (LE) is a rare chronic cutaneous lupus erythematosus (CCLE) characterized by the appearance of violaceous plaques in acral regions most exposed to cold. The isolated form affects middle-aged women, while the familial form manifests in early childhood and is associated with mutations in the TREX1 gene. Result(s): A 13-year-old adolescent, with no relevant family history, was referred in March 2021 for suspected chilblain-like lesions associated with COVID-19 infection. The patient presented with multiple violaceous papules on hands and feet. The lesions were slightly painful. Small hyperkeratotic papules were also observed on finger pads. Physical examination also revealed some aphthae affecting the lips. No other systemic symptoms were reported. A skin biopsy and blood tests were performed due to presumed chilblain LE with probable systemic involvement. Histology revealed basal vacuolar damage and intense perivascular and periadnexal lymphocytic inflammatory dermal infiltrate. Remarkably, mucin was noted among the collagen bundles. Leukopenia and positive ANA antibodies (titre 1:320) were detected. Complement levels were normal. SARS-CoV2 infection was ruled out. Skin lesions disappeared within 1 month under topical corticosteroids. Hydroxychloroquine was afterwards started by Rheumatology without recurrence of skin symptoms until last follow-up. Discussion(s): We present an uncommon case of an adolescent with systemic LE presenting as chilblain LE. Chilblain LE can be accompanied by other discoid CCLE. It can progress to systemic LE in up to 20% of patients, especially when concomitant CCLE is present. This rare presentation of CCLE should be differentiated from typical chilblain and other resembling lesions, such as SARS-CoV2-associated chilblain and acral purpuric lesions (COVID toes). The Mayo Clinic diagnostic criteria can be helpful, particularly in this last SARS-CoV2 outbreak scenario, when the reporting of similar skin lesions has been significant.

Erythema nodosum following the first dose of AstraZeneca COVID-19 vaccine

Introduction (contexte de la recherche): Erythema nodosum (EN) is a type IV delayed hypersensitivity reaction to a variety of antigens stimuli. In fact, EN is commonly caused by a range of conditions, including infections and vaccines. EN induced by COVID-19 vaccines is rarely reported. Objectif: Herein, we report an original clinical observation of EN occurring after the first dose of AstraZeneca COVID-19 vaccine (vaxzevria), a viral vector vaccine, without recurrence after the second dose. Methodes: This case was notified on August 2021 to Tunisian National Centre of Pharmacovigilance and was analyzed according to the French updated method for the causality assessment of adverse drug reactions. Resultats: A 46-year-old woman with no medical history, presented with diffuse erythematous painful and nodular lesions, located symmetrically over her legs. Eleven days before, she had received the first dose of vaxzevria which was followed by a sudden asthenia, and oedema over her lower limbs. The patient reported no recent infectious episodes. She had no known drug allergy. Skin examination showed multiple, tender, erythematous nodules, which ranged from 3 to 4 cm in diameter located over the tibial area. Some were regressive according to biligenesis shades. Laboratory tests including a complete blood count, renal and hepatic tests and antistreptolysin O titer were carried out and were negative except an elevated c-reactive protein of 45 mg/dL. The dermatological examination found lesions on both legs to be consistent with EN and started therapy with prednisone 40 mg daily for one week, subsequently gradually tapered and suspended, with complete regression of lower limb skin lesions within 10 days. No skin biopsy was performed due to the typical clinical presentation, color evolution and a complete response to steroid therapy. The patient subsequently received the second dose after two months without the reappearance of EN. Conclusion(s): In this case the role of vaccine was suspected in front of a temporal association between the first dose of vaccine and the onset of EN and the absence of another etiology. However, the good evolution of this skin manifestation will help reassure patients in the safety of vaccine administration.Copyright © 2023

Leukocytoclastic vasculitis following immunization with COVID-19 vaccine

Case report Introduction: Vaccines have been recognized as agents associated with development of different forms of vasculitis. We describe the case of a leukocytoclastic vasculitis which developed after immunization with inactivated COVID-19 vaccine. Case presentation: A 68-years old female patient presented with painful purpuric papules and plaques, and areas of necrosis, dominantly localized on her feet (Figure 1), developing 12 days after she received first dose of inactivated COVID-19 vaccine (BBIBP Cor-V). There were no other symptoms except mild fatigue and low-grade temperature of 37.3degreeC. Skin biopsy showed damaged vessel wall with perivascular, neutrophilic inflammatory infiltrate, leucocytoclasia and erythrocytes extravasation (Figure 2). Thorough work-up, including broad immunoserological and virological analysis didn't reveal any other potential trigger. Three months before vaccination the patient recovered from COVID-19 pneumonia. After the four weeks course of prednisone (initially 20 mg/day) with tapering a complete resolution of skin changes was achieved. The patient was followed for one year with no relapses. Conclusion(s): COVID-19 immunization should be considered as a potential trigger for development of cutaneous vasculitis.

Toxic epidermal necrolysis as a result of chlorthalidone and cyclophosphamide combination

Case report Introduction: Toxic epidermal necrolysis (TEN), is an immune-mediated disease characterized by severe mucocutaneous symptoms and is the result of an inflammatory response that leads to keratinocyte necrosis and perivascular lymphocyte infiltration, mostly drug-related. Case report: A 35-year- old male, with a history of recently diagnosed systemic lupus under treatment with prednisone, hydroxychloroquine, mycophenolate and cotrimoxazole forte evolves with persistent proteinuria, it is decided to add losartan, chlorthalidone and atorvastatin. Nevertheless despite immunosuppression, proteinuria and skin involvement persisted, so mycophenolate was suspended and a bolus of cyclophosphamide 1 g was administered. Eight weeks after adjusting treatment, the patient went to the emergency department due to a confluent, pruritic, maculopapular rash with blistering lesions on the trunk, upper limbs, face, and oral mucosa, associated with fever over 38degreeC, that evolved during one week. On admission, the following was confirmed: confluent erythematous macular exanthem associated with multiple flaccid blisters on the chest, upper limbs and neck, Nikolsky's sign (+), keratoconjunctivitis and dryness on the lips. Admission tests included complete blood count with no leukocytosis or eosinophilia, ESR 29 mm/hr, C-RP 19.8 mg/L, no liver profile abnormalities, creatinine 0.8 mg/dl, and urine test with proteinuria 300 mg/dl. Negative infectious study for mycoplasma, herpes 6 virus, cytomegalovirus, Epstein barr virus, hepatitis A, B, C, E and SARS-COV2 virus. Due to severe mucosal skin involvement, TEN/SJS was suspected v/s (TEN)-like Lupus presentation, drugs used prior to admission (chlorthalidone, losartan, atorvastatin) were discontinued, and treatment was started with Hydrocortisone 100 mg every 8 hours IV, Immunoglobulin 2 g/kg daily IV for 4 days, plus skin and mucous membrane care. Patient had a favorable evolution, with resolution of skin and mucosal lesions and no signs of infection. Skin biopsy showed necrotic epidermis, necrotic basal keratinocytes, and sparse lymphocytic inflammatory infiltrate in the papillary dermis, consistent with erythema multiforme/toxic epidermal necrolysis. Conclusion(s): Extensive mucosal involvement is one of the cardinal signs of the presentation of SJS/ETN and given its severity, a high index of suspicion is important with the consequent suspension of suspected drugs and support management for a favorable evolution. In this case the suspected culprit drug was the combination of cyclophosphamide and chlorthalidone, due to reports of increased toxicity of cyclophosphamide in combination with diuretic drugs.

First reported case of parvovirus triggering painful widespread livedoid vasculopathy: another virus causing hypercoagulability?

Livedoid vasculopathy (LV) is a noninflammatory thrombotic disease caused by occlusion of dermal small vessels associated with systemic autoimmune disorders and coagulopathies. However, LV is often reported as being 'idiopathic', despite extensive investigation. We report a case of severe LV in an otherwise healthy 27-year-old woman, associated with parvovirus infection. The patient presented with a short history of a livedoid rash initially covering her torso, which spread to acral sites. Burning pains in the lower limb caused reduced mobility;systemically, she remained well and stable throughout. Examination revealed generalized acral skin pallor, livedoid patches of violet erythema and purpura with deep serpiginous ulcerations over extensor aspects of upper and lower limbs with a more broken/racemosa nonulcerated livedoid appearance on the trunk. On admission a transaminitisareas continued to ulcerate. Codeine was present with a creatine kinase of 1569 U L.1, but other blood test results were unremarkable including erythrocyte sedimentation rate, complement, cryoglobulins, antinuclear antibodies, antineutrophil cytoplasmic antibodies, extractable nuclear antigen, rheumatoid factor, myositis screen, antiphospholipid screen and thrombophilia screen. Parvovirus IgG and IgM were both positive and tested for, as the patient's young daughter had recently been diagnosed with 'slapped cheek disease'. Magnetic resonance imaging of the thighs showed a diffuse mild myositis;electromyography, nerve-conduction studies, barium swallow and computed tomography of the chest, abdomen and pelvis were all normal. An incisional skin biopsy was performed, which revealed a blood vessel with organizing (Solimani F, Mansour Y, Didona D et al. Development of severe pemphigus vulgaris following SARS-CoV-2 vaccination with BNT162b2. J Eur Acad Dermatol Venereol 2021;35: e649- 51) have been reported. The main proposed mechanisms for AstraZeneca vaccine-induced pemphigus could be a hyperimmune reaction in genetically predisposed individuals, with eventual formation of anti-desmoglein antibodies. An alternative hypothesis is that vaccine components could act as foreign antigens resulting in a cross-reaction with pemphigus antigens. The close association of COVID-19 vaccination with the acute onset of pemphigus in our patient, as well as exacerbations after subsequent vaccine administration, is more than coincidental. Considering the recent pandemic with COVID-19 and the widespread administration of the COVID-19 vaccine, continued observation and documentation of true adverse events is essential.

Case report of an antimelanoma differentiationassociated protein 5 antibody-associated amyopathic dermatomyositis

Autoantibodies against melanoma differentiation-associated protein 5 (MDA5) associated with dermatomyositis have recently been described in Asians with rapidly progressive respiratory disease. Here we report the case of a middle-aged white woman with anti-MDA5 antibody-associated amyopathic dermatomyositis with interstitial lung disease (ILD), which is stable with minimal immune suppression. A 55-year-old woman was referred to a virtual dermatology clinic during the COVID-19 pandemic suspected of having widespread eczema involving the chest, face, arm and hands on the background of atopy. On direct questioning, she admitted to having constitutional symptoms, exertional dyspnoea, joint pain and symptoms of proximal muscle weakness. On clinical suspicion of possible connective tissue disorder, she was urgently reviewed in the hospital, where she was found to have a photodistributed rash involving cutaneous ulceration and violaceous plaques. Hand examination showed mechanic's hand mimicking hand eczema, ragged nail cuticles and acute tenosynovitis in the left index finger. Her upper and lower limb muscle power was normal and respiratory examination revealed bi-basal fine end-expiratory crepitation. Her repeated biochemical, haematological and muscle enzymes remained normal. Skin biopsy taken from photosensitive rash over the wrist showed hypergranulosis, Civatte body formation, colloid bodies and dyskeratotic keratinocytes, in keeping with severe lichenoid eruption. Superficial dermis showed patchy red-cell extravasation, perivascular chronic infiltration, dermal oedema and serum on the surface, in keeping with ulceration secondary to severe inflammatory processes. There were no eosinophils and eccrine coils were free of inflammation, raising the suspicion of a drug eruption. Her antinuclear antibody and double-stranded DNA were repeatedly negative. Myositisspecific antibody panel was performed owing to a high clinical suspicion of photosensitive dermatoses, both clinically and histologically. Histology revealed positive anti-MDA5 antibodies;repeated positive testing confirmed this. Although lung function was normal, computed tomography revealed evidence of ILD. We made a diagnosis of anti-MDA5 antibodyassociated amyopathic dermatomyositis with ILD. Her malignancy screening was negative. The patient was started on lowdose prednisolone and hydroxychloroquine 200 mg twice daily, with topical steroid applications, which resulted in remarkable clinical improvement. Anti-MDA5 associated dermatomyositis has characteristic cutaneous lesions consisting of skin ulceration and tender palmar papules, mechanic's hands, inflammatory arthritis and rapidly progressive ILD, which is frequently fatal. Although our patient had ILD, she was relatively stable on minimal immunosuppression. It is important for clinicians to have an increased awareness of this disease as it could have a highly variable clinical presentation in the white population.

Leser-Trelat sign: can it follow COVID-19 infection?

Seborrhoeic keratosis is a benign brownish-black skin lesion that is almost always seen in middle-aged and elderly populations. The sudden onset and rapid increase in size and/ or number of seborrhoeic keratoses is called the Leser-Trelat sign, suggesting a paraneoplastic manifestation of internal malignancy. However, eruptive seborrhoeic keratoses are also described in some nonmalignant conditions such as human papillomavirus infection and HIV infection. Herein, we report a case with Leser-Trelat sign in a patient following COVID-19 infection. A 50-year-old man presented to our dermatology clinic complaining of the sudden appearance of multiple warty-like lesions on his back, which had occurred 2 months after recovery from COVID-19 infection. According to his medical history, the patient presented with cough, fever and dyspnoea about 2 months prior to the appearance of his skin lesions. He was referred to a health centre, where a nasopharyngeal swab was taken, and his polymerase chain reaction test for COVID-19 was positive. In addition, bilateral patchy ground-glass infiltration was reported in his high-resolution computed tomography (HRCT) scan, all in favour of COVID- 19 infection. The patient was then treated with acetaminophen, dexamethasone (intramuscular injection), salmeterol and a fluticasone inhaler, and his symptoms improved. Two months after recovery from his mild COVID-19 infection, several small asymptomatic pigmented verrucous papules appeared on his back. Physical examination revealed multiple rough, oval-shaped, brownish papules of varying size. Dermatoscopy of the lesions was also performed. Both clinical and dermoscopic findings were in favour of seborrhoeic keratosis. In order to reach a final diagnosis, a skin biopsy was performed, and microscopic examination of the biopsy specimen showed hyperkeratosis and well-defined epidermal hyperplasia composed mainly of the proliferation of benignlooking basaloid cells and fewer squamoid cells and horn cysts and increased melanin, mostly at the dermoepidermal junction. The dermis showed no significant change. Based on the above findings, the patient was diagnosed with eruptive seborrhoeic keratosis. To determine the possible cause of this eruption, the patient was further evaluated. In his past medical history, he was generally healthy before his COVID-19 infection and had no history of comorbidities. The patient underwent a workup to rule out any internal malignancies. Laboratory tests revealed normal results and included a complete blood count, liver and kidney function tests, electrolytes, prostate-specific antigen and urine analysis. Gastrointestinal endoscopy and colonoscopy ruled out any gastrointestinal malignancy. Chest X-ray and HRCT revealed no malignant lesion. In addition, the patient's abdominopelvic sonography was normal. The patient had no family history of similar skin lesions and gave no history of any chronic inflammatory skin diseases or viral conditions. Therefore, the appearance of the Leser-Trelat sign after COVID- 19 infection was a possibility in this patient. The role of transforming growth factor-alpha and tumour necrosis-alpha in eruptive seborrhoeic keratoses, as well as in COVID-19 infection, can be a common area of interest to explore in the aetiology of this entity.

Two-week wait skin cancer referrals to a paediatric dermatology clinic: a service evaluation

Skin cancer in children is rare. Data from the USA indicate that paediatric melanoma accounts for approximately 1% of melanomas and up to 5% of all childhood cancers, and its incidence is declining. Paediatric nonmelanoma skin cancer (NMSC) is also rare and often associated with genetic conditions or iatrogenic risk factors such as prolonged immunosuppression. In the UK, suspected cancers are referred from primary care via the '2-week wait' (2WW) pathway. National Institute for Health and Care Excellence guidance (NG12) provides criteria to guide recognition and referral, aimed at improving cancer outcomes through early detection and diagnosis. Melanoma and squamous cell carcinoma are diagnosed in approximately 6% of all 2WW skin cancer referrals;however, the vast majority of these are in adults. We evaluated all urgent paediatric dermatology referrals made via the 2WW skin cancer pathway over a 21- month period (August 2019-May 2021). In total, 172 referrals were made. Fifty-two per cent were female and mean age at time of referral was 10 years (range 2 months-17 years). The mean wait time from referral to clinical review was 9.9 days (range 1-28). Skin biopsy was arranged in 27 (15.6%) patients;nine (33.3%) of these biopsies were completed by paediatric dermatologists and 18 (66.6%) were referred to plastic surgery. There were no confirmed cases of skin cancer. Referrals were deemed inappropriate in 22% of cases. Of these, 15 (41%) were misdirected referrals and the remainder included nonlesional dermatology, including cutaneous infections (24%) and inflammatory conditions (22%). The histological diagnoses are outlined in the Table. As 2WW referrals rise, services must plan efficient and cost-effective pathways for the provision of care. Referral rates for any suspected cancer are disproportionately high in young people, including for melanoma. Signs of a 'changing mole' are less sensitive in a paediatric cohort where melanoma is more likely to present as an amelanotic or nodular lesion. Over a 21-month period, we did not identify a paediatric skin cancer among patients referred on a 2WW pathway. The service burden related to 'stopping the clock' and patient tracking is considerable and has not been formally costed. As we attempt recovery following the COVID-19 pandemic, we plan to introduce greater use of teledermatology triage to address this issue. (Table Presented).

Family History of Alport Syndrome with Spectrum of Chronic Kidney Disease, Dialysis and Transplantation

Introduction: Alport syndrome should be considered in the differential diagnosis of patients with persistent microhematuria. Electron microscopic examination of renal tissue remains the most widely available and applied means for diagnosing AS. The presence of diffuse thickening and multilamellation of the GBM predicts a progressive nephropathy, regardless of family history. Unfortunately, ultrastructural information alone does not establish the mode of transmission in a particular family. Method(s): 18 years-old male patient was followed in the clinic due to persistent microscopic haematuria and proteinuria. Family history is significant for one brother in his early 20s, who started to have the presentation early in life and his initial biopsy showed thin basement membrane disease. The brother subsequently progressed to renal failure and a repeat biopsy confirmed the presence of Alport syndrome. Another brother had end-stage renal disease and underwent renal transplantation. The patient status was revised, and genetic studies confirmed the presence of an autosomal recessive type of Alport syndrome involving collagen for A3 chain COL4A3. His kidney function remained stable initially with an estimated GFR of approximately 90 mL/min/1.73 m2. The most recent eGFR is around 70 ml/min/1.73 m2. His proteinuria disappeared once Losartan 25 mg was added to Ramipril 5 mg. His blood pressure has been on target. Creatinine increased to 147 micromol/L and he was diagnosed as having acute kidney injury on chronic renal disease which was obvious post covid infection, then back to baseline. Current proteinuria 3 g/g Cr on Angiotensin receptor blockers. BP 110/70, all other systemic examination is unremarkable. No hearing or visual abnormalities. Result(s): The initial renal manifestations in early childhood include asymptomatic-persistent microscopic hematuria and rarely gross hematuria. At the onset, the serum creatinine and blood pressure are normal. Over time, proteinuria, hypertension, and progressive renal insufficiency develop. ESRD usually occurs between the ages of 16 and 35 years and rarely can occur between 45 and 60 years. Renal biopsy findings of thinning and multilaminar splitting of the glomerular capillary basement membrane seen on electron microscopic examination are pathognomonic. In 2013, an expert panel issued guidelines recommending genetic testing as the gold standard for the diagnosis of Alport syndrome. Currently, a skin biopsy using commercially available monoclonal antibody against the type IV collagen alpha-5 chain (COL4A5). If the protein is clearly absent in a suspected male, a diagnosis of Alport syndrome can be made without further testing. Conclusion(s): Males with X-linked AS due to a deletion mutation of the alpha 5 chain of type IV collagen usually progress to ESRD by the second or third decade of life. Likewise, patients with autosomal recessive AS due to mutations affecting alpha 3 or 4 chains of type IV collagen tend to progress to ESRD by age 30. Autosomal-dominant AS with heterozygous mutations of COL4A3 or COL4A4 usually has a slower progression of CKD. Treatment is blood pressure control with RAAS inhibitors where clinically appropriate. Cyclosporine may be helpful in some patients with stage I and II CKD with significant proteinuria. Caution using calcineurin inhibitors is indicated in all patients with more advanced CKD stages due to potential nephrotoxicity. No conflict of interestCopyright © 2023

Small Fiber Neuropathy Following COVID-19 Infection

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection has been associated with the development and persistence of various neurological symptoms in some patients. There have been few prior case reports of small fiber neuropathy (SFN) associated with this infection. However, literature is limited, and the etiology of these symptoms is unclear. Some reports suggested neuroinflammation. Objective(s): To present case series of 3 patients who developed small fiber neuropathy after SARS-COV2 infection. Method(s): We identified patients with SFN after SARSCOV2 infection from our neuromuscular database. We performed chart review and obtained clinical, demographic and, outcomes information of these patients. Result(s): The age of patients was 46, 56 and 71 years. Two female and one male. Time to neuropathy symptom evaluation in clinic from positive COVID19 test was 4 months, 6 months, and 10 months, respectively. None of the patients were hospitalized or given additional medications for COVID treatment. Patients 1& 3 had mild respiratory symptoms. Patient 2 had no symptoms, just a routine pre-op test was positive. All patients had numbness, tingling and painful paresthesias as the main symptoms. The second patient reported autonomic symptoms of heart racing and temperature dysregulation. Nerve conduction studies did not show large fiber peripheral neuropathy in any of the patients. Skin biopsy was performed at 7 months, 8 months and 13 months respectively post COVID infection and was positive in all 3 patients. There was no other etiology identified for the neuropathy Treatment included gabapentin for the first patient, the second patient received narcotic medication for a surgery and continued this for her neuropathic symptomsand the third patient is not on any medications for SFN. Conclusion(s): SFN can be associated with prior SARSCOV infection. There is need for further research to determine possible underlying neuropathological mechanisms and find effective treatments in COVID-related SFN.

Paediatric Aps - Children Are Not Just Small Adults

Introduction/Background: Antiphospholipid syndrome (APS) is a rare autoimmune multisystem disease characterised by thrombosis and pregnancy morbidity in the presence of persistently elevated titres of: lupus anticoagulant, anticardiolipin and/or anti-glycoprotein 1. It may be primary (occurring alone) or secondary (in combination with another disease, most commonly systemic lupus erythematosus (SLE)). Recent publications highlighted clinical criteria limitations for children and raised awareness of the burden and prevalence of non-criteria manifestations in this population. This case report adds further weight to the need to raise multi-specialty awareness of non-criteria manifestations to aid recognition and treatment of this rare condition with potentially severe sequelae. Description/Method: 13-year-old female with SLE diagnosed aged 8 in India with bilateral optic neuritis occurring two months later. ANA positive at diagnosis with low complement and thrombocytopenia. Treated with prednisolone and hydroxychloroquine. Patient moved to the UK aged 9;initial abnormal bloods: mildly positive ANA (ENA negative), thrombocytopenia, strong lupus anticoagulant. As serology not strongly suggestive and optic neuritis rare in lupus diagnosis questioned. Ophthalmology review confirmed bilateral optic atrophy without evidence of previous vasculitis. There was debate whether the postretinal demyelination was due to antiphospholipid syndrome or a primary demyelinating condition. Hydroxychloroquine stopped and azathioprine started. Following normal neurology investigations (brain, spine MRI/MRV/MRA) concluded if patient developed new APSrelated symptoms or worsening visual evoked potentials anticoagulation would be discussed. Patient remained stable over four years with chronic thrombocytopenia and ESR persistently elevated. Azathioprine changed to Mycophenolate mofetil (MMF) due to side effects. Routine medication monitoring bloods in 2022 showed ESR 97, CRP 78, Platelets 61. Review identified vasculitic rash on soles of both feet with palpable nodules and normal pulses. Further investigation confirmed antiphospholipid antibody triple positivity. Aspirin commenced, hydroxychloroquine restarted, MMF dose increased and rituximab administered. Left foot rash settled but right progressed with toe discolouration and numbness. Skin biopsy considered but not performed due to skin integrity concerns. Foot pulses remained present and normal. Bilateral lower limb doppler reported as normal;increased symptoms resulted in CT angiogram which revealed bilateral non-occlusive popliteal thrombus and left pulmonary embolus. Subsequent echocardiogram was normal. Patient was anticoagulated with low molecular weight heparin followed by warfarin. Vascular surgical team advocated medical management and patient received seven infusions of Iloprost followed by Sildenafil. She achieved near total resolution of skin changes to toes with only minimal loss of skin over tip of right great toe. Patient will now require long-termanticoagulation. Discussion/Results: APS was considered in initial differential diagnosis but patient did not meet current clinical criteria as no past evidence of thrombosis. Lupus anticoagulant was consistently strongly positive and anticardiolipin repeatedly negative. As anti-B2 glycoprotein 1 antibody is not routinely tested and must be verbally requested, it was only checked once (negative) prior to discovery of triple positivity. ANA reported as strongly positive at time of SLE diagnosis but reviewing original notes from India titre was 1:100 and therefore not highly convincing. ENA negative and complement and white cell count normal on repeat testing since. Therefore, it is probable that this patient has primary APS as opposed to secondary APS in association with SLE. However, it is possible that this patient may develop more symptoms of SLE over time. When this patient presented with foot rash there were high numbers of children presenting with varying severity of painful, itchy toes coined 'covid toes' due to suspected lin to SARS-CoV-2 infection. Patient had exposure history, and COVID antibody serology was difficult to interpret due to recent vaccination. Dermatology found appearance to be consistent with 'covid toes' and advised supportive treatment. The triple APS antibody positivity result provided probable aetiology. Providing evidence of thrombus was problematic with false reassurance from apparently normal lower limb arterial doppler when actually popliteal arteries were not checked in view of the presence of normal flow proximally at the groin and distally in the feet. This case highlights the need to continue to search for thrombus in presence of high titres antiphospholipid antibodies and particularly in the case of triple positivity as although patient presented with colour change to toes, she was entirely asymptomatic from her PE and her left foot improved spontaneously despite a left popliteal thrombus also being present. Key learning points/Conclusion: Non-criteria manifestation of thrombocytopenia (occurs in 25% paediatric APS patients) was present throughout and patient had past history of haematuria (a recognised renal non-criteria manifestation). A paediatric specific APS criteria including these may have resulted in earlier detection of triple antiphospholipid antibody positivity and thus earlier treatment escalation and possible avoidance of thrombus. It has been reported that a high proportion of children with positive antiphospholipid antibodies don't develop a thrombus. However, it is interesting that our patient was entirely asymptomatic from her pulmonary embolus which was an incidental finding on her CT angiogram. This prompts a discussion about how much imaging should be performed in those with high levels of persistent positive antiphospholipid antibodies. Rituximab resulted in normalisation of platelet count and ESR for the first time since initial presentation. Anticardiolipin antibodies normalised, lupus anticoagulant decreased from strong to moderate and anti- B2 glycoprotein levels decreased but remained positive. Rituximab is a recognised treatment for catastrophic antiphospholipid syndrome (CAPS) but not routinely used in APS. The consistently raised ESR in an apparently clinically well patient is a reminder to continue to search for causes of inflammation. As the CRP was largely in normal range, this demonstrates the unique value of the ESR. In view of anti-B2 glycoprotein 1 antibody requiring to be verbally requested, discussions are ongoing with the laboratory department regarding the possibility of electronic request and a comment with recommendation to check other two antiphospholipid antibodies following one positive antibody result. As a result of this case, a plan will be put in place to ensure annual screening of antiphospholipid antibodies in all juvenile SLE patients in our care. It is hoped that this case report promotes discussion amongst the paediatric rheumatology community regarding further research required for development of paediatric specific APS criteria and management.

A case report of IgA vasculitis following CoronaVac vaccination in a Filipino patient

Introduction: Coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV- 2) are emerging. There is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity. Vaccines can trigger immunity as many vaccine-related immunological adverse events have been described. Case Presentation: A case of a 32 years old Filipino female with no known co-morbidity who presented with rashes on bilateral lower extremities one day after receiving her second dose of CoronaVac-Sinovac vaccine. These were non-pruritic nor painful, which appeared to be initially well-defined round erythematous macules, papules, and plaques, mostly raised. It was associated with colicky abdominal pain and inflammatory arthritis affecting the both knees and ankles. She has no vices but known to have allergy with seafood. There were multiple well defined erythematous round to irregularly shaped purpuric macules, papules and plaques, non-blanching, flat and raised, on arms near the antecubital fossa, abdomen and lower extremities. She underwent skin biopsy and direct immunofluorescence showed interface dermatitis with leukocytoclastic vasculitis and IgA +1 vessel wall, and fibrinogen +2 vessel wall, respectively. There was microscopic hematuria and proteinuria. The Urine protein creatinine ratio was normal at 0.193 gm/gm. She was managed as a case of IgA vasculitis and was given moderate dose of steroid (0.5mg per kilogram per day prednisone equivalent) and omeprazole. She was discharged improved with resolution of rashes evident during follow up at the out-patient consultation. Conclusion(s): We report a case of an adult Filipina developing IgA vasculitis following CoronaVac COVID-19 vaccination. She responded well following initiation of steroid therapy. Autoimmune phenomenon following immunization is possible through different mechanisms. These include molecular mimicry, a hyper-stimulated inflammatory state, and autoimmune syndromes induced by adjuvants. While no strategies have been found to prevent autoimmunity following vaccination, it should be emphasized that vaccine recipients should seek medical care for any untoward events following receipt of any immunization.

Catastrophic Antiphospholipid Crisis Triggered by Anticoagulant Switch

Case report - Introduction: The COVID-19 pandemic led to drastic changes for some patients on warfarin for venous thromboembolic (VTE) disease and atrial fibrillation. Warfarin monitoring necessitates frequent interaction with healthcare workers, which is sufficiently risky for COVID-19 transmission. As a result, selected patients were swapped over to novel oral anticoagulants (NOACs). Our patient was changed without investigating for antiphospholipid syndrome (APLS);it later transpired he was triple antibody positive. He presented in a crisis and we describe his narrative. Patients on warfarin due to presumed unprovoked venous thromboembolic disease should not be swapped to NOACs without completing, or checking, previous antiphospholipid antibody testing. Case report - Case description: A 73-year-old gentleman presented locally in August 2020 with erythema over the anterolateral surface of his left leg. He was initially treated with antibiotics for presumed cellulitis. Within a few days this lesion became necrotic and rapidly spread. At this point, he was transferred to a tertiary rheumatology centre. Within days to weeks, he developed several necrotic lesions affecting his trunk and limbs, with facial sparing noted. Approximately 30-35% of his whole-body surface became involved. He soon developed an oxygen requirement, with CTPA demonstrating lymphocytic interstitial pneumonitis without evidence of pulmonary emboli (PE). Throughout his admission, he had several other pathologies such as hyponatraemia that required level 2 care and severe noninfectious diarrhoea. Skin biopsy identified thrombotic vasculopathy. Serology confirmed triple positive antiphospholipid antibody status and a dsDNA titre of>400 iU/mL. This was the first-time serology had been undertaken despite a history of three deep vein thrombosis (DVT) episodes and two PE incidents. He had no history of SLE symptoms. His initial management for vasculitis secondary to APLS at the point of limited necrosis consisted of IV methylprednisolone followed by rituximab and PO prednisolone. While there was some delay in the progression of his disease, new areas of necrosis arose, leading to the patient receiving cyclophosphamide. Low molecular weight heparin was used for anticoagulation. This gentleman later developed proteinuria and neurological symptoms, fulfilling the criteria for catastrophic antiphospholipid syndrome. He received plasma exchange, without an improvement. He developed complications from his disease and treatment, including poor wound healing. It became apparent his condition would not improve and active treatments were stopped. He passed away 6 weeks after initial presentation. Prior to his admission to hospital, his warfarin was swapped to a NOAC. This is thought to have been the trigger behind catastrophic thrombosis. Case report - Discussion: After excluding other conditions such as necrotising fasciitis, this gentleman was rapidly started on IV methylprednisolone to halt any further progression. This is because glucocorticoids have the greatest evidence base for managing this poorly understood acute disease manifestation. After this failed to manage his condition, he was given a further immunosuppressive agent in the form of rituximab. This was used after his serology confirmed triple antibody status. It was hoped this would stop any further immunological mediated disease progression. Oral prednisolone was started at 40mg at this stage and kept under review with a tapering schedule. Cyclophosphamide was given within a few days of rituximab, with hope of a quicker onset of action. A careful MDT decision was made on these drug choices, particularly regarding their combined use and appreciating their side effect profiles. Cyclophosphamide has evidence behind its use, especially for those with APLS associated with lupus. While he did not develop any infections related to treatment, his condition progressed. Case reports suggest that plasma exchange can be useful in the management of catastrophic antiphospholipid syndrome, so the team recommen ed this. Consent at this stage became tricky due to his altered mental status, but it was felt he did demonstrate capacity for this specific decision. As his condition did not improve after this level of immunosuppression, the team reached the decision that no other treatments would likely change the outcome. He remained on oral steroids for the remainder of his admission. The other management facet of APLS crises pertains to anticoagulation. Low molecular weight heparin was recommended by the haematologists. His NOAC was stopped after the diagnosis was confirmed. Warfarin was restarted later in his admission given he had been well on this for years. Case report - Key learning points: This fascinating case exemplifies the importance of completing an antiphospholipid antibody screen for patients who present with unprovoked venous thromboembolic disease. NOACs are commonly used anticoagulant medications. Several case reports have demonstrated that patients with antiphospholipid syndrome experience breakthrough thromboembolic events when treated with NOACs. The highest risk is associated with history of arterial thrombosis and those with triple positive antibody status. Three clinical trials have either been completed or are in the process of investigating whether NOACs sufficiently prevent thromboembolic disease in these patients. The TRAPS study compared rivaroxaban to warfarin in those with triple antibody positive antiphospholipid syndrome. The study was terminated early given that higher adverse events were observed in the rivaroxaban arm (19%, n11/59) versus warfarinised patients (3%, n2/61). The RAPS study found no difference in thromboembolic risk and results from the ASTRO-APS study looking into apixaban are awaited. There is insufficient evidence to suggest that NOACs prevent VTE in a similar fashion to warfarin, so many still advocate the use of warfarin. The optimal immune management of this acute complication is not well elucidated, with a shortfall in mechanistic pathological understanding. The conference will generate discussion on this subject matter in detail. During the COVID-19 pandemic, it has been observed for patients to change anticoagulation from warfarin to NOACs. Given NOACs do not require monitoring, this medication change reduces the number of interactions patients have with healthcare services. We postulate this change triggered the crisis in our patient, where we suggest continuation of warfarin would have been ideal. This is due to the history of several unprovoked thromboembolic events without a prior antiphospholipid screen being completed. Dissemination of learning points from this case are imperative to ensure decision-making encompasses patients who may have undiagnosed antiphospholipid syndrome.

Multiple opportunistic infection in a male with systemic lupus erythematosus and concomitant human immunodeficiency virus infection

Background/Purpose: Concomitant systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection cases are rare worldwide. It is established that SLE patients have an increased risk of opportunistic infection due to immune dysregulation, as well as in HIV. Method(s): A case of a 25-year- old Filipino man with systemic lupus erythematosus admitted due to a 1-week intermittent fever associated with headache, loss of appetite, and generalized body weakness was reviewed in a tertiary hospital in the Philippines. Result(s): An initial diagnosis was made from the clinical presentation of Raynaud's phenomenon, an elevated antinuclear antibody (1:320;nuclear, speckled), 2+ proteinuria, thrombocytopenia, and nail fold capillaroscopy findings consistent with mixed connective tissue disease. Patient was started on hydroxychloroquine and prednisone. He was admitted as a case of Streptococcus bacteremia with COVID-19 pneumonia after initial diagnosis, presenting as fever, and thrombocytopenia as low as 23.000/mul. Patient presented with a scaly erythematous annular lesion at his left wrist since December 2021 where a skin punch biopsy showed findings consistent with dermatophytosis. Direct immunofluorescence staining showed deposition of granular IgM (+3), C3 (+1), Fibrinogen (+3), and C1q (+1) in the basement membrane zone consistent with Lupus Erythematosus. Additional findings were oral thrush, dermatophytosis, and Pneumocystis pneumonia. Patient was started on antibiotics, remdesivir, and antifungal medications. Being severely immunocompromised, work up for HIV was initiated. Rapid HIV screening was positive, CD4 count revealed 7 (3.14%), and subsequent confirmatory western blot was positive. Additional treatment included hydroxychloroquine, methylprednisolone pulse therapy, and platelet concentrate transfusion. He was referred for CD4 monitoring, and ARV treatment enrollment, however, the patient expired a month after his discharge. Conclusion(s): This case is thereby reported to document a rare case of systemic lupus erythematosus (SLE) male patient with concomitant HIV, SARS-CoV- 2, and opportunistic infections secondary to AIDS. Diagnosis becomes challenging in patients with autoimmune diseases and multiple infectious diseases as clinical presentations tend to overlap and may show similar manifestations. In this setting, skin biopsy utilizing direct immunofluorescence can help establish an accurate diagnosis especially when clinical features and histopathology are overlapping.

A case of morphea following the inactivated COVID-19 vaccine

Background: The emergence of the coronavirus disease (COVID-19) prompted pharmaceutical companies to develop effective vaccines to address the problem. While studies prove the vaccines are safe, rare systemic side effects remain possible. All types can cause various vaccine-related adverse reactions which are continuously being monitored. This paper aims to highlight new data on immunologic reactions to COVID-19 vaccines. Morphea demonstrated after COVID-19 vaccination is rare. Herein, we report a case of morphea that was most likely triggered by the immune response against inactivated COVID-19 vaccine. Method(s): A case of morphea was reviewed at the clinic in a tertiary hospital in the Philippines. Result(s): A 48 year old Japanese male had no underlying co-morbidities and no previous COVID-19 infection. He had his first dose of inactivated COVID-19 vaccine, coronaVac (sinovac) with no untoward reactions. After a month, he had his second dose. One week later, the patient started to have a red plaque on his upper back, palpable, tender on palpation and pruritic. Review of systems was unremarkable. The patient denied any insect bites or skin trauma. No medications applied or taken. No known allergies to food, medications or vaccines. He is a 32 pack years smoker. No family history of any autoimmune diseases. In five months, the skin lesion insidiously progressed, thickened and now spreading to the left side of the back. The patient sought consult with a dermatologist and rheumatologist. Physical examination revealed thickened skin and subcutaneous tissue on the upper back with post-inflammatory hyperpigmentation. Work-up showed normal complete blood count, normal chest x-ray, non-reactive Hepatitis B antigen. Antinuclear antibody (ANA) was positive with 1:80 titer and nuclear speckled pattern. Anti-double stranded DNA (anti-dsDNA), anti-smith, antinuclear ribonucleoprotein (anti-RNP), anti-SSA, anti-SSB and anti-Jo- 1 were all negative. The patient's skin biopsy to the reticular dermis showed findings that are consistent with Morphea. The patient was then started on Methotrexate. Conclusion(s): People should be educated about the possible outcomes of COVID-19 vaccines. One of these are immune-related diseases, such as morphea. The underlying mechanism of morphea is multifactorial but one hypothesis highlighted that the spike glycoprotein from vaccination drives these skin reactions. Other studies demonstrated molecular mimicry to viral epitopes. Discussing this cutaneous manifestation secondary to COVID-19 vaccine stressed the importance of this clinical condition, in order to provide a proper diagnosis and therapeutic management. Although there are novel case reports of morphea induced by COVID-19 mRNA vaccine, inactivated COVID-19 vaccine-related morphea has not been reported yet.

Updates on the Diagnosis and Treatment of Peripheral Autonomic Neuropathies.

PURPOSE OF REVIEW: Autonomic neuropathies are a complex group of disorders and result in diverse clinical manifestations that affect the cardiovascular, gastrointestinal, urogenital, and sudomotor systems. We focus this review on the diagnosis and treatment of peripheral autonomic neuropathies. We summarize the diagnostic tools and current treatment options that will help the clinician care for individuals with peripheral autonomic neuropathies. RECENT FINDINGS: Autonomic neuropathies occur often in conjunction with somatic neuropathies but they can also occur in isolation. The autonomic reflex screen is a validated tool to assess sympathetic postganglionic sudomotor, cardiovascular sympathetic noradrenergic, and cardiac parasympathetic (i.e., cardiovagal) function. Initial laboratory evaluation for autonomic neuropathies includes fasting glucose or oral glucose tolerance test, thyroid function tests, kidney function tests, vitamin-B12, serum, and urine protein electrophoresis with immunofixation. Other laboratory tests should be guided by the clinical context. Reduced intraepidermal nerve density on skin biopsy is a finding, not a diagnosis. Skin biopsy can be helpful in selected individuals for the diagnosis of disorders affecting small nerve fibers; however, we strongly discourage the use of skin biopsy without clinical-physiological correlation. Ambulatory blood pressure monitoring may lead to early identification of patients with cardiovascular autonomic neuropathy in the primary care setting. Disease-modifying therapies should be used when available in combination with nonpharmacological management and symptomatic pharmacologic therapies. Autonomic function testing can guide the therapeutic decisions and document improvement with treatment. A systematic approach guided by the autonomic history and standardized autonomic function testing may help clinicians when identifying and/or counseling patients with autonomic neuropathies. Treatment should be individualized and disease-modifying therapies should be used when available.