Rash and Blue Toes

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Submission ID :
ESPR222
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Abstract: :

History (including the chief complaint, history of present illness, and relevant past medical and family history). 

A 7-year-old previously healthy female presents to the Emergency Department (ED) with one month history of non blanching lower extremity rash, joint pain, and three days of painful blue discoloration of her toes. One month prior, patient began to have intermittent low-grade fevers, joint pain and "bug bites" on her bilateral lower extremities. Upon presentation, she had a darker lace-like rash with ulcerations. Her initial workup revealed elevated ANA titers (1:160 speckled), elevated inflammatory markers (ESR 63, CRP 9), elevated anticardiolipin (IgG 36.7, IgM 36.4), and hypocomplementemia (C3 47, C4 <5). The patient's exam was notably concerning for acutely worsening rash with ulcerations and scabbing, and bluish discoloration of several of her toes. She also had difficulty ambulating secondary to severe bilateral foot pain and so was sent to the ED for further evaluation.


Physical Examination: Vital signs, pertinent physical examination findings.

On initial examination, she is afebrile, tachycardic to 133, tachypneic to 24, nontoxic, but in moderate distress secondary to pain. Multiple small anterior cervical lymph nodes were palpable bilaterally. Abdominal exam is notable for mild splenomegaly, nontender to palpation. Skin exam is notable for lacy reticular rash to upper and lower extremities with multiple areas of overlying ulcerative lesions most prominently to the left lateral thigh; most notably, large scab-like lesions with capillary bleeding and skin necrosis. Foot exam is concerning for bilateral blue discoloration of halluces, left foot worse than right, with bluing of tips of second and third toes. Feet are cool to touch, dorsalis pedis pulses palpable. The ulcerative lesions are non-tender, but with notable significant tenderness to bilateral feet.


Laboratory testing and/or diagnostic imaging

ED evaluation reveals benign comprehensive metabolic panel, anemia (Hb 9.7, Hct 30.5), elevated inflammatory markers (CRP 12, ESR 80, ferritin 177), elevated D-dimer (2.04), hypocomplementemia (C3 52, C4 <5), prolonged coagulation studies (PTT 55.2, PT 12.4, INR 1.17), and negative COVID PCR and IgG.

Additional laboratory workup performed after admission was notable for elevated dsDNA antibody (76), elevated anticardiolipin antibody (IgG 36.7, IgM 36.4), elevated lupus anticoagulant (SCT screen/confirm 1.67, dRVVT screen/confirm 1.91), elevated ß2 glycoprotein I antibody (IgA 22.5, IgG 55.3, IgM 85.4), and positive direct Coombs. Patient workup negative for anti Smith Ab (8.24), anti RNP (4.46) and SSA/SSB (SS-A Ab 2.57, SS-B Ab 4.52). Lower extremity arterial ultrasound with doppler was within normal limits. Echocardiogram showed right coronary artery dilation in the setting of elevated inflammatory markers without evidence of intracardiac thrombus. 


Final Diagnosis

Her presentation and lab findings are consistent with childhood onset systemic lupus erythematosus with antiphospholipid syndrome and rapid onset necrotizing livedoid vasculopathy.


Discussion

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a heterogeneous group of clinical manifestations and multisystem involvement. Childhood onset SLE is relatively rare but more severe than adult onset, accounting for approximately 10-20% of all patients with SLE. Typical age of disease onset is between ages 12 to 16. Onset prior to age 10 is uncommon.1 Cutaneous manifestations are a common presenting feature of SLE. Skin involvement is found in approximately 72-85% of patients, presenting as the first noticeable sign in 25%.2 Patients with both SLE and antiphospholipid syndrome (APS) may be at greater risk of developing livedo reticularis.5

Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE classification includes fulfillment of at least four criteria with at least one clinical criterion and one immunologic criterion or lupus nephritis as the sole clinical criterion with presence of ANA or anti-dsDNA antibodies. Clinical criteria include: acute cutaneous lupus (most commonly noted as malar rash), chronic cutaneous lupus, oral ulcers, nonscarring alopecia, synovitis involving two or more joints, serositis, renal or neurologic involvement, hemolytic anemia, leukopenia, and thrombocytopenia. Immunological criteria include: ANA above laboratory reference range, anti-dsDNA above laboratory reference range, anti-Smith antibody, antiphospholipid antibody, low complement, and direct Coombs test in absence of hemolytic anemia.4

In pediatric SLE patients, persistent presence of antiphospholipid antibodies have been shown to increase the risk of thromboembolic events. Reported rates of thromboembolic events in pediatric SLE patients range from 9-17% and if lupus anticoagulants are present, the probability increases to 38-42%. Due to the high likelihood of thromboembolic events, consideration for lifelong anticoagulation is essential after an initial event to decrease morbidity.Other factors associated with thrombosis in pediatric SLE include vasculitis and avascular necrosis.7

APS is defined as a multisystem autoimmune disorder characterized by increased risk of thromboembolic events including arterial, venous or small vessel and pregnancy morbidity and presence of persistent antiphospholipid antibodies. APS occurs as a primary disorder in approximately 50% of patients while the rest of cases are considered to be secondary, occurring with a concurrent underlying multisystem autoimmune disease, including SLE.Testing for antiphospholipid antibodies include measurements with the anticardiolipin antibody enzyme linked immunosorbent assay (ELISA), lupus anticoagulant test, or  ß2 glycoprotein I antibody ELISA. The pathophysiology of APS is still under investigation.

The most common presenting symptom of pediatric APS is venous thrombosis, particularly lower limb deep venous thrombosis, which occurred in approximately 60% of children. Other venous thrombotic events included cerebral venous sinus thrombosis, portal vein thrombosis, upper extremity deep venous thrombosis, superficial vein thrombosis and left atrial thrombus. Arterial thrombotic events included ischemic stroke, occurring in 79% of arterial events, peripheral artery thrombosis, retinal artery thrombosis, myocardial infarction, renal artery thrombosis and splenic infarction. Small vessel thrombosis which manifests as digital ischemia or renal thrombotic microangiopathy affected about 6% of children.9

Our patient met SLICC criteria due to fulfillment of clinical criterion of acute cutaneous lupus and synovitis and immunological criteria of elevated ANA titers, elevated anti dsDNA, presence of antiphospholipid antibody, hypocomplementemia and positive direct Coombs test without evidence of hemolytic anemia. However, her case was unique in that the majority of pediatric SLE cases present with renal involvement, whereas our patient presented with digital ischemia: an extremely rare presenting symptom for pediatric SLE. The digital ischemia could have been attributed to SLE, presence of antiphospholipid antibodies or the possibility of emboli and vascular phenomena. Antiphospholipid antibodies are present in approximately 40% of patients with childhood SLE and in general, it is associated with hypercoagulability in vivo. However, fewer than 50% of these patients manifest thrombotic or thromboembolic phenomena.3  In vitro, anticardiolipin antibodies have been shown to prolong kaolin clotting time or other measures of the intrinsic coagulation pathway and this effect is irreversible with the addition of plasma.14

Our patient demonstrated the presence of multiple antiphospholipid antibodies including ß2 glycoprotein I antibodies, lupus anticoagulant, anticardiolipin antibodies and therefore had increased risk of thromboembolism. Our case highlights the need to recognize the rarer presentations of childhood SLE and APS as these have the potential to cause significant morbidity. 


References

  1. Malattia C, Martini A. Paediatric-onset systemic lupus erythematosus. Best Practice and Research Clinical Rheumatology 2013; 27: 351-362.
  2. Chottawornsak N, Rodsaward P, Suwannachote S, et al. Skin signs in juvenile and adult-onset systemic lupus erythematosus: clues to different system involvement. Lupus 2018; 27: 2069-2075.
  3. Levy D, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am. April 2012; 59(2): 345-364.
  4. Yu C, Gershwin ME, Chang C, Diagnostic criteria for systemic lupus erythematosus: a critical review, J Autoimmun, 2014, 48-49
  5. Walling H, Sontheimer R. Cutaneous lupus erythematosus. Am J Clin Dermatol 2009; 10 (6): 365-381.
  6. Levy DM, Massicotte MP, Harvey E, et al. Thromboembolism in paediatric lupus patients. Lupus 2003; 12: 741-746.
  7. Driest KD, Sturm MS, O'Brien SH, et al. Factors associated with thrombosis in pediatric patients with systemic lupus erythematosus. Lupus 2016; 25: 749-753.
  8. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. June 2015; 74(6): 1011-8. Epub 2014 Jan 24.
  9. Madison J, Zuo Y, Knight J. Pediatric antiphospholipid syndrome. Eur J Rheumatol 2020; 7 (Supp 1): S3-S12.
  10. Aguiar C, Soybilgic A, Avcin T, et al. Pediatric antiphospholipid syndrome. Curr Rheumatol Rep 2015; 17:27
  11. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. doi:10.1111/j.1538-7836.2006.01753.x
  12. Kuemmerle-Deschner JB, Hansmann S, Wulffraat NM, et al. Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative. Ann Rheum Dis. 2018;77(3):319-327. doi:10.1136/annrheumdis-2017-211904
  13. Shen CC, Chung HT, Huang YL, Yeh KW, Huang JL. Coronary artery dilation among patients with paediatric-onset systemic lupus erythematosus. Scand J Rheumatol. 2012;41(6):458-465. doi:10.3109/03009742.2012.694470
  14. Mackworth-Young CG. Antiphospholipid syndrome: multiple mechanisms. Clin Exp Immunol. 2004;136(3):393-401. doi:10.1111/j.1365-2249.2004.02497.


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Associated Sessions

Maria Fareri Children's Hospital/Westchester Medical Center
Westchester Medical Center/Maria Fareri Children's Hospital
Westchester Medical Center/Maria Fareri Children's Hospital
Westchester Medical Center/Maria Fareri Children's Hospital

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