Bone abnormalities reported in 2 aHUS patients on long-term Soliris
Doctors unsure if 'peculiar skeletal impairment' is due to Soliris or FH deficiency
Bone abnormalities were reported in two teenage girls who were on long-term treatment with Soliris (eculizumab) for atypical hemolytic uremic syndrome (aHUS) associated with a deficiency of the complement factor H (FH).
Clinicians are unsure whether these previously undescribed bone abnormalities, including pain, deformities, and joint swelling, were a side effect of maintenance Soliris treatment or a rare consequence of FH deficiency.
“The data presented here are still too preliminary to formally conclude that [Soliris] could induce bone lesions, but long-term monitoring seems necessary, especially since France was one of the first countries in the world to have routine access to [Soliris],” researchers wrote.
The study, “Bone impairment in atypical hemolytic and uremic syndrome treated by long-term eculizumab,” was published in Pediatric Nephrology.
aHUS is a rare disease marked by red blood cell destruction, low platelet counts, and blood clots in small blood vessels that damage internal organs, particularly the kidneys.
Genetic mutations that interfere with factor H production are present in 20% to 30% of aHUS patients. While these and other mutations in genes coding for components of the immune complement cascade are known risk factors for aHUS, other factors are typically needed to trigger the disease.
Soliris designed to suppress complement cascade
AstraZeneca’s Soliris is an infusion therapy approved in the U.S. and European Union in 2011 to manage aHUS in children and adults. It is designed to suppress the complement cascade, which is overactive in the disease, by blocking a complement protein called C5.
However, “due to the rarity of the disease and the relatively recent approval, its long-term effects, if any, remain to be described,” the researchers wrote.
In the report, a team of researchers in France described what they called a “peculiar bone impairment” in two young girls with FH deficiency-related aHUS and who were on long-term Soliris treatment.
The first case was a 13-year-old girl with a known disease-causing genetic mutation that leads to the production of a nonworking FH. She was diagnosed at 2 months of age, had mild kidney disease, and was on Soliris since she was 1.5 years old, “with several unsuccessful withdrawal attempts,” the team wrote.
Around puberty, she developed bone and joint pain, with stiffness and deformities of her ankles, knees, wrists, and elbows. Imaging scans revealed osteochondritis, a condition marked by the death of bone tissue underneath a joint cartilage due to lack of blood flow.
During ankle and elbow surgery, clinicians took samples of her healthy and damaged bones. While the biopsy samples had no signs of aHUS-related blood vessel abnormalities, they showed increased bone formation as well as many areas of bone reabsorption, indicative of increased bone turnover.
Both healthy and diseased bone samples also showed a significant buildup of C3c, a complement component that may accumulate when C5 is blocked, possibly indicating a potential side effect of Soliris.
The girl’s symptoms stabilized at the end of puberty.
The second case was an 11-year-old girl, who also carried a genetic mutation resulting in FH deficiency. She was diagnosed at 11 days old, with kidney and heart failure. She began Soliris treatment around 3 weeks of age and continued treatment as maintenance therapy.
Noninflammatory joint pain in ankles, knees, wrists, with joint swelling
Similar to the first case, around puberty, she developed noninflammatory joint pain in her ankles, knees, and wrists, with joint swelling. However, she did not have any bone deformity or stiffness.
Further bone tests revealed low bone mineral density in her lower spine and upper leg bones, and abnormal blood flow, particularly in her left foot and right hand.
“A multi-disciplinary evaluation did not find any other cause for this bone [profile], which is intriguing and could be secondary to aHUS,” the researchers wrote.
The role of the complement cascade in bone formation and growth suggests aHUS-related dysregulation of these immune proteins could lead to bone abnormalities, particularly at the peak of bone formation during puberty. Also, mice lacking FH have bone abnormalities that “may correspond to those observed in the patient’s biopsy,” the team wrote.
Still, “our results are too preliminary to know whether [this new bone profile] is secondary to [Soliris] … [or] inherent in the FH deficiency itself,” the researchers wrote.
As no other cases were identified in France, “a European survey on the topic will be of interest to identify other cases and better understand the underlying [mechanisms] of this peculiar skeletal impairment in aHUS,” the team concluded.
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