Systemic Lupus Erythematosus — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Ms L is a 29-year-old woman with a 3-year history of systemic lupus erythematosus — confirmed by the 2019 EULAR/ACR criteria with positive ANA, anti-dsDNA and anti-Smith antibodies, low C3 and C4, and a class III or IV renal biopsy — who now presents with a renal flare: new peripheral oedema, hypertension at 152 over 96, a urine protein-to-creatinine ratio of 220 milligrams per millimole with dysmorphic red cells and red cell casts, and a creatinine that has risen from 68 to 124 micromoles per litre over 2 weeks. Her anti-dsDNA has risen from 28 to 210 and her complement has fallen, confirming serological disease activity. Her renal biopsy shows ISN/RPS class IV (A over C) diffuse proliferative lupus nephritis with crescents in 25 per cent of glomeruli, an activity index of 12 out of 24 and a chronicity index of 2 out of 12. She is currently on hydroxychloroquine 400 milligrams daily and no other immunosuppression. Critically, she wishes to have children in the future. [1]

Her main problems are: (1) active proliferative class IV lupus nephritis requiring urgent induction immunosuppression to prevent irreversible scarring and progression to end-stage kidney disease; (2) significant hypertension contributing to renal damage; (3) the need to select an induction regimen that preserves her future fertility; (4) her anti-Ro status, with implications for future neonatal lupus and congenital heart block; and (5) the psychosocial impact of a chronic relapsing disease in a young woman. My priorities are to establish induction therapy within days, control her blood pressure with RAAS blockade, continue hydroxychloroquine, plan a steroid-sparing maintenance strategy, and counsel her on pregnancy planning." [1]

Examiner probing questions and model answers

Q1: "Walk me through your rationale for choosing mycophenolate mofetil over cyclophosphamide for this patient's induction." [1]

"My decision rests on three considerations. First, the evidence of efficacy. The ALMS trial (Appel et al, 2009) was the pivotal randomised comparison of mycophenolate mofetil against high-dose intravenous cyclophosphamide for induction of proliferative lupus nephritis [3]. It did not meet its primary endpoint of superiority, but established that mycophenolate is non-inferior, with response rates of 56.2 per cent versus 53.0 per cent. The Euro-Lupus Nephritis Trial (Houssiau et al, 2002) had earlier shown that a low-dose cyclophosphamide regimen — 500 milligrams intravenously every 2 weeks for 6 doses, cumulative 3 grams — was as effective as the high-dose NIH regimen with fewer severe infections [4]. So both mycophenolate and low-dose cyclophosphamide are evidence-based first-line options per the 2019 EULAR/ERA-EDTA recommendations [7].

Second, toxicity and fertility. Cyclophosphamide is gonadotoxic and in a 29-year-old woman who wishes to conceive, this is a major concern — it risks premature ovarian failure. Mycophenolate is not gonadotoxic. While it is teratogenic and must be stopped before pregnancy, it does not impair fertility. This patient's future fertility is a priority, which favours mycophenolate. [1]

Third, the disease characteristics. My patient has crescents in 25 per cent of glomeruli, which is significant but not the rapidly progressive crescentic pattern (over 50 per cent) where I might lean towards cyclophosphamide. She is not of African or Hispanic ancestry (where a subgroup signal in ALMS favoured mycophenolate, but where severe disease often pushes towards cyclophosphamide). Given these factors, mycophenolate is my preferred first-line agent, with the option to escalate to the Euro-Lupus cyclophosphamide regimen if she does not respond by 3 to 6 months. I would also consider adding voclosporin to the mycophenolate — the AURORA trial showed this combination increased complete renal response at 52 weeks to 41 per cent versus 23 per cent [6], with an early separation by 4 weeks, which is attractive given her active crescentic disease."

Q2: "Why is hydroxychloroquine the foundation of SLE management, and would you ever stop it?" [1]

"Hydroxychloroquine is the cornerstone of SLE therapy because its benefits span every domain of the disease. It reduces disease activity and flare frequency, reduces corticosteroid requirements, reduces thrombosis risk, improves pregnancy outcomes including a higher live birth rate, reduces the risk of congenital heart block in an anti-Ro positive mother, reduces renal recurrence, and most importantly improves survival. The LUMINA cohort study (Alarcon et al, 2007) showed that hydroxychloroquine use was independently associated with improved survival in SLE, with an odds ratio for death of 0.32 after adjusting for propensity [2]. It is dosed at 5 milligrams per kilogram per day — about 200 to 400 milligrams daily for most adults.

I would essentially never stop hydroxychloroquine in a patient with SLE unless there is a clear contraindication. The principal toxicity is retinopathy, which is dose- and duration-dependent and rare — the risk becomes meaningful after 5 to 10 years of therapy. The approach is surveillance, not pre-emptive cessation: baseline ophthalmological assessment including spectral-domain OCT, and annual screening from 5 years of therapy. The very small risk of retinopathy is overwhelmingly outweighed by the survival, flare-reduction, renal-protective and pregnancy-protective benefits. The only situations I would consider stopping are confirmed retinopathy on screening, or a severe allergic reaction." [1]

Q3: "How would your induction strategy change if she were to become pregnant in the next 12 months?" [1]

"This is a critical question because several of the standard lupus nephritis drugs are teratogenic. My approach would be to defer conception until at least 6 months of renal quiescence — inactive urinary sediment, stable creatinine, and proteinuria controlled. Premature pregnancy in active nephritis dramatically increases the risk of flare, pre-eclampsia, fetal loss and progression to end-stage kidney disease. [1]

For the medications: I would stop mycophenolate mofetil at least 3 months before conception and switch to azathioprine (2 milligrams per kilogram per day), which is safe in pregnancy and lactation. Cyclophosphamide is both gonadotoxic and teratogenic, so it would be avoided entirely if pregnancy is imminent — if it were essential for induction, I would consider GnRH agonist ovarian protection. I would continue hydroxychloroquine throughout the pregnancy because it reduces flare frequency and the risk of congenital heart block, given she is anti-Ro positive. Corticosteroids — I would use prednisone at the lowest effective dose, as it is largely inactivated by placental 11-beta-hydroxysteroid dehydrogenase type 2, avoiding fluorinated steroids (dexamethasone, betamethasone) unless specifically indicated for fetal heart block. Calcineurin inhibitors such as tacrolimus are safe in pregnancy and can be used for nephritis maintenance. I would screen for antiphospholipid antibodies — if positive, she would need prophylactic low molecular weight heparin plus low-dose aspirin in pregnancy. The overarching principle is that active maternal disease is worse for the pregnancy than well-chosen, pregnancy-compatible medications." [1]

Q4: "Her lupus anticoagulant is positive and she has a history of a first-trimester miscarriage. How does this change your management?" [1]

"This finding suggests antiphospholipid syndrome coexisting with her SLE — secondary APS. I would confirm the laboratory criteria by repeating the lupus anticoagulant, anticardiolipin and anti-beta-2 glycoprotein I at least 12 weeks apart, as required by the Sydney (2006) criteria [8]. If confirmed, she has definite APS with pregnancy morbidity as her clinical event.

For her current lupus nephritis flare, the APS changes my anticoagulation planning but not the immunosuppressive induction. For future pregnancy, she would need prophylactic low molecular weight heparin combined with low-dose aspirin, commenced once pregnancy is confirmed and continued through pregnancy and for 6 weeks postpartum. If she were to thrombose at any point, she would need lifelong therapeutic anticoagulation with warfarin — warfarin is preferred over a DOAC in triple-positive or arterial APS, and is safe in lactation (though teratogenic and avoided in pregnancy itself, where LMWH is used). I would also be vigilant for the most feared manifestation — catastrophic antiphospholipid syndrome, multi-vessel thrombosis over days with 30 to 50 per cent mortality, precipitated typically by infection or surgery, and treated with combination anticoagulation, corticosteroids, plasma exchange and intravenous immunoglobulin." [1]

Q5: "How do you interpret her falling C3 and C4, and how does this pattern help you distinguish lupus nephritis from other glomerular diseases?" [1]

"The fall in both C3 and C4 together is the hallmark of classical complement pathway activation by immune complexes — the mechanism of tissue injury in active lupus. Pathogenic antigen-antibody complexes, particularly those containing anti-dsDNA, circulate and deposit in the glomeruli, activating the classical pathway and consuming both C3 and C4. This is why a rising anti-dsDNA titre with falling C3 and C4 is the classic serological signature of an impending lupus flare, particularly a renal flare. [1]

This complement pattern is diagnostically useful. In lupus nephritis, both C3 and C4 fall (classical pathway). In ANCA-associated vasculitis and IgA nephropathy, complement levels are typically normal because these are not immune-complex classical pathway diseases. In post-streptococcal glomerulonephritis and C3 glomerulopathy, only C3 falls with a normal C4, because these activate the alternative pathway. So the complement pattern helps me triangulate the mechanism: low C3 and low C4 points to immune complex classical pathway activation (lupus, cryoglobulinaemia, post-infectious endocarditis-related GN), low C3 with normal C4 points to alternative pathway, and normal complement points to a non-complement-activating process. I would also expect a 'full house' immunofluorescence pattern on her biopsy — IgG, IgA, IgM, C3 and C1q all deposited — which is characteristic of lupus nephritis and reflects polyclonal immune complex deposition." [1]

Q6: "What is your target at 6 months, and how do you decide whether she is a responder?" [1]

"The target at 6 months is a renal response, which I define using the composite criteria endorsed by KDIGO 2021 and the EULAR/ERA-EDTA recommendations. A complete response is a urine protein-to-creatinine ratio below 50 milligrams per millimole with stable renal function (no significant rise in creatinine). A partial response is at least a 50 per cent reduction in proteinuria with stable renal function. If she achieves at least a partial response by 6 months, I continue the same induction agent into the maintenance phase. If she has no response — persistent nephritic activity, uncontrolled proteinuria, or a rising creatinine — I switch induction agents: from mycophenolate to cyclophosphamide (or vice versa), add a calcineurin inhibitor (voclosporin or tacrolimus), consider rituximab despite the negative LUNAR trial, and involve a nephrologist regarding the trajectory towards end-stage kidney disease. Early response is prognostically important — the AURORA trial showed significant separation in renal response as early as 4 weeks with voclosporin, underscoring the value of rapid disease control in preventing irreversible chronic damage." [1]

Short Case Discussion

Examination of the hands and face in SLE

Examiner instruction: "Examine this patient's hands and face. She is a 32-year-old woman with a chronic multisystem illness." [1]

Candidate's model answer: [1]

"I would like to examine this patient's hands and face systematically — inspection, palpation, movement, function, and then a screen for multisystem features. [1]

Inspection (face): I am inspecting the face. I can see a fixed erythematous rash over both cheeks and the bridge of the nose in a butterfly distribution. Critically, the nasolabial folds are spared — this distinguishes the malar rash of systemic lupus erythematosus from rosacea and seborrhoeic dermatitis, which involve the folds. The rash is photosensitive in nature. There is no scarring, which distinguishes it from discoid lupus. I also note patchy non-scarring alopecia at the hairline and oral ulceration on the hard palate. [1]

Inspection (hands): Looking at the dorsal and palmar surfaces of both hands, I can see a symmetrical deforming arthropathy. There is ulnar deviation at the metacarpophalangeal joints and swan-neck deformities (PIP hyperextension with DIP flexion). However, the deformities are reducible when I ask her to flatten her hand — this is Jaccoud arthropathy, a non-erosive deforming arthropathy caused by tendon and ligament laxity rather than joint destruction. This is a key distinction from rheumatoid arthritis, which is erosive and fixed. There is also periungual erythema and a mottled net-like discolouration over the fingers consistent with livedo reticularis, raising the possibility of associated antiphospholipid syndrome. [1]

Palpation: The MCP and PIP joints feel mildly boggy with soft tissue swelling but no bony proliferation or warmth. There is no palpable synovial proliferation. The caput ulnae sign is not present. I am checking the nailfolds for dilated capillary loops, which are seen in lupus and other connective tissue diseases. [1]

Movement: Active and passive range of motion is full and the deformities reduce passively — confirming Jaccoud arthropathy. [1]

Function: Grip and pinch are preserved, consistent with a non-destructive arthropathy. [1]

Synthesis: My findings are a symmetrical non-erosive deforming arthropathy with reducible Jaccoud deformities, a photosensitive malar rash sparing the nasolabial folds, oral ulceration, non-scarring alopecia, periungual erythema, and livedo reticularis. This combination is consistent with systemic lupus erythematosus with possible associated antiphospholipid syndrome. I would like to complete my examination by screening for multisystem features — examining the chest for pleural or pericardial rubs and interstitial lung disease crackles, the heart for a pericardial rub or murmur of Libman-Sacks endocarditis, the abdomen for splenomegaly, and the legs for oedema, vasculitic lesions and palpable purpura. [1]

I would confirm the diagnosis with ANA, anti-dsDNA, anti-Smith and complement levels, screen for renal involvement with urinalysis and proteinuria, and assess for antiphospholipid antibodies." [1]

Examiner: "What is the mechanism of the Jaccoud arthropathy?" [1]

"Jaccoud arthropathy is a non-erosive, reducible deforming arthropathy caused by inflammation-induced laxity of the tendons, ligaments and joint capsule rather than by destruction of the articular cartilage or bone. Repeated episodes of synovitis and periarticular inflammation stretch the capsuloligamentous structures, allowing the imbalance of tendon forces to produce the characteristic deformities — ulnar deviation, swan-neck and Z-thumb. The key distinction from rheumatoid arthritis is that the radiographs in Jaccoud arthropathy show no erosions and the deformities are correctable, whereas rheumatoid arthritis causes fixed, erosive, deforming change through pannus-driven cartilage and bone destruction. Jaccoud arthropathy is most associated with SLE but can also occur in rheumatic fever and other connective tissue diseases." [1]

Examiner: "How would you distinguish the malar rash from rosacea at the bedside?" [1]

"Three features distinguish the malar rash of SLE from rosacea. First, the nasolabial folds: the malar rash of SLE spares the nasolabial folds, whereas rosacea (and seborrhoeic dermatitis) typically involves them. Second, photosensitivity: the malar rash is photosensitive, often triggered or worsened by sun exposure, while rosacea is triggered by heat, alcohol, spicy food and emotional flushing rather than specifically by ultraviolet light. Third, associated features: the malar rash of SLE coexists with other lupus features (oral ulcers, non-scarring alopecia, arthralgia, cytopenias), while rosacea is an isolated dermatological condition often with telangiectasia and rhinophyma in chronic cases. Discoid lupus is another important distinction — it scars, with follicular plugging and a carpet-tack sign, whereas the malar rash of SLE does not scar." [1]