This week in morning report we discussed a fictional case of a patient with systemic lupus erythematosus (SLE). Our patient had presented with alopecia at the crown of the head and eyebrows, oral ulcers and a photosensitive rash on the face as well as a previous episode of pericarditis. There were no other ulcerations, rashes, or joint pains. I’m going to start this post by reviewing the classification of lupus!

1. Classification of Lupus

Remember that lupus can be classified into any of the following six disease entities, a summary of each is included below:

Systemic Lupus Erythematosus (SLE) is defined in the subsequent section but let’s review the other five subtypes first.

Systemic Lupus Erythematosus (SLE)	See clinical features in the next section
Acute cutaneous lupus erythematosus	Can be localized (malar rash, discoid rash), generalized, or toxic-epidermal necrolysis (TEN)-like
Subacute cutaneous lupus erythematosus	Various forms: papulosquamous, drug-induced, annular, among others Drug-induced SCLE includes HCTZ, diltiazem, ACE-inhibitors, have anti-Ro/SSA Ab(+)
Drug-induced lupus	Isoniazid, procainamide, hydralazine, quinidine, TNF-alpha inhibitors Most commonly present with fever, arthralgias, myalgias, rash and/or serositis Anti-histone antibodies (+)ve Anti-dsDNA typically absent but associated with anti-TNF alpha inhibitors
Neonatal lupus	Passive transfer of autoantibodies from the mother to the fetus results in fetal and neonatal disease Test mom for anti-Ro/SSA, anti-LA/SSB, in utero surveillance for heart block
Chronic cutaneous lupus erythematosus	Includes discoid lupus erythematosus, chilblain LE, lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome), among others

The major manifestations of neonatal lupus are cutaneous and cardiac (structural abnormalities and hear block), abnormal liver function, cytopenias, CNS findings with hydrocephalus. See section #5 below for take-away points on management of lupus in pregnancy. See the figure below for an example of cutaneous manifestations of neonatal lupus:

2. Diagnosis of Systemic Lupus Erythematosus

In the case of our fictional patient, they were diagnosed with SLE as they had an ANA titre of 1:640, and the additive criteria included low complements, positive anti-dsDNA, oral ulcers, non-scarring alopecia, previous pericarditis, leukopenia and thrombocytopenia.

Based on the 2019 EULAR/ACR criteria are listed below. In order to make the diagnosis of lupus, you must have a titre of 1:80 or higher as an entry criterion. This has a 96.1% sensitivity and 93.4% specificity. The additive criteria come after this and you need at least 10 points total to make the diagnosis of SLE. Lupus nephritis class III or IV (proliferative) automatically makes the diagnosis of SLE.

3. Clinical Manifestations of SLE

The clinical features of SLE are reviewed below.

Constitutional Symptoms	– Fatigue – in 80 to 100% of patients – Fever – manifestation of active disease, seen in over 50% of patients with SLE – Myalgia is also common among patients with SLE, whereas severe muscle weakness or myositis is relatively uncommon – Weight changes: weight loss often occurs prior to the diagnosis of SLE, unintentional weight loss can be due to decreased appetite, side effects of medications, GI disease – Weight gain in SLE is related to salt and water retention associated with hypoalbuminemia/nephrotic syndrome – Or increased appetite related to glucocorticoids
MSK	– Arthritis with demonstratable inflammation occurs in 65 to 70% of patients and tends to be migratory, polyarticular, symmetrical – Moderately painful, does not cause erosions and rarely deforming – Occasionally erosive arthritis like RA
Mucocutaneous Involvement	– Facial eruption cutaneous lupus erythema “butterfly rash” malar distribution over the cheeks and nose sparing the nasolabial folds – Appears after sun exposure – Some develop discoid lesions which are more inflammatory and tend to scar – Photosensitivity is a common theme
Vascular	–Raynaud’s phenomenon: Vasoactive process that is induced by cold in up to 50% of patients –Vasculitis –> Small vessel involvement is the most common, cutaneous manifestations including palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, splinter hemorrhages, and superficial ulcerations -Other specific types of vasculitis involvement: mesenteric vasculitis, hepatic vasculitis, pancreatic vasculitis, coronary vasculitis, pulmonary vasculitis, and retinal vasculitis, as well as vasculitis of the peripheral or central nervous system –Thromboembolic disease
Renal	-Clinically apparent in 50% of patients –Lupus nephritis –Class I & II: bland sediment –Class III/IV: proliferative: need IV pulse of prednisone 1 mg/kg + another agent –Class V: nephrotic range proteinuria, ACEi, BP control, HCQ, consider induction with MMF/prednisone
Pulmonary	– Diaphragmatic dysfunction – Pulmonary hypertension – Interstitial lung disease – Lupus pneumonitis (acute rapid onset of fever, cough dyspnea sometimes hemoptysis) – Shrinking lung volumes
Neuropsychiatric	– Cognitive dysfunction, delirium, psychosis, seizures, headache, and/or peripheral neuropathies – Psychosis related to steroids – Thromboembolic events, often in association with antiphospholipid antibodies or with lupus anticoagulant, may occur in a substantial minority (20 percent) of patients with SLE
Cardiac	– Pericarditis, with or without an effusion, is the most common cardiac manifestation of SLE, occurring in approximately 25 percent of patients at some point during their disease course – Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but it can produce valvular insufficiency and can serve as a source of emboli Myocarditis is uncommon but may be severe
GI	-Majority of gastrointestinal symptoms are caused by adverse medication reactions and viral or bacterial infections
Hematologic Abnormalities	– Anemia of chronic disease – Leukopenia – Thrombocytopenia
Ophthalmologic abnormalities	– Keratoconjunctivitis sicca being the most common manifestation as a result of secondary Sjögren’s syndrome – Other less common ophthalmologic manifestations of SLE include optic neuropathy, choroidopathy, episcleritis, scleritis, and anterior uveitis (iritis, iridocyclitis)

We reviewed some cutaneous manifestations and oral lesions that can be seen in lupus erythematosus. See table below for an approach:

4. Treatment of SLE

Moving onto treatment: The treatment of SLE involves non-pharmacologic strategies listed above – don’t forget to test all patients with SLE for anti-phospholipid antibodies! Treatment of non-renal SLE is based on severity as above.

All patients with SLE should be treated with hydroxychloroquine, unless contraindicated such as if there is a known hypersensitivity to the drug or 4-aminoquinoline derivatives, or any component of the formulation. HCQ is usually dosed at 200 to 400 mg orally daily in single or divided doses; should not exceed 5 mg/kg/real BW. In the absence of risk factors for retinal toxicity, ophthalmologic evaluation should be performed at baseline, after 5 years, and yearly thereafter.

For chronic maintenance treatment (aside from flares), glucocorticoids should be minimized to less than 7.5 mg per day (prednisone equivalent) and when possible, withdrawn.

In patients not responding to HCQ (alone or in combination with steroids) or patients unable to received glucocorticoids below doses acceptable for chronic use, one can consider adding immunomodulating agents such as methotrexate, azathioprine, or Mycophenolate.

Cyclophosphamide can be used for severe organ-threatening or life-threatening SLE as ‘rescue’ therapy in patients not responding to other agents. Other considerations are biologics.

5. Lupus in Pregnancy

We ended off our teaching with some take away points of management of lupus in pregnancy.

• Low disease activity prior to pregnancy leads to –> better maternal and fetal outcomes
• Continue HCQ during pregnancy
• Start ASA 81 mg po daily prior to 16 weeks to reduce pre-eclampsia risk
• Positive ANTI-RO or ANTI-LA antibodies in mom
  • No history of neonatal lupus: HCQ + serial fetal echo from week 16-26
  • History of neonatal lupus: HCQ + serial fetal echo weekly from week 16-26
• POSITIVE ANTI-PHOSPHOLIPID:
  • No Anti-phospholipid antibody syndrome = ASA alone
  • Obstetric Anti-phospholipid antibody syndrome *
    • Management: ASA + Prophylactic heparin until 6-12 weeks post-partum
  • Thrombotic anti-phospholipid antibody syndrome **
    • Management: ASA + Therapeutic heparin during pregnancy and post-partum

*Obstetric APS = An unexplained death of normal fetus at >= 10 weeks gestation OR 1 or more premature delivery of normal fetus < 34 weeks gestations because of pre-eclampsia or placental insufficiency OR 3 or more unexplained consecutive miscarriages < 10 weeks gestation
**Thrombotic APS means having >= 1 episode of arterial, venous or small vessel thrombosis.

References:

1. EULAR/ACR Criteria for Lupus – https://www.rheumatology.org/Portals/0/Files/Classification-Criteria-Systemic-Lupus-Erythematosus.pdf
2. BMJ Reference for Treatment of SLE – https://ard.bmj.com/content/78/6/736
3. Oral Ulcers in Systemic Disease – https://www.aafp.org/afp/2010/1201/p1381.html
4. Management of anti-phospholipid ab syndrome in adults – https://ard.bmj.com/content/78/10/1296.long
5. Reference on approach to Oral ulcers – Natarajan E., Goupil M.T. (2019) Soft Tissue Oral Pathology. In: Ferneini E., Goupil M. (eds) Evidence-Based Oral Surgery. Springer, Cham. https://doi.org/10.1007/978-3-319-91361-2_17 Website: https://link.springer.com/chapter/10.1007/978-3-319-91361-2_17
6. Link to alopecia and lupus – Concha JSS, Werth VPAlopecias in lupus erythematosusLupus Science & Medicine 2018;5:e000291. doi: 10.1136/lupus-2018-000291, Reference: https://lupus.bmj.com/content/5/1/e000291.citation-tools