Comment on: Changing patterns in clinical–histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis.Moroni G, Vercelloni PG, Quaglini S, et al Ann Rheum Dis. 2018 Sep;77(9):1318-1325. doi: 10.1136/annrheumdis-2017-212732. Epub 2018 May 5.
Commented by: Dimitrios T. Boumpas, Medical School, National and Kapodistrian University of Athens, Greece
Patient and renal survival of patients with lupus nephritis have improved in the last few decades. G Moroni and colleagues examined the changes in demographic, clinical and histological features at the time of LN onset in a large cohort of patients during an impressive period of 46-year follow-up! Importantly, they looked at LN prognosis during the course of the follow-up and searched for the prognostic factors associated with patient and renal outcomes.
For this study, 495 patients followed in four Italian referral centers (Renal Divisions of Ospedale Maggiore Milano, San Carlo Hospital Milano and University of Parma, and Rheumatology Unit of Padova University)were included. Patients had biopsy-proven LN performed between January 1970 and December 2016. The 46-year follow-up was subdivided into three periods (P), 15 years each: P1 from January 1970 to December 1985, P2 from January 1986 to December 2001 and P3 from January 2002 to December 2016, and patients accordingly grouped based on the year of LN diagnosis. From 1970 to 1985 (P1) corticosteroid monotherapy was progressively replaced by combination treatment of corticosteroids with either azathioprine or cyclophosphamide.Intravenous methylprednisolone pulses were also largely used in this period. From 1986 to 2001 (P2), high-dose intravenous cyclophosphamide was commonly used as induction and maintenance therapy following the long-term controlled trials carried out at the National Institutes of Health. In the same period, the use of a combined oral immunosuppressive regimen as maintenance therapy became progressively more popular. Interestingly, the proportion of patients who received steroids alone as induction therapy decreased from 29% in P1% to 18% in P2 and further declined to 5% in P3. Finally, from 2002 to 2016 (P3), the evidence that MMF has a similar efficacy compared with cyclophosphamide in the induction phase and is more effective than azathioprine in the maintenance phase led to an increase in the use of MMF for induction and maintenance therapy. The main results are summarized below.
From 1970 to 2016 a progressive increase in patient age at the time of LN diagnosis and a longer time between systemic lupus erythematosus onset and LN occurrence was observed.Whether this may reflect better recognition and management of SLE and the increasing use of hydroxychloroquine remains to be seen. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased and -more importantly-that of isolated urinary abnormalities increased suggesting an increasing awareness of the renal involvement and a more vigorous screening and performance of renal biopsy. Of interest, no changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016.Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). In agreement with older studies, the multivariate analysis showed that male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD.The authors conclude that clinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival which may have been a result of a lower threshold for renal biopsy.
The most promising and reassuring observation of this study is the progressively milder clinical-not histologic- presentation of LN from P1 to P3. Presentation with isolated urinary abnormalities significantly increased from 25% in P1 to about 50% in P3. This finding was accompanied by the progressive decrease in the frequency of renal insufficiency at presentation, while the percentage of nephrotic syndrome did not significantly change over time. The decreased severity in clinical presentation from 1970 to 2016, is in concert with the progressive decline in serum creatinine at the time of LN diagnosis.It is likely that earlier recognition of LN leading to earlier biopsies may have contributed to better outcomes.
To this end, the EULAR-ERA/EDTA recommendations (1-3) clearly state that “because of the potentially aggressive nature of LN, the thresholds for performing a renal biopsy should be low. Any sign of renal involvement -especially in younger male patients- combined with non-renal lupus activity and /or active serology can be an indication for renal biopsy.Clinical, serologic or laboratory tests cannot accurately predict histology”. The progressive improvement in renal survival in this cohort is the result of a comprehensive multidisciplinary approach, which includes a prompt diagnosis of renal involvement combined with alower threshold for renal biopsy, treatment tailored to the renal biopsy findings and finally increased awareness and clinical experience in managing LN.
References
- Bertsias GK, Joint European League against rheumatism and European renal Association-European dialysis and transplant association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:1771–82. doi:10.1136/annrheumdis-2012-201940.
- Fanouriakis A, 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019 Jun;78(6):736-745. doi: 10.1136/annrheumdis-2019-215089.
- Fanouriakis et l 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis Ann Rheum Dis. 2020 Mar 27. pii: annrheumdis-2020-216924. doi: 10.1136/annrheumdis-2020-216924.
