Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis

INTRODUCTION — Up to one-third of patients with focal or diffuse lupus nephritis (LN) who initially achieve a complete response on immunosuppressive therapy will have a relapse (also called renal flare) following reduction or cessation of immunosuppression or nonadherence to oral drug therapy.

The treatment of relapsing focal or diffuse LN will be reviewed here. The treatment of focal or diffuse LN and lupus membranous nephropathy, the treatment of resistant disease, as well as issues related to end-stage LN, are presented separately:

●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)

●(See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)

●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)

DEFINITION OF RELAPSE — Relapse of focal or diffuse lupus nephritis (LN) following an initial response to therapy is primarily defined as recurrent inflammatory activity, usually manifested by any of the following parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts, white blood cells in the absence of infection), increased urine protein excretion, and/or an increased serum creatinine [1-3]. Relapses may occur while on immunosuppressive therapy or after reduction or discontinuation of therapy.

Disease relapse is different from resistant disease, which refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Establishing resistant disease'.)

EPIDEMIOLOGY AND RISK FACTORS — Relapses of focal or diffuse lupus nephritis (LN) occur in as many as one-third of patients during follow-up of up to 10 years [4-10].

Risk factors for relapsing disease include intentional cessation or reduction of immunosuppression, nonadherence to oral drug regimens, more severe disease at baseline, low levels of serum C3 and high levels of anti-double-stranded DNA (anti-dsDNA), a delay in reaching a complete response, and attainment of a partial compared with complete response to initial therapy [1,4,5,10-18].

ESTABLISHING RELAPSING DISEASE

Monitoring for relapse — Regular, indefinite follow-up and monitoring is needed for all patients with focal or diffuse lupus nephritis (LN), even for those in complete clinical remission for several years. Relapses can occur at any time during the course of LN, including during the initial treatment phase or during long-term subsequent therapy intended to lower the frequency of relapses. Monitoring during initial and subsequent therapy is discussed separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Monitoring the response to therapy'.)

In patients who have completed initial and subsequent therapy, we continue to monitor patients every three to four months to assess for relapse. Laboratory data obtained during follow-up visits include:

●Urinalysis with examination of the freshly prepared urinary sediment

●Quantification of urine protein excretion (usually with a random spot urine protein-to-creatinine ratio, but some experts confirm changes with a 24-hour urine)

●Serum creatinine (as well as a basic metabolic profile)

●Serum complement levels (C3 and C4)

●Anti-double-stranded DNA (anti-dsDNA) antibody levels

●Complete blood count with differential and platelets

●Erythrocyte sedimentation rate and/or C-reactive protein level

Patients who have an increase in anti-dsDNA titers or new hypocomplementemia after achieving a complete response should be monitored more frequently (particularly over the ensuing three months) but are not treated for relapse solely based upon changes in serologic activity.

The rationale for serologic monitoring is based in part upon the observation that an elevation in the anti-dsDNA antibody titer and, to a lesser degree, a fall in circulating complement levels are associated with a high likelihood (over 75 percent in one report) of subsequent clinical relapse, which typically occurs within the ensuing 8 to 10 weeks [19]. Also, it has been suggested that a fall in complement levels is a more valuable predictor of subsequent relapse than is the absolute plasma concentrations, as there may be a prolonged reduction in C4 levels long after a complete response has been achieved [20]. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Titer, pathogenicity, and disease activity'.)

Diagnosis of relapse — The diagnosis of a relapse of diffuse or focal LN is largely clinical and based on the presence of recurrent inflammatory activity, usually manifested by any of the following parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts, white blood cells in the absence of infection), increased urine protein excretion, and/or an increased serum creatinine in the absence of an alternative diagnosis. An increase in anti-dsDNA antibody levels and/or a decrease in serum complement levels are also supportive of a diagnosis of relapse [19,20]. All patients with suspected relapse should be evaluated for their adherence to therapy. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Assessment of patient adherence to therapy'.)

A kidney biopsy is frequently required to verify recurrent active LN rather than nonimmunologic progression of kidney disease or an alternative diagnosis (see "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'). Some patients with focal or diffuse LN have a proteinuric relapse, characterized by increased proteinuria (≥2 g/day increase in protein excretion over baseline) with an inactive urine sediment and a stable serum creatinine [1,2]. Repeat biopsy may be helpful since such patients may have proteinuria as a consequence of chronic scarring, active disease, or transformation to lupus membranous nephropathy. However, in patients with clinical and serologic findings consistent with active disease, a biopsy may not be necessary, particularly if the results are unlikely to alter therapy. In those patients where the clinical indicators are equivocal, a biopsy is still recommended. (See 'Patients with concurrent lupus membranous nephropathy' below.)

Estimation of the glomerular filtration rate (GFR) alone may be misleading when monitoring the course of LN that seems to be inactive. As in other kidney diseases, nephron loss in LN is associated with compensatory hypertrophy and intraglomerular hypertension in the remaining normal or less-affected glomeruli [21]. As a result, the GFR and the serum creatinine may initially remain stable, and the degree of proteinuria may fall after the resolution of active inflammation following immunosuppressive therapy [21]. However, over time, there is frequently increasing glomerulosclerosis on repeat kidney biopsy, often in the absence of clinical or serologic evidence of active systemic lupus erythematosus (SLE) [21,22]. In one study, for example, the number of sclerotic glomeruli increased from 15 to 60 percent over a three-year period despite a relatively stable GFR [21]. Both healing of previous inflammatory injury and nonimmunologic mechanisms of progression can account for these findings without requiring relapse and active disease [22].

A slowly progressive decline in GFR resulting from worsening glomerulosclerosis due to nonimmunologic mechanisms should not be treated with immunosuppressive agents. Therapy should instead be directed toward aggressive antihypertensive and antiproteinuric therapy with blockade of the renin-angiotensin system (eg, angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor blocker [ARB]). These issues are discussed separately. A repeat kidney biopsy should be performed if there is any uncertainty about the cause of the GFR decline. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Blood pressure goal' and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Proteinuria goal' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'General supportive measures in all patients'.)

MANAGEMENT

Approach based on disease severity — The treatment of relapsing focal or diffuse lupus nephritis (LN) depends upon the initial immunosuppressive regimen and the severity and timing of relapse (algorithm 1).

Mild relapse — Mild relapse is defined as increased activity of urine sediment and, possibly, a modest (eg, less than 50 percent) increase in urine protein excretion but with a stable serum creatinine.

The approach to the treatment of a mild relapse depends on whether the relapse occurs while the patient is still receiving ongoing therapy (algorithm 1) (see "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Subsequent therapy'):

●Relapse during therapy – For most patients who develop a mild relapse while still receiving therapy, we suggest increasing the dose of glucocorticoids and, if possible, increasing the dose of the immunosuppressive agent. As an example, in a patient receiving tapering doses of prednisone and azathioprine, the prednisone dose can be increased back to 60 mg/day (although lower starting doses may be adequate), and the azathioprine can be increased to 2 mg/kg per day (to a maximum of 150 to 200 mg/day). Similarly, in a patient receiving mycophenolate mofetil (MMF), the dose can be increased to 1500 mg twice a day if tolerated. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dosing and duration of subsequent therapy'.)

However, for those who cannot easily increase the doses of their original immunosuppressive regimen (eg, a patient with diabetes who does not wish to receive higher dose glucocorticoids or a patient on MMF or azathioprine with leukopenia at higher doses), switching to an alternative initial regimen is also an option. As an example, switching from MMF to a cyclophosphamide regimen, or vice versa, is reasonable.

For patients with mild relapsing focal or diffuse LN with a predominance of increased proteinuria, some clinicians would add a low dose of a calcineurin inhibitor if the patient is on MMF or azathioprine. The use of calcineurin inhibitors in combination with MMF for focal or diffuse LN is discussed in detail separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Calcineurin inhibitors plus mycophenolate'.)

●Relapse after discontinuation of therapy – For patients who develop a mild relapse after discontinuation of immunosuppressive therapy, we suggest reinstitution of the prior subsequent therapy regimen in combination with a short course of glucocorticoids, rather than switching to an alternative subsequent therapy regimen. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dosing and duration of subsequent therapy'.)

As an example, in a patient who previously received mycophenolate for initial and subsequent therapy, mycophenolate can be readministered using the same dose as before discontinuation.

There are no data to guide the optimal treatment of a patient with a mild relapse of diffuse or focal LN, and our approach is largely based upon clinical experience and observational data.

Moderate to severe relapse — Moderate to severe relapse is generally defined as an active urine sediment and a greater increase in proteinuria (eg, greater than 50 percent), and sometimes with a rise in serum creatinine. These manifestations may be accompanied by a flare in extrarenal manifestations of systemic lupus erythematosus (SLE).

The approach to the management of moderate to severe relapse varies among clinicians, as there is no high-quality evidence to guide the optimal therapy of such patients. Our approach is as follows (algorithm 1):

●Initial therapy for relapse – For most patients with moderate to severe relapse, we suggest reinstitution of the same initial therapy that was used to achieve a clinical response, rather than switching to a different initial therapy regimen. Exceptions include patients who have received multiple prior courses of cyclophosphamide for whom there is concern for cumulative toxicity or risk of infertility; in such patients, it may be preferable to use a mycophenolate-based initial therapy regimen. Patients who are not able to reliably adhere to oral medication regimens may have improved adherence if treated with intravenous cyclophosphamide.

Alternatively, some clinicians might choose to modify the initial therapy regimen rather than restart the previous initial therapy regimen. As an example, if a patient relapsed while on MMF alone for initial therapy, treating with MMF plus either a calcineurin inhibitor (voclosporin, tacrolimus, or cyclosporine) or belimumab would be reasonable options for initial therapy after relapse. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Initial therapy with mycophenolate or cyclophosphamide' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Combination regimens'.)

The duration of initial therapy that is used during a relapse depends upon the clinical response. If reinstitution of initial therapy results in relatively rapid clinical improvement within four to six weeks, then it may be reasonable to shorten the duration of therapy provided that careful attention is paid to clinical parameters of disease activity.

●Subsequent therapy for relapse – Once the course of initial therapy is completed and the patient has achieved a complete or partial response, the patient is continued on subsequent therapy. For most patients with moderate to severe relapse who have achieved a complete or partial response to initial therapy, we suggest using the same regimen as was previously used for subsequent therapy. This includes patients who were identified as being nonadherent to subsequent therapy at the time of relapse, provided that intolerance to treatment was not the reason for nonadherence and that patients are confident they have developed new strategies that will enable them to adhere to those therapies.

However, some clinicians choose to modify the subsequent therapy regimen in patients whose relapse occurred while on the original course of therapy. As an example, if a patient relapsed while on MMF alone for subsequent therapy, treating with MMF plus either a calcineurin inhibitor (voclosporin, tacrolimus, or cyclosporine) or belimumab would be a reasonable choice. Alternatively, some clinicians might try MMF plus rituximab. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dosing and duration of subsequent therapy' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Most trials on remission induction in patients with focal or diffuse LN do not distinguish between those patients treated for a new or relapsing presentation of their disease, and the evidence for new or relapsing disease comes from the same studies. These data are discussed in detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Initial therapy with mycophenolate or cyclophosphamide' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Choice of subsequent therapy'.)

The interest in the role of rituximab, a B cell-depleting chimeric monoclonal antibody, was largely based on observational data that suggested improved clinical response in patients with LN [23-29]. However, this effect has not been supported by clinical trials. In the multinational Lupus Nephritis Assessment with Rituximab (LUNAR) study, 144 patients with class III or class IV LN were randomly assigned to receive intravenous placebo or rituximab and were followed for 52 weeks; all patients also received MMF [30]. The incidence of complete or partial response was higher with rituximab as compared with placebo (57 versus 46 percent), but this difference was not statistically significant. The frequency of serious infections and hospitalizations, at least over the short term, was similar with rituximab and placebo. One possible explanation for the lack of benefit of rituximab is the small number of patients in this randomized controlled trial. Another possible explanation is the potency of rituximab in depleting peripheral B cells. A post-hoc analysis of the LUNAR trial found that peripheral B cell depletion with rituximab was variable among study participants, and those participants with complete peripheral B cell depletion had a higher renal response at 52 and 78 weeks compared with those who did not [31]. It should be noted, however, that the LUNAR trial was not designed to study the effect of rituximab on relapsing LN.

Patients with concurrent lupus membranous nephropathy — The treatment approach for patients who relapse and have combined focal or diffuse LN and lupus membranous nephropathy is the same as for patients with relapsing focal or diffuse LN. (See 'Approach based on disease severity' above.)

PROGNOSIS — In addition to requiring additional immunosuppressive therapy, relapses, particularly those with a nephritic sediment, also predict a worse kidney prognosis [1,2,12]. In one report, for example, nephritic relapses (active urine sediment, increase in serum creatinine at least 30 percent above previous baseline, and usually, increased proteinuria) were associated with a marked increase in the rate of a persistent doubling of the serum creatinine at a median follow-up of 10 to 11 years (relative risk was 6.8) [2].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Definition of relapse – Relapse of focal or diffuse lupus nephritis (LN) following an initial response to therapy is primarily defined as recurrent inflammatory activity, usually manifested by any of the following parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts, white blood cells in the absence of infection), increased urine protein excretion, and/or an increased serum creatinine. Relapses occur in as many as one-third of patients during follow-up of up to 10 years and may occur while on immunosuppressive therapy or after reduction or discontinuation of therapy. (See 'Definition of relapse' above and 'Epidemiology and risk factors' above.)

●Monitoring for relapse – Regular, indefinite follow-up and monitoring is needed for all patients with focal or diffuse LN, even for those in complete clinical response for several years. We monitor patients every three to four months to assess for relapse and determine whether the patient is experiencing toxicity from therapy. (See 'Monitoring for relapse' above.)

●Diagnosis of relapse – The diagnosis of a relapse of diffuse or focal LN is largely clinical and based on the presence of recurrent inflammatory activity, usually manifested by any of the following parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts, white blood cells in the absence of infection), increased urine protein excretion, or an increased serum creatinine in the absence of an alternative diagnosis. An increase in anti-dsDNA antibody levels and/or a decrease in serum complement levels are also supportive of a diagnosis of relapse. A kidney biopsy is frequently required to verify recurrent active LN rather than nonimmunologic progression of kidney disease or an alternative diagnosis. However, in patients with clinical and serologic findings consistent with active disease, a biopsy may not be necessary, particularly if the results are unlikely to alter therapy. (See 'Diagnosis of relapse' above.)

●Management – The treatment of relapsing focal or diffuse LN depends upon the initial immunosuppressive regimen and the severity and timing of relapse (algorithm 1):

•Mild relapse – Mild relapse is defined as increased activity of urine sediment and, possibly, a modest (eg, <50 percent) increase in protein excretion but with a stable serum creatinine.

-For most patients who develop a mild relapse while still receiving therapy, we suggest increasing the dose of glucocorticoids and, if possible, increasing the dose of the immunosuppressive agent (Grade 2C). However, for those who cannot easily increase the doses of their original immunosuppressive regimen, switching to an alternative initial regimen is also an option.

-For patients who develop a mild relapse after discontinuation of immunosuppressive therapy, we suggest reinstitution of the prior subsequent therapy regimen in combination with a short course of glucocorticoids, rather than switching to an alternative subsequent therapy regimen (Grade 2C). (See 'Mild relapse' above.)

•Moderate to severe relapse – Moderate to severe relapse is generally defined as an active urine sediment and a greater increase in proteinuria (ie, >50 percent), often with a rise in serum creatinine.

-For most patients with moderate to severe relapse, we suggest reinstitution of the same initial therapy that was used to achieve a clinical response, rather than switching to a different initial therapy regimen (Grade 2C). Exceptions include patients who have received multiple prior courses of cyclophosphamide for whom there is concern for cumulative toxicity or risk of infertility; in such patients, it may be preferable to use a mycophenolate-based initial therapy regimen.

-For most patients with moderate to severe relapse who have achieved a complete or partial response to initial therapy, we suggest using the same subsequent therapy regimen as was previously used for subsequent therapy (Grade 2C). This includes patients who were identified as being nonadherent to subsequent therapy at the time of relapse, provided that intolerance to treatment was not the reason for nonadherence and that patients are confident they have developed new strategies that will enable them to adhere to those therapies. However, some clinicians choose to modify the subsequent therapy regimen in patients whose relapse occurred while on the original course of therapy. (See 'Moderate to severe relapse' above.)