Is it lupus?

Table of Contents

Table of Contents

Published May 2024

Author(s): Carly Conran, MD1; JoAnn Zell, MD2
Section editor: Merideth Morcos, MD3
Executive editor: Brandon Fainstad, MD4

1Fellow, Division of Rheumatology, University of California San Francisco

2Associate Professor, Division of Rheumatology, University of Colorado

3Assistant Professor, Division of Rheumatology, University of Colorado

4Associate Professor, Division of General Internal Medicine, University of Colorado


  1. Describe the two major pathophysiologic mechanisms underlying the clinical and immunologic manifestations of systemic lupus erythematosus (SLE).
  2. Identify the most common clinical pathologies seen in patients with SLE using a systems-based approach.
  3. Identify which signs and symptoms should prompt a workup for SLE and which are less concerning for SLE.
  4. Obtain the appropriate diagnostic work-up for a patient with a clinical presentation concerning for SLE.

Teaching Instructions

Plan to spend at least 30 minutes preparing for this talk by using the Interactive board for Learning/Preparing, clicking through the graphics, and becoming familiar with the order the content appears on the graphic. The teaching script below details how to walk through the talk. Every interactive or “clickable” element is denoted with a mouse icon that should serve as a prompt to ask the audience a question before clicking it.

Anticipated time to deliver the talk without cases: 20 minutes. The cases may take an additional 15 minutes.

The talk is meant to be presented with the interactive board with audience participation throughout.


This talk covers the pathogenesis of lupus, then goes into detail about each of the major clinical manifestations. Importantly, it addresses many clinical common signs and symptoms that often prompt providers to order an ANA but differentiates which should be more vs less concerning for lupus. The talk goes on to discuss the recommended workup for suspected lupus. It then presents 7 mini cases followed by 3 longer cases.

Objective 1. Describe the two major pathophysiologic mechanisms underlying the clinical and immunologic manifestations of SLE

  • What is autoimmunity?
    • Click through the progression from normal immunity to clinical illness, then add genetic and environmental factors
    • This graphic demonstrates the paradigm for the development of clinical illness specifically in lupus. It was based on a large VA study in which 115 of 130 vets with SLE were found to have autoantibodies in their blood up to 9.4 years before the onset of clinical diagnosis (benign autoimmunity) [1]. Even after the detection of autoantibodies and before any symptoms, they found a predictable course of autoantibody accumulation of additional antibodies. For some, these could be present for many years, before causing pathogenic autoimmunity (i.e., “brewing” but not yet manifesting as noticeable signs or symptoms), followed shortly thereafter by clinical disease.  
  • Why is SLE associated with such a wide array of complications?
    • Sunlight -> apoptosis -> macrophage will be presented upfront
      • Explain that this is a schema to represent a major (but one of many) pathways that leads to the wide array of clinical manifestations in lupus
      • Patients with SLE are particularly susceptible to cell death (apoptosis) due to UV light. However, regular cell turnover spills the same nuclear contents as cells die. Antigen presenting cells (like macrophages) then “see” parts of the dead cell’s nucleus and kick off multiple pathways. The problem arises when macrophages pick up self-antigen and kick off “normal” immune pathways against SELF.
      • For the purposes of this talk, we’ll focus on the pathways in SLE that lead to antibody (ANA) production and inflammation.
    • Click one step at a time through the ‘antibody’ pathway
      • An antigen presenting cell (macrophage here) picks up self-antigen and then activates a T-helper cell.
      • The T-helper cell turns around and activates a B-cell (and antibody-producing cell)
      • The B-cell then produced antibodies against the original self-antigen (these are the antinuclear antibodies – ANA!)
      • Once antinuclear antibodies are created, they…
        • Can cause direct cellular destruction
        • Can deposit in tissues and cause surrounding tissue destruction
        • Cause a positive ANA lab test
      • Click one step at a time through the ‘inflammatory’ pathway
        • Antigen can bind to toll-like receptors (TLRs) on macrophages
        • Intracellular cascades are set off by TLR activation
        • These intracellular cascades lead to the production of inflammatory cytokines like IL-1, IL-6 and IFN-a
        • Wherever in the body this occurs, it can result in severe inflammation

Objective 2:  Identify the most common clinical pathologies seen in patients with SLE using a systems-based approach.

  • What are the clinical manifestations of SLE?
    • This slide begins with the body diagram and headers. Ask audience members to list the specific manifestations one system at a time.
      • These clinical criteria came largely from the EULAR/ACR 2019 Classification Criteria for Systemic Lupus Erythematosus [2].
    • If people incorrectly guess clinical s/sx that are listed in the yellow boxes on the next slide, flag them as a talking point for the transition between this slide and the next
    • Of note, for each of these manifestations to be potentially relevant to lupus, they need to be unable to be explained by another, more probable or obvious cause
    • Constitutional:
      • The guidelines specify a temp of 38.3 to qualify as a fever
    • Mucocutaneous:
      • Malar rash
        • Sun-sensitive facial rash that spares the nasolabial fold. It is usually rough and raised (as opposed to rosacea which is typically smooth and flat)
      • Sun-sensitive rashes
        • In addition to malar rash, can have photosensitivity anywhere; often occurs on the fingers and notably spares the knuckles
      • Alopecia
        • Can be diffuse or demarcated. Can be scarring (discoid lupus) or non-scarring.
      • Oral + nasal ulcers
        • Indicate active disease. They can be painful but are often painless. For that reason, it is important to do a thorough exam to look for ulcers.
      • Raynaud’s
        • Fingers and/or toes turn white (then blue) in the cold with a clear demarcating line between the affected and unaffected areas. Can lead to finger ulcerations.
      • Sicca
        • Objective dry eyes (can’t make tears) and dry mouth on exam (look under the tongue for saliva)
    • Gastrointestinal:
      • Autoimmune hepatitis (AIH)
        • Rare, but SLE is thought to potentially be underrecognized in patients with AIH. Affects people of all ages [3].
      • Mesenteric Vasculitis
        • Very rare. Presents as abdominal angina or generalized abdominal pain, abdominal distension and/or pseudo-blockage. Will have elevated inflammatory markers [4].
    • Genitourinary:
      • Recurrent/late miscarriage
        • >1 miscarriage or a miscarriage after 10 weeks gestation
    • Hematologic:
      • Cytopenias [5]
        • Anemia – be on the lookout for hemolytic anemia, as well
        • Leukopenia – WBC <4, especially lymphopenia or neutropenia, always get a diff
        • Thrombocytopenia – if Plt < 20, more likely ITP
      • VTE
        • Arterial or venous; be sure to look back for DVT/PEs that were previously considered “provoked”
        • 30%–40% of patients with SLE are positive for antiphospholipid antibodies and they are associated with increased risk of vascular events and death in SLE [6].
        • If patient has a valid reason for a provoked VTE, wouldn’t typically send a hypercoagulability workup. If they have had multiple clots, could send antiphospholipid antibodies with or without an ANA depending on whether they have any other s/sx SLE.
    • Neuropsychiatric
      • Psychosis
        • Unusual initial presentation of SLE; think about other primary psych diagnoses and/or drug use first. In a large, Retrospective cohort study of 709 SLE patients, only 2.5% had psychosis over a mean follow up of 11 years [7].
      • Seizures
        • More common in young females. Can occur any time after diagnosis, but most commonly early in disease course. Also associated with more active disease [8].
    • Serosal
      • Pleural effusion [9]
        • Extremely common, will affect 40-60% of patients with lupus. Often asymptomatic.
      • Pericardial effusion
        • Also extremely common (>40%), and often asymptomatic, but can be complicated by tamponade [10].
      • Acute pericarditis
        • Very common (seen on >50% of echocardiograms in SLE patients). Often asymptomatic [11].
      • All in this category are typically benign, and are atypical as an initial presenting symptom of SLE. In a patient with known SLE, these may be indicators of active lupus and may lead to a change in SLE meds.
    • Pulmonary [9]
      • Interstitial lung disease
        • Much more common in systemic sclerosis and should prompt looking for an overlap syndrome
      • Pulmonary artery HTN (PAH)
        • Relatively uncommon in lupus (<10%) and should also prompt a workup for systemic sclerosis. Also need to rule out other possible causes of PAH.
    • Renal
      • Proteinuria
        • If >0.5g of protein in a patient without other clear cause of renal disease, could check an ANA with or without a renal biopsy
      • Hematuria
        • Unexplained hematuria (no stone, negative urine cx) should go for cystoscopy first in the right patient population (older patients, those with a smoking history), though should consider ANA in younger and otherwise healthy patients
      • Patients with lupus nephritis often have a normal creatinine, but a rising creatinine should prompt an even more urgent workup and referral
      • Up to 50% of patients with lupus will have lupus nephritis at some point in their disease course [12].
    • Musculoskeletal
      • Synovitis
        • 50% of lupus patients may have joint problems as the first sign of their disease [13].
        • Red, hot, (objectively) swollen joints
        • Most commonly affects the hands (especially MCP, PIPs) but also commonly affects the wrists, knees, elbows, toes
      • Myositis
        • Commonly presents as quadriceps weakness. Dx with CK and EMG [14].

Objective 3. Identify which signs and symptoms should prompt a workup for SLE and which symptoms are less concerning for SLE

  • What clinical signs/symptoms are less concerning for lupus?
    • Constitutional:
      • Fatigue/Weight changes – common complaints with a wide differential. Certainly common in lupus, but without additional/more-specific SLE clinical manifestations, should not prompt sending an ANA.
    • Mucocutaneous:
      • Hair loss in shower – when asking patients about “hair loss,” many will say “yes.” Important to clarify that this is more than a normal amount lost while bathing.
    • Gastrointestinal:
      • Abdominal pain: More consistent with IBS
      • Chronic diarrhea: More consistent with IBS
      • Hematochezia: More consistent with IBD
    • Genitourinary:
      • Only 1 miscarriage or miscarriage before 10 weeks are less c/f APLAS
    • Hematologic:
      • If anemia, first check iron studies. If any e/o iron deficiency and no other cytopenias, replete iron before thinking about an ANA
    • Neuropsychiatric
      • Anxiety, Depression, Brain fog – these can all be seen in patients with established lupus (“Type B” symptoms of lupus). However, they would not be the only clinical symptoms seen in lupus. These are very common in
    • Serosal
      • Atypical chest pain – once an appropriate cardiac workup has been done (if indicated), this is a common complaint in patients with fibromyalgia.
    • Pulmonary
      • Dyspnea – chronic dyspnea without hypoxia is also a common complaint that is difficult to treat when an underlying cause is not apparent. In the absence of a pericardial or pleural effusion or pericarditis, would not expect lupus to cause this.
    • Renal
      • Pyuria – more likely related to an infection in the urinary tract or an STI. Would anticipate hematuria and/or pyuria if suspecting lupus nephritis.
    • Musculoskeletal
      • Generalized aches/Chronic myofascial pain/chronic muscle pain/ joint pain without swelling– diffuse pain is a major reason for which ANAs are often inappropriately sent. When there is no objective evidence of inflammation (a red, hot, swollen joint and/or elevated inflammatory markers), differential is more likely fibromyalgia vs thyroid disease vs OA vs another autoimmune disease like spondyloarthritis.

Objective 4:  Obtain the appropriate diagnostic work-up for a patient with a clinical presentation concerning for SLE.

  • What testing should be done to evaluate for suspected SLE?
    • Headers and visual clues will already be presented on the slide; ask participants what tests should be ordered and what abnormal results they’d be looking for
    • CBC with differential: any cytopenia; within leukopenia, neutropenia and lymphopenia are especially common in lupus
    • CMP: elevated Cr – c/f lupus nephritis; transaminitis – c/f AI hepatitis; hyperbilirubinemia – c/f hepatits and possibly hemolysis
    • Complement proteins: low C3 and low C4 would be expected
    • Inflammatory markers: ESR is often elevated out of proportion to CRP, and CRP is often normal. If the CRP is extremely high, consider RA (or RA overlap) and/or infection
    • Autoantibodies:
      • ANA – needs to be positive to diagnose lupus
      • Anti-dsDNA Ab – specific to SLE + titer fluctuates with disease activity
      • Anti-Smith Ab – specific to SLE, associated with lupus nephritis
      • Anti-RNP Ab – mixed connective tissue disease + Raynaud’s
      • Anti-SSA/B Abs – Sjogren’s and neonatal lupus
    • Antiphospholipid antibodies:
      • Anti-cardiolipin / Anti-β2 glycoprotein / Lupus anticoagulant – Antiphospholipid antibody syndrome is extremely common in lupus.
      • Do not need to have had a clot to diagnose this
      • Dx requires high titer lupus anticoagulant or moderate-high titers of IgG or IgM anticardiolipin or anti-beta-2-glycoprotein Abs
    • UA: looking for signs of lupus nephritis – hematuria + proteinuria
  • If abnormal results in the context of other unexplained SLE-specific clinical manifestations, refer to Rheumatology

Get an ANA?' cases

  • These are to test learner’s takeaways from this talk and to answer the question “Should an ANA be ordered with the initial workup?” based on information from this session.
  • Consider asking the audience to raise a hand for ‘yes’ or ‘no’ votes
  1. A 37yo F presents to the ED with chest pain. She has been recovering from COVID-19 for the past week. Her VS are normal aside from HR 110. Her troponins peaked at 206. Her EKG ST-segment elevation in all leads. She is diagnosed with pericarditis and started on colchicine and NSAIDs.
    • NO – most likely a viral pericarditis; her sx can be more likely explained by another cause
  2. The patient’s chest pain resolves over the next week and she has no residual symptoms. One year later, she develops chest pain again, and presents to her PCP. Again, she has EKG changes consistent with recurrent pericarditis. On a basic lab workup, her labs are notable for a normal WBC but with a low ANC.
    • YES – now she has more unexplained symptoms, in addition to more hematologic findings that could be concerning for lupus.
  3. A 32yo F with a h/o GAD, MDD and IBS presents to her PCP with a constellation of symptoms that have progressed over the past year, including: fatigue, diffuse bilateral leg pain, neck pain, headaches, weight loss and diffuse body stiffness.
    • NO – this is more likely fibromyalgia or a similar condition like chronic fatigue syndrome
  4. A 50yo F with alcohol use disorder presents to the ED with fatigue and severe abdominal pain. She is found to have pancytopenia with a WBC 2.7, Hgb 9.7, Plt 56. Her AST/ALT are 360/180 and her T Bili is 4.1. EtOH level is 124 (H) and UTox is negative. One day after admission, she develops visual hallucinations.
    • NO – her findings can all be explained by heavy alcohol use and alcoholic hepatitis; then, she likely develops delirium tremens
  5. A 27yo M soccer player presents to his PCP for joint pain. He has noted pain and weakness in his legs over the past week, making it difficult for him to train. On exam, his VS are wnl, his thighs are tender to palpation, and you note a raised rash on his face and arms. His CK is elevated at 12,000. An MRI of thighs demonstrates muscle edema.
    • YES – Unexplained weakness and an elevated CK are concerning for myositis, confirmed by the MRI. In addition to being worked up for dermatomyositis/polymyositis, he should get an ANA.
  6. A 19yo F college student presents to her PCP for fatigue. She is on a pre-med track and has become unable to attend class due to extreme exhaustion. She was told she has mono by the student health clinic after she was found to have a T 101. Now that she has been laying in bed for weeks, her arms and legs are starting to feel sore. On exam, she is afebrile, has normal-appearing skin over her extremities, has a normal gait and normal ROM of her knees and elbows, but is noted to have tender and swollen wrists.
    • YES – fevers and swollen joints should prompt a workup for lupus in a previously healthy, young patient.
  7. A 32yo M with PMH of stimulant use disorder is brought to the ED by EMS after being found down. He is febrile. On exam, he has an erythematous, swollen L elbow. Labs are notable for a Cr 2.3 and WBC 1.7. On a trauma scan, he is found to have splenic infarct.
    • NO – this patient is likely septic from endocarditis


  1. This is the case of a 27yo F presenting with new lupus. This is meant to help think through what a new diagnosis of lupus might look like in a primary care clinic – from symptom evaluation to initial testing and counseling.
  2. This is the case of a 40yo F with known lupus and lupus nephritis who is coming in septic. This case stresses the importance of broadening the differential from “lupus flare” to remind learners to think about many associated complications – especially infection. This patient most likely has a new pneumonia and should be worked up/treated as such (in addition to managing underlying lupus).
  3. This is the case of a 35yo F with diffuse pain and other rather non-specific symptoms like fatigue. Her pain sounds more myofascial and her rash sounds like eczema. She has a low-positive ANA. While these were all ‘yellow box’ symptoms from above, and testing ANA should likely be avoided in these patients, many patients will have already had the ANA ordered. In this case, with a lack of any other clinical evidence of lupus, they can be reassured that a low-positive ANA is very common in the general population (31.7% of individuals at 1:40 serum dilution, 13.3% at 1:80, 5.0% at 1:160) [15]. Conversely, many patients with established lupus also have fibromyalgia [16, 17].


Presentation Board

Take Home Points

  1. SLE causes a wide array of clinical complications, but they are likely all driven by pathologies within a few immune pathways
  2. When a diagnosis of SLE is suspected, use a standard biological systems-based approach to look for SLE-specific clinical manifestations to assess the likelihood of SLE before ordering an ANA
  3. If clinical suspicion for SLE is high enough to order an ANA, consider adding a broader metabolic and immunologic workup to screen for more of the major manifestations of SLE. 


  1. Arbuckle, M.R., et al., Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med, 2003. 349(16): p. 1526-33.
  2. Aringer, M., et al., 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol, 2019. 71(9): p. 1400-1412.
  3. Aranow, C., B. Diamond, and M. Mackay, 52 – Systemic Lupus Erythematosus, in Clinical Immunology (Sixth Edition), R.R. Rich, et al., Editors. 2023, Elsevier: New Delhi. p. 657-677.
  4. Xie, J.J., et al., Lupus with initial mesenteric vasculitis. Rheumatol Immunol Res, 2023. 4(2): p. 102-103.
  5. Fayyaz, A., et al., Haematological manifestations of lupus. Lupus Sci Med, 2015. 2(1): p. e000078.
  6. Unlu, O., S. Zuily, and D. Erkan, The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus. Eur J Rheumatol, 2016. 3(2): p. 75-84.
  7. Abrol, E., et al., Psychosis in systemic lupus erythematosus (SLE): 40-year experience of a specialist centre. Rheumatology, 2021. 60(12): p. 5620-5629.
  8. Rodriguez-Hernandez, A., et al., Seizures in systemic lupus erythematosus: A scoping review. Seizure, 2021. 86: p. 161-167.
  9. Shin, J.I., et al., Systemic Lupus Erythematosus and Lung Involvement: A Comprehensive Review. J Clin Med, 2022. 11(22).
  10. Rosenbaum, E., et al., The spectrum of clinical manifestations, outcome and treatment of pericardial tamponade in patients with systemic lupus erythematosus: a retrospective study and literature review. Lupus, 2009. 18(7): p. 608-12.
  11. Dein, E., et al., Pericarditis in Lupus. Cureus, 2019. 11(3): p. e4166.
  12. Almaani, S., A. Meara, and B.H. Rovin, Update on Lupus Nephritis. Clinical Journal of the American Society of Nephrology, 2017. 12(5).
  13. Sicakyüz, S.E., D. Lupus and Joint Involvement – Top 10 Series. 2023; Available from:
  14. Tiniakou, E., et al., Clinical and histopathological features of myositis in systemic lupus erythematosus. Lupus Sci Med, 2022. 9(1).
  15. Tan, E.M., et al., Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum, 1997. 40(9): p. 1601-11.
  16. Blumenthal, D.E., Tired, aching, ANA-positive: does your patient have lupus or fibromyalgia? Cleve Clin J Med, 2002. 69(2): p. 143-6, 151-2.
  17. Wolfe, F., et al., Fibromyalgia, systemic lupus erythematosus (SLE), and evaluation of SLE activity. J Rheumatol, 2009. 36(1): p. 82-8.
Brandon Fainstad


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