Abstract
Despite decades of clinical research aimed at finding the most appropriate immunosuppressive regime, lupus nephritis (LN) remains one of the major disease manifestations of systemic lupus erythematosus (SLE) with a great impact on survival and quality of life. We start this review by defining the disease burden, the real-world challenges and the poor prognostic factors. We then discuss the current anti-inflammatory, cytotoxic and biologic therapies, with special emphasis on the need for optimal global care.
Case presentation
Jane is a 32-year-old Caucasian lady newly diagnosed as suffering from systemic lupus erythematosus (SLE) on the basis of a recent history of fever, arthritis, chest pain and malar rash. Antinuclear antibodies (Ab) are strongly positive (1/2560) and correspond to anti-DNA Ab (675 U ml −1 by Farr assay; nl: <10). The serum complement C3 and C4 levels are very low, at 32 and 5 mg dl −1 , respectively. Renal function is severely impaired (serum creatinine: 2.7 mg dl −1 ) and proteinuria is within the nephrotic range (7.8 g day −1 ). The renal biopsy is consistent with International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class IV (G) (A) lupus nephritis (LN), with crescents in 20% of the 14 glomeruli. How would you handle this case? It was submitted to the 280 voting participants of a continuous medical education symposium organised during the 2013 EULAR Annual Scientific Meeting. Thirty-one percent chose to prescribe glucocorticoids (GC) and Euro-Lupus (EL) intravenous (IV) cyclophosphamide (CY; 500 mg; q2w × 6). Twenty-six percent would prefer GC and IV CY according to the National Institutes of Health (NIH) regimen (0.75–1 g m −2 ; qm × 6), 26% GC and mycophenolate mofetil (MMF; 2–3 g day −1 ), 8% GC and azathioprine (AZA; 2 mg kg −1 day −1 ) and the remaining 8% no GC and rituximab (RTX). The results of this pool on an ‘easy’ and brand new case of LN illustrate how different decisions can be taken at the bedside, despite three decades of intense clinical research in the field, including more than 10 randomised controlled trials (RCTs).
Disease burden, challenges and poor prognostic factors
By and large, 40% of the SLE patients suffer from renal involvement during the course of their disease . The most fortunate promptly responds to standard immunosuppression and runs a ‘one-shot’ disease. At the other end of the spectrum, others suffer from one or more renal relapse(s) or develop refractory LN and end-stage renal disease (ESRD) after having experienced the many side effects of several drugs which failed to control their disease. We are pleased to claim that only 5–10% of LN patients developed ESRD at 5–10 years in recent randomised trials. However, what does a 10-year renal survival rate mean for a teenager? Moreover, these figures obtained in tertiary referral centres may considerably differ from those achieved in the real world. In this respect, the finding of an increasing incidence of ESRD attributable to SLE (from 1.13/10 6 in 1982 to 4.9/10 6 in 2004) is worrying and clearly demonstrates the limits of our current therapies.
The main challenges in LN are to achieve a prompt response within months, to maintain this response and avoid flares, to prevent any degree of renal impairment in the very long term, to prevent and treat damage and co-morbidities and to fulfil these objectives with maximal quality of life and minimal toxicity.
Many poor prognostic markers have been described , including the Afro-American or Hispanic race, poor socioeconomic status, the severity of initial clinical presentation, the presence of chronic lesions on baseline renal biopsy, etc. In our view, very less attention has been paid to three other critically important poor prognostic factors, namely (i) delayed response to treatment, (ii) lack of adherence to therapy and (iii) suboptimal global care. Their importance is further strengthened by the fact that all can be positively impacted by a ‘best-practice’ policy.
Delayed response to treatment
Several long-term studies have clearly demonstrated that the absence of an early response to immunosuppressive therapy (persistent proteinuria and failure to normalise renal function at 6 months) is the most important long-term poor prognostic factor in LN . Conversely, the positive predictive value for a good long-term renal outcome is as high as 90% in patients who experience a reduction in proteinuria of at least 50% by 6 months. We must therefore offer SLE patients not only early diagnosis of renal involvement and prompt therapy but also obsessional follow-up during the first months through easy access to our lupus clinics and very regular clinical and laboratory monitoring. Whether a change in treatment is warranted in non-responding patients after 6–12 months of treatment is not too far-fetched but is not demonstrated so far.
Lack of adherence to therapy
Until recently, the issue of non-adherence to therapy has been completely overlooked by lupologists. Yet, imagine an 18-year-old lupus girl to whom you prescribe GC, another immunosuppressant, hydroxychloroquine (HCQ), an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), another blood pressure-lowering drug, a diuretic, a lipid-lowering drug, not to mention calcium salts and vitamin D3 supplements, sometimes more than 20 pills a day, with their well-known side effects. Not surprisingly, many patients do not strictly (if at all!) follow our advice, as recently demonstrated by HCQ blood titre measurements. HCQ has a very long circulating half-life (40 days) and the drug accumulates in the blood, thereby allowing capturing patients who take the drug only occasionally, for example, a few days before the visit to the clinic. This phenomenon, known as ‘white-coat compliance’, is very common in chronic diseases. Thus, a hypertensive patient who wants to please his physician will take a few blood pressure-lowering pills for a short period of time preceding the visit and will be considered as compliant since his/her blood pressure levels measured the day of the visit will be deemed satisfactory. By contrast, patients taking HCQ once in a while will be unmasked by whole blood HCQ measurements. Quite interestingly, in a retrospective analysis, more lupus flares were observed in these less (non) compliant patients . A transatlantic prospective study performed in flaring SLE patients is currently under way to confirm these findings. How can the issue of non-adherence in clinical practice be addressed? First, repeated explanations can be given to LN patients and their relatives on the reasons why each drug is prescribed. Second, the global treatment plan over time can be sketched as soon as the treatment is started, so that patients understand that many of the drugs will be progressively withdrawn or their dose tapered, even if some (mainly the immunosuppressants) will be prescribed for several years. In this respect, the help of a nurse practitioner in our busy LN clinics is most valuable, more so as patients are more keen to discuss some issues with a nurse than with a physician. Third – but this applies to clinical studies only – questionnaires can be aimed at detecting noncompliance, and pill counters can be used to evaluate the adherence to treatment.
Suboptimal global care
The third important poor prognostic factor that should never be underemphasised is suboptimal coordinated multidisciplinary care aimed at controlling all aspects of the disease (patients with LN also suffer from SLE!) and of drug- or disease-related co-morbidities. As lupologists (be it a rheumatologist, a nephrologist or an internist according to different training and care programmes in different countries), it is indeed our duty to take care of the patient’s smoking habits, weight and blood pressure control, diabetes, dyslipidaemia, osteoporosis, osteonecrosis, immunisations, fatigue, life style, etc. All these very time-consuming items are likely to be more influential on the long-term outcome of LN than the choice of the immunosuppressive regimen (see below)! Psychosocial aspects, taking into account the patient-reported outcomes, also belong to global care, in particular in a disease with an impact on the patient’s body image (mainly due to the side effects of therapy). In our experience, the lupologist herself or himself, always in collaboration with the patient, must coordinate all investigations and be responsible for the full treatment plan. Needless to say, subspecialists’s advice must be sought but care must be coordinated by one senior physician who manages all aspects of the disease and who follows enough LN cases to be considered as an expert.
Related posts:
Paediatric-onset systemic lupus erythematosus
Biologics in SLE: Towards new approaches
Fatigue, health-related quality of life and other patient-reported outcomes in systemic lupus erythematosus
Management of infection in systemic lupus erythematosus
Pulmonary hypertension in systemic lupus erythematosus
Managing lupus patients during pregnancy
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