Journal Club: Rituximab Off-Label

Jan 12 2011 Published by under Journal Club

My last act before I pack for Science Online will be journal club.

Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report

Gulati et al. Clin J Am Soc Nephrol. 2010 Dec;5(12):2207-12

PMID: 20798255   PMCID: PMC299408

I chose this article because it is one of the few in which patients with nephrin (NPHS1) and podocin (NPHS2) mutations have been treated with rituximab for steroid-resistant nephrotic syndrome (NS); unfortunately, the authors don't answer the question I had in mind.

Anyway, here it goes:

NS is relatively common in the world of pediatric nephrology. Approximately 85% of affected children have minimal change disease (kidney looks normal by light microscopy) and respond to glucocorticoid treatment. Most will have a relapsing course, with respiratory infections triggering proteinuria, but the condition then resolves after a few years. (Lay summary of NS here.)

Some children with NS relapse so quickly that we consider them steroid-dependent, and the side effects of glucocorticoids become problematic. Other children do not respond at all to the medication, and they are steroid-resistant. This latter group often has focal segmental sclerosis or other nasty kidney lesions that often lead to kidney failure. Since some children respond to immunosuppressive therapy, we began trying other immunosuppressive agents. Cyclophosphamide, calcineurin inhibitors, and mycophenolate may each be effective in some children, particularly those who are steroid-dependent. Some resistant patients also respond to these agents. Some children respond to none of the above.

Rituximab: Usual course is 2 injections (Image courtesy PhotoXpress)

A few years back, in a desperate attempt to treat these children, someone tried the newest immunosuppressant-on-the-block, rituximab. This drug is a chimeric monoclonal antibody that targets the CD20 receptor on B lymphocytes. Its FDA approval is for treatment of non-Hodgkin lymphoma, but it has been used successfully in rheumatoid arthritis and vasculitis syndromes including systemic lupus erythematosus. Most reports focused on immediate response to rituximab in NS; this report looks at patients followed for at least 12 months after treatment.

Of the patients classified as steroid-resistant, approximately half had no response to rituximab. About half of the remaining patients had a reduction in proteinuria, but continued to have active NS (partial remission), while the others had a complete remission. Most of these patients maintained their complete response over 12 months after therapy. Two of these patients had heterozygous mutations (1 copy bad, 1 copy normal) in NPHS2, the gene that codes podocin; however, the authors never comment on whether these particular patients had any response to the medication!

Overall, the steroid-dependent patients did better. One year after treatment, more than 80% remained in remission, often without other medications.

None of the 57 patients in this series suffered any infectious complications of treatment. Only 3 had mild infusion-related reactions, including chills and muscle pain.

Numerous reports now support rituximab's ability to induce remission of NS, particularly in steroid-dependent children. The results lag a bit in steroid-resistant patients, but given the lack of other treatments, a course of rituximab is ultimately indicated for most of those children as well. Having recently found a heterozygous mutation of NPHS1 in one of my steroid-resistant patients, I would like to know if anyone has experience treating patients with these mutations with this agent. Unfortunately, this is the only paper I have located where patients with mutations were treated with rituximab, and the results in those two patients were not specified.

Filtration Slit (From

So why would rituximab not work in a patient with a mutation?

NPHS1 (nephrin) and NPHS2 (podocin) initially came to light through studies of children with severe congenital NS that results from homozygous mutations (both copies bad) in these genes.  The proteins coded by these genes form the slit diaphragm, the barrier to protein leakage in the filtration unit of the kidney (see diagram above). Having one copy of nephrin or podocin mutated may result in milder, later-onset NS. Not all people who have one bad gene copy get NS, though, making a "2-hit model" a likely scenario. Thus, even though a structural protein may be out-of-whack, some dysregulation of the immune system may trigger the onset of NS, making immunosuppressant therapy effective.

We also do a lot of "let's see if this works" treatment in nephrology:

  • Most patients with NS respond to steroids
  • This patient did not respond
  • Try another immunosuppressant drug
  • Repeat until one works or you run out of drugs.

I hope someday we get a study that reports about rituximab in heterozygous NPHS1 and NPHS2 mutations. If it does not work in the face of these mutations in structural proteins, then relatively simple genotyping can spare our patients the side effects and expense of rituximab. If it does work, it provides further evidence to the "2-hit model" of NS, and may open up other novel research avenues and therapeutic targets.

No responses yet

Leave a Reply