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01 When and how to escalate therapy in an impending flare
  1. Bevra Hahn
  1. University of California, Los Angeles, USA


Twenty to thirty percent of patients with systemic lupus erythematosus (SLE) patients experience a disease flare each year. Official definitions are available: The most used are based on physician decisions to change treatment; if treatment is added or escalated, that defines flare. Much research has focused on detecting flares before symptoms occur. The most effective and available is a decline in serum complement levels (C3 or C4), which often precedes symptoms; a recent study showed falling complement has a positive predictive value of 0.74 (very good) and a negative predictive value of 0.90 (excellent).1 Other biomarkers include rising titers of anti-dsDNA, falling platelet counts and for nephritis increase in proteinuria and appearance of red blood cells in the urine. Other blood markers, less available but probably better, include increased proportions of activated monocytes and naïve B cells, increases in levels of serum cytokine/chemokines ICAM-1 and IP-10, and increased numbers of RBC, platelets or B cells binding the complement split product, C4d. Several urinary biomarkers are likely to predict flares of nephritis, including MCP, NGAL and TWEAK, but these are not consistent across studies. As soon as symptoms of flare begin, the patient saying s/he is flaring is the best sign and is usually accompanied by changes in the laboratory values associated with that individual, such as falling platelet, WBC or RBC counts, increase in proteinuria, rising erythrocyte sedimentation rate, etc. Prevention of flare is a major goal of therapy and the effective treatments that induce improvement also reduce flare rates, including hydroxychloroquine, glucocorticoids, cyclophosphamide, mycophenolate, azathioprine, belimumab, rituximab, and calcineurin inhibitors.

The physician must also rule out other causes of the ‘flare’ that are NOT SLE. In my experience, fever in an SLE patient is more often a sign of infection than of lupus flare (presence of shaking chills and of very high levels of C-reactive protein are more likely in infection); the urinary tract is the most common source of infection, followed by upper respiratory tract infection and pneumonia, septicemia is also common.2 3 Appropriate cultures should be obtained before escalating immunosuppression. Risk of infection will be lower if the patient has received all appropriate immunisations and is taking preventive medications while immunosuppressed. Similarly, ischemia of heart, brain, gastrointestinal tract can result from clotting with or without vasculitis, and you may consider anticoagulation while evaluating for active SLE. Serositis can result from uremia. When the physician decides SLE is flaring there are several approaches that suppress flare; probably the quickest is to give an intramuscular dose of long-acting glucocorticoid, such as 40–80 mg of triamcinolone acetonide or 20–40 mg of methylprednisolone acetate, which usually suppresses flare and lasts 2–4 weeks. If flare recurs, increase the daily glucocorticoid dose (patients often do this themselves – before consulting the physician). If there is still disease activity and you cannot taper prednisolone/prednisone to less than 10 mg daily, increase immunosuppression, either by increasing dose of immunosuppressive being given (e.g. azathioprine) or adding a new immunosuppressive.4 During this time, consider whether the patient is compliant with the regimen you established prior to flare: Compliance (defined as taking the medication as directed 80% of the time) occurs in only 50–70% of SLE patients: Poor compliance is associated with young patients, those with poor social and economic support systems, less educated, and those with strong beliefs in adverse effects of Western medications and/or utility of other healing approaches.5 I may choose to use intravenous medications in situations such as these. Most SLE patient use complementary supplements: Those that should be discouraged include St John’s wort, which interferes with metabolism of many drugs. Vitamin D levels should be normalised. N-acetylcysteine, polyphenols, omega-3 fatty acids, fish oil and thundervine herb may all have benefits but have not reached general acceptance in the medical community. Since the number of SLE flares is strongly correlated with damage to many body systems, with poor quality of life, and with most of the causes of death of SLE patients, physicians and other caregivers are obligated to identify SLE flares early and suppress them.

Learning objectives

  • Differentiate between infection and flare in patients with SLE

  • Describe key biomarkers associated with SLE flare

  • Explain how best to differentiate infection from SLE flare


  1. Parker B, Bruce I. Clinical markers, metrics, indices and clinical trials. Dubois’ Lupus Erythematosus and Related Syndromes. 9th edition, Wallace D and Hahn B eds: Elsevier, 2019.

  2. Ospina FE, Echeverri A, Zambrano D, et al. Distinguishing infections vs flares in patients with systemic lupus erythematosus. Rheumatology (Oxford, England) 2017;56(suppl_1):i46-i54.

  3. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78(6):736–45.

  4. Lu R, Guthridge JM, Chen H, et al. Immunologic findings precede rapid lupus flare after transient steroid therapy. Scientific reports 2019;9(1):8590–90.

  5. Costedoat-Chalumeau N, Houssiau F, Izmirly P, et al. A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self-Administered Questionnaires. Clinical pharmacology and therapeutics 2018;103(6):1074–82.

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