Differences in Ethnic Groups
Several studies have shown a higher risk of LN and a worse prognosis in African–American and Hispanic lupus patients.
The ALMS trial provided some information about ethnicity. Although MMF and CYC showed similar overall efficacy, it was interesting to see that more patients in the high-risk group responded to MMF, which had a more consistently effective response in all racial groups, while CYC is less effective in African or Hispanic patients. In the maintenance phase, MMF was also superior independently of race. Pharmacokinetic studies did not show differences in metabolism in different races and the risk of infection was also similar.
The EXPLORER study suggests that the patients from American, African and Hispanic groups, can benefit from the addition of rituximab (p = 0.0408).
These results showed that ethnicity, race and geographical location are important because they can affect patients' response to different treatment.
Many countries have started to collect data on patients that are treated with biologic therapy in national large-scale registers, to learn more about the 'real life' experience with these drugs.
In the UK, the BILAG BR is ongoing. It is a prospective observational cohort study of SLE patients treated with biologic drugs. One of the goals of this register is to know whether the patients with this treatment have an increased risk of infection and hospitalization, compared with conventional therapy. The other purpose of the BILAG BR is to determine the long-term efficacy of biological therapies in the treatment of SLE.
Recent Guidelines: EULAR & ACR
For the initial treatment of LN class III, IV and V, EULAR and ACR recommend MMF (3 g per day) or CYC as the first choice treatment, together with intravenous pulses of methylprednisolone or high doses of glucocorticoids (0.5 mg/kg/day). EULAR and ACR's guidelines recommend the low-dose CYC regimen (3 g/3 months) as the preferred one. The high-dose regimen (0.5–1 g/m intravenous per month for 6 months) is reserved for patients with worse clinical or histological features (EULAR) or may be the first option in a non-Caucasian population (ACR).
For subsequent treatment, MMF is unanimously the first choice because of its proven superiority.
The recommended treatment for class I and II LN with podocytopathy is low-dose of prednisone (0.25–0.5 mg/kg/day), with the addition of AZA (1–2 mg/kg/day) as a steroid-sparing agent.
In the case of refractory disease (failure to improve in 3–4 months, not achieving partial response in 6–12 months or remission in 2 years), a switch is recommended to a different immunosuppressive drug that can be mycophenolic acid, MMF, CYC or rituximab, added to the previous treatment or as monotherapy.
Biopsies should be undertaken in all patients with clinical evidence of active, new-onset and untreated LN.
Both guidelines mention the importance of HCQ and ACR suggests prescribing this drug to all lupus patients with nephritis.
Clinical Trial Design
Clinical trials design in SLE is fundamental but complex. The difficulty is evident because lupus is a relatively uncommon condition, very heterogeneous, whose activity is difficult to assess, with a relapsing–remitting clinical course, and has few standardized biomarkers. It is clear the clinical trial design in most SLE studies has been suboptimal. Wofsy et al. analyzed this matter when reflecting on a trial of abatacept in LN. They concluded that the definition of primary outcome is essential for the ability of the trial to detect therapeutic benefits and a correct and unanimous definition of complete remission in SLE is needed to define the main outcomes in a clinical trial.
Therefore, EULAR has developed recommendations for conducting clinical trials. The main points to consider are:
Define primary (e.g., level of disease activity assessed with a standardized index, causes of death and adverse events) and secondary end points (such as health status and quality of life) with care;
Follow CONSORT guidelines and Good Clinical Practice guidelines. It is necessary to define the hypothesis, the type of trial, methods and duration, and plan the statistical analyses. It is also essential to define the efficacy of the drug, remission, response and treatment failure;
Eligibility criteria (disease definition, its duration since the diagnosis and demographic characteristics) should be defined to allow comparisons between studies and subgroup evaluation if needed;
Characterize concomitant medications (immunosuppressive drugs, corticosteroids and other drugs). It is necessary to define the drugs allowed in the clinical trial, the dose range and the duration of the treatment.