What is your treatment approach when managing patients with relapsing lupus nephritis who previously achieved remission with mycophenolate and steroids?

Remember that each lupus nephritis (LN) flare is accompanied by permanent loss of nephrons, as much as a third! Each flare increases the risk for poor response (Perez-Arias et al., PMID 36318456). Relapse is not to be taken lightly.

I am a big believer in considering combination therapy as initial therapy in most patients (hydroxychloroquine, HCQ + MMF or CYC + limited steroids + belimumab, BEL or a calcineurin inhibitor, CNI) per the latest EULAR SLE and LN management guidelines.

For a relapser, it is a no-brainer... combo therapy absolutely should strongly be considered to give this patient the greatest chance of not evolving to end-stage renal disease.

1. Hopefully, they were on HCQ, which increases remission rates and reduces flares in LN (Rao et al, PMID 37530940 (Kasitanon et al., PMID 16830883).
2. Everyone please get used to checking through whole blood HCQ drug levels regularly in patients. I would aim for 1000 - 1200 ng/mL in this sort of patient. You will be very surprised how often poor adherence is involved (Garg et al., PMID 37667434).
3. Don't forget vitamin D supplementation to keep the 25-OH vitamin D around 40 ng/mL per Petri et al., PMID 23553077.
4. Religious sunscreen use and UV avoidance is a must in all LN patients, even those who do not think they are sensitive. Skin cell damage releases nuclear antigens like dsDNA, which can form immunocomplexes with anti-dsDNA, travel to the kidneys, and contribute to the pathogenesis.
5. Do a biopsy to ensure it is an LN flare and not something else (FSGS etc) per studies and advice of experts like Brad Rovin, OSU.
6. If LN is proven... I'd read MMF or CYC (depending on the clinical scenario) PLUS either BEL or a CNI. If proteinuria is greater than 3 gms per day, I lean toward a CNI, either voclosporin or tacrolimus. 
7. Of course, we cannot forget our proteinuria-sparing meds like ACEi, ARB, and SGLT2 inhibitors. 

It depends on the clinical context.

1. Was the patient completely off MMF and prednisone when they had the relapse.
2. How long after stopping the medications, they had relapse?
3. If they claim to be on MMF, then were they really taking it- would recommend getting levels, calling their pharmacy to get their refill history.
4. How severe is the relapse? 

But to answer the question at hand, I would re-induce with prednisone and MMF if the patient had relapsed off MMF and prednisone. 

If they were still on MMF and actually taking it and then relapse, then it depends on the severity of the relapse. Switch to cyclophosphamide vs adding another agent along with MMF. 

If they have been off of MMF and steroids for a while, then would resume therapy with MMF and steroids. The trick here would be to wean off immunosuppression slowly so it does not recur again and they will need higher dose of maintenance therapy once they achieve remission again. 

If this is a relapse ON MMF, I question maintenance dose and I question compliance. If the dose is decent (2-3 g/d depending on patient size etc), I would consider adding rituximab. Once the patient is in remission, I might consider adding benlysta or voclo. The other question I always wonder is was the patient EVER really in remission? My feeling is that we use cyclophosphamide a bit too little these days and ESRO lupus is very well tolerated and I believe will realist in longer remission (however you define that).

Rebiopsy is probably underperformed, and there have been suggestions (data for) of protocol biopsies, but remember we have treated lupus pretty successfully without them for decades, using our clinical parameters alone.

If this is OFF MMF, I question not being on any maintenance regimen. Lupus nephritis is about as bad as lupus can get, and every time you relapse off medication it requires reinduction and that means steroids. My approach is to rarely stop maintenance for SLE with class 3 or 4 nephritis. I have always felt that whatever bad comes from potentially unneeded maintenance (steroid-free), is not as bad as what bad comes from repeated induction with real steroid doses.

Add Lupkynis.

Great answers above.

Would first rebiopsy!