Difficult to treat Lupus nephritis

Molly Mary Thabah MD Medicine
Professor and Head
Clinical Immunology & Rheumatology, JIPMER Puducherry, India

What is Difficult to treat lupus nephritis

The current standard of care for induction of remission in lupus nephritis (LN) is glucocorticoids and immunosuppression (IST) with either intravenous (IV) cyclophosphamide (CYC) or oral mycophenolate mofetil (MMF). A complete response to treatment as per EULAR/ERA-EDTA and BSR recommendations should ideally be achieved within 12 months of starting induction therapy. This is defined by the normalization of kidney function, marked by stable or improving glomerular filtration rate (GFR), and reduction in proteinuria to normal or near-normal levels (< 0.5 g/day or a urine protein-to-creatinine ratio (UPCR) <500 to 700mg/g). Some patients respond partially, defined as a reduction in proteinuria by at least 50% from baseline levels, with the UPCR falling < 500–700 mg/g within 6 to 12 months.

There is a subset of patients who show no significant reduction in proteinuria, who have persistent active urinary sediments, or worsening renal function—they are classified as having refractory or difficult-to-treat (DTT) lupus nephritis.

American College of Rheumatology (ACR) provides a slightly different treatment response timeline and considers lupus nephritis as a refractory if there is disease worsening at 3 months or if treatment failure is evident by 6 months. Thus, the ACR definition leads to an earlier declaration of refractory disease compared to the EULAR/ERA-EDTA criteria, as the assessment is done within 3-6 months of initiating therapy.

Nevertheless, when we talk about refractory or DTT it generally means a failure to achieve adequate response to first-line immunosuppressive therapies within a specified timeframe.

Causes of Difficult-to-Treat Lupus Nephritis

The causes of difficult-to-treat lupus nephritis are multifactorial and are listed below

Immunological Factors:

Persistent immune activation by anti-dsDNA antibodies and excess pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IFN-gamma, may perpetuate kidney inflammation. The presence of antiphospholipid Antibodies may further complicate LN by causing microvascular damage.

Histopathological Features:

Severe Proliferative lesions (class III or IV LN and a high activity score index)
A high chronicity index (glomerular sclerosis, tubular atrophy, and interstitial fibrosis) A transformation of lupus nephritis from a proliferative type to a more chronic type (class VI)

Genetic Factors:

Variations in genes encoding for complement proteins or Fc receptors and certain epigenetic modifications like DNA methylation, and histone modifications in immune cells can influence gene expression, leading to an exaggerated immune response

Patient-Related Factors:

Non-adherence to therapy due to various reasons like side effects of medicines, polypharmacy, complexity of the treatment regimen, socioeconomic barriers, and inability to buy treatment. Non-adherence leads to suboptimal drug levels, resulting in inadequate disease control.
Comorbid Conditions such as hypertension, diabetes, and infections

How to Identify DTT Patients at Early Stages

Clinically if the patient is having persistent Proteinuria despite ongoing treatment, uncontrolled hypertension at the onset or during treatment and an increase in serum creatinine levels or a decline in the estimated glomerular filtration rate (eGFR) are predictors for developing DTT
Presence of Serological and histological Markers (as listed above)
Certain ethnic groups, such as African Americans, Afro-Caribbeans, and Indo-Asians and Family History of Autoimmune Diseases are more at risk of developing refractory LN

Management of Difficult-to-Treat (DTT) Lupus Nephritis (DTT)

Managing DTT LN involves a combination of optimizing existing therapies (figure 1) namely IV CYC, MMF, rituximab, and calcineurin inhibitors (tacrolimus).
New therapies include B cell depletion with obinituzumab. Newer calcineurin inhibitors (Voclosporin), and belimumab are important add-on therapies in refractory disease. The goal is to prevent disease progression and minimize the risk of end-stage renal disease (ESRD).
Emerging and Experimental Therapies
CAR T cell therapy
JAK Inhibitors, Plasma Exchange, and Hematopoietic Stem Cell Transplantation
Prolonged cycles of immunoadsorption combined with azathioprine or MMF in CYC refractory patients(Stummvoll et al.)

Figure 1: Diagnostic and therapeutic approach to DTT LN
(DTT: Difficult-to-treat; LN: lupus nephritis; MMF: mycophenolate mofetil; GFR: glomerular filtration rate; CYC: cyclophosphamide; IST: immunosuppressive therapy)

Preventing DTT

Monitoring for Treatment Efficacy

Regular measurements of proteinuria, serum creatinine, and complement levels, as well as periodic renal biopsies in selected cases to assess histological response, and adjustments to the therapeutic regimen.

Addressing Non-Adherence

Non-adherence to therapy is a significant cause of treatment failure. Providing patients with education about their disease, simplifying treatment regimens, and addressing psychosocial barriers are important strategies to improve adherence.

Infection Prophylaxis and Vaccination

What is the Prognosis

The prognosis of DTT LN is generally less favorable compared to treatment-responsive lupus nephritis.
Up to 30-40% of patients with refractory disease may progress to ESRD within a few years of diagnosis. The 10-year renal survival (the time until the patient progresses to ESRD or requires dialysis) is often <50%, which contrasts sharply with the much higher survival rates seen in treatment-responsive lupus nephritis.
Overall Mortality Rates are higher than in those with treatment-responsive disease. probably due to the disease itself, infections related to immunosuppression, cardiovascular disease, and thrombotic events.
The uncertainty of disease progression, coupled with the challenges of managing a chronic illness, can lead to anxiety, depression, work-life imbalance and other psychosocial issues.