Crohn’s Disease May Lessen Soliris’ Effectiveness in aHUS Patients
Relapses of Crohn’s disease, an inflammatory bowel condition, lessened the efficacy of Soliris (eculizumab) in an adolescent girl with atypical hemolytic uremic syndrome (aHUS), a case study reported.
“Increased doses of [Soliris] may be necessary to maintain therapeutic blood levels of [Soliris] and full complement blockade, especially if the intestinal disease is not under control,” the researchers noted.
The study, “Atypical HUS and Crohn’s disease—interference of intestinal disease activity with complement-blocking treatment,” was published in the journal Pediatric Nephrology.
aHUS is caused by the uncontrolled activation of the complement system, a part of the immune system that helps destroy disease-causing microbes. Often triggered by an infection, aHUS can lead to the formation of blood clots in small blood vessels that can damage internal organs, especially the kidneys.
Although an altered immune response causes aHUS, little is known about its association with other immune-related conditions.
Scientists at the Semmelweis University in Hungary described the case of a adolescent who developed aHUS with acute kidney injury alongside Crohn’s disease — a condition that causes chronic inflammation in the gastrointestinal tract, mainly in the small and large bowel.
Her symptoms began at age 13 with regular diarrhea, mucus in the stool, and weight loss.
Stool analysis indicated a lack of disease-causing microbes, elevated anti-fungal antibodies, and high levels of the inflammatory marker calprotectin, which suggested Crohn’s disease. Her twin brother had been previously diagnosed with severe Crohn’s, and experienced complications that required repeated surgeries.
At the same time, blood tests revealed she had high levels of proteins and red blood cells in her urine, and rapidly increasing creatinine (a kidney disease marker), as well as anemia.
After an abdominal ultrasound showed her kidneys were enlarged, a kidney biopsy revealed the presence of blood clots in small blood vessels — a typical hallmark of aHUS.
Due to her rapidly declining kidney function, she received into-the-vein steroid injections, plasma transfusions, and completed several plasma exchange sessions to remove and replace her plasma — the liquid component of blood that lacks blood cells. While her anemia was stopped, creatinine levels in the blood remained high, as did the levels of proteins and red blood cells in the urine.
Six weeks after her aHUS diagnosis, the approved therapy Soliris, which acts by blocking a protein component of the complement cascade, limiting its activation, became available.
She was immediately treated with 900 mg of Soliris every two weeks to prevent kidney failure. Despite showing immediate signs of reduced complement activity, peaks of complement-related proteins were found in her blood that coincided with the emergence of bowel symptoms.
In response, her Soliris dose was increased to 1,200 mg every two weeks. This dose increment was still unable to control complement activation taking place during Crohn’s relapses.
To investigate Soliris’ lower effectiveness, blood levels of the therapy were analyzed shortly before the next dose was given. Results showed Soliris levels to be subtherapeutic, or unable to trigger a therapeutic effect, despite regular dosing. However, no signs of aHUS-related blood clots were seen during Crohn’s relapses.
“The reason for decreased [Soliris] activity is not clear. Possible explanations include local inflammation in the gut or intestinal [Soliris] loss,” the researchers wrote.
“Further studies are needed to clarify the mechanism of [Soliris] consumption in the gut and the role of concurrent immune-mediated diseases during long-term complement-blocking therapy,” they added.
Following a biopsy of the small intestine, which confirmed the presence of Crohn’s disease, conventional treatment with anti-inflammatory steroid therapies was started, which led to rapid remission. However, the patient experienced a severe relapse of Crohn’s symptoms due to lack of steroid therapy compliance.
She again achieved remission after starting treatment with adalimumab, a biological therapy approved for inflammatory bowel diseases that is sold under the brand name Humira, among others.
Notably, shortly after initiating treatment with adalimumab, therapeutic levels of Soliris in the bloodstream were reached with stable 1,200 mg doses every two weeks.
Soliris’ use continued until her blood creatinine and urine protein levels dropped to a normal range, and her kidneys stabilized. After that, supportive transfusions and plasma exchange were stopped.
Genetic analysis revealed she carried a previously unreported mutation that was predicted to be likely disease-causing. She also carried two other aHUS-related genetic risk factors. These same three genetic signatures were found in her twin brother and mother. Despite these findings, the family had no recorded history of aHUS.
“In conclusion, Crohn’s disease can be one of the possible causes of secondary aHUS in children,” the scientists wrote. “In aHUS cases secondary to [Crohn’s disease], close monitoring of both complement inhibition and serum [Soliris] levels is needed as intestinal disease can interfere with complement-blocking treatment.”