Long-Term Safety of Intravenous Human Umbilical Cord Blood-Derived Mesenchymal Stem Cell Therapy in Rheumatoid Arthritis: A 5-Year Follow-Up Study

Major Points and Findings:

Most arthritis studies summarised on this site concern osteoarthritis and injections into the knee. This one concerns rheumatoid arthritis (RA), an autoimmune disease, and the cells were given intravenously. The authors follow nine Korean patients for five years after one infusion of mesenchymal stem cells grown from umbilical cord blood, which they describe as one of the longest follow-up periods available for this therapy in RA.

The study addresses two questions, late safety and the duration of benefit. In these nine people, no cancers, blood clots, opportunistic infections or deaths occurred, and none of the serious events that did occur was judged related to the cells. Disease activity fell sharply by 3 to 6 months, held for about a year, and then drifted back towards where it started. Nine patients with no control group cannot settle either question. The study was funded by the company that makes the cells.

Aim:

To assess the long-term safety of a single intravenous infusion of human umbilical cord blood-derived MSCs (hUCB-MSCs) in RA over five years, with disease activity tracked alongside to give the safety data clinical context.

Methods:

The study is a prospective, observational 5-year extension of the CURE-iv trial (NCT02221258), a phase I, open-label, dose-escalation study at Seoul Metropolitan Government-Seoul National University Boramae Medical Center.

Participants were adults of 18 or over who met the 2010 ACR/EULAR classification criteria for RA and still had at least moderate disease activity (DAS28 above 3.2) despite methotrexate. All nine patients from the phase I trial entered the extension and all nine completed five years.

• Mean age was 57.4 years, 7 of 9 were women, and mean disease duration was 9.5 years
• Rheumatoid factor positive in 6, anti-CCP positive in 4
• All were taking methotrexate (mean 14.2 mg per week), and 7 were taking low-dose oral corticosteroid (mean 3.1 mg prednisolone equivalent per day)
• None had ever received a biologic drug, so these were not the most treatment-resistant patients

Each patient received one intravenous infusion of hUCB-MSCs at one of three dose levels (25 million, 50 million or 100 million cells), with three patients per level. There was no repeat dosing. Afterwards patients received standard care, and changes in anti-rheumatic drugs were recorded.

Assessments: Adverse events (AEs) and serious adverse events (SAEs, by FDA definition) were recorded at 3, 6 and 12 months and then yearly, with physical examination, blood tests and ECG at each visit. Events of special interest were defined in advance: serious infections, opportunistic infections, major adverse cardiovascular events, thromboembolism and malignancy. Whether an event was related to the infusion was judged by the investigating physicians. There was no independent adjudication committee. DAS28 was taken from medical records at baseline, week 4, months 3 and 6 and yearly.

Results:

Adverse events: Every patient had at least one, and 97 events were recorded over five years (37, 30 and 30 across the three dose levels). The most common were:

• Osteoarthritis, 4 patients (44.4%), including all 3 in the highest dose group
• Nasopharyngitis (common cold), 4 patients (44.4%)
• Abdominal pain or discomfort, 3 patients
• Osteopenia or osteoporosis, 3 patients
• Lumbar spinal stenosis, 2 patients, and hypertension, 2 patients

Severe events occurred in 3 patients, one in each dose group. None was life-threatening.

Serious adverse events: Nine SAEs occurred in 5 of 9 patients (55.6%). They were cellulitis, compression fracture, limb deformity, lumbar spinal stenosis, colorectal polyp, diabetes mellitus, sinusitis, meniscus lesion and arthralgia. Six of the nine occurred in the lowest dose group. The investigators judged none to be related to the infusion.

Events of special interest were as follows:

• Serious infection: 1 case of cellulitis needing intravenous antibiotics, more than 12 months after infusion, in a 100 million cell patient who was also taking anti-rheumatic drugs. It resolved.
• Cardiovascular: 1 case of heart failure, years after infusion, in a 100 million cell patient with pre-existing hypertension. It recovered without lasting effects.
• Benign tumours: a benign ovarian tumour (25 million cell group) and a breast adenoma (50 million cell group), both reported three years after infusion.
• There was no malignancy, thromboembolism or opportunistic infection, and there were no deaths.

Blood counts, creatinine, cholesterol and liver tests stayed within the normal range in all patients. One patient had raised triglycerides at 3 months that normalised without treatment, and one had mild eosinophilia at 60 months without symptoms.

Disease activity: Mean DAS28 fell from 4.76 at baseline to 2.24 at 3 months, the lowest point, and improvement was “generally maintained up to 1 year”. Over the following years disease activity “gradually returned toward baseline”. Two of the nine patients (22.2%) had to step up to stronger drugs, one to tocilizumab and one to tofacitinib. Table 1 of the paper gives the baseline DAS28-ESR as 4.53. The results text gives 4.76. The authors do not explain the difference.

Conclusions:

The authors conclude that a single intravenous dose of hUCB-MSCs has an acceptable long-term safety profile in RA, and that because the effect wore off, repeated-dose regimens may be needed for sustained control and would need their own safety evaluation.

They give the following limitations:

• With nine patients, the study had no statistical power to compare dose levels. Both events of special interest fell in the highest dose group, which the authors say must not be read as a dose-response finding. Rare or very late harms also cannot be excluded.
• The design was open-label and single-arm. Without a control group, events caused by the cells cannot be separated from what would be expected anyway in people of this age with RA on these drugs.
• Only one infusion was studied. In their words, “repeated infusions could change the long-term risk profile”.

The disease activity data are uncontrolled and drawn from medical records, so the early improvement cannot be attributed to the cells with confidence. The study was funded by Kangstem Biotech, and one author is the company’s founder.

Background Information:

Biologic and targeted drugs have transformed RA, but the authors note their known risks, namely tuberculosis with TNF inhibitors, hepatitis B with rituximab, shingles with JAK inhibitors, and concern about malignancy with JAK inhibitors. MSCs are being studied because they dampen immune activity by other routes, for example by raising regulatory T cells and lowering Th1 and Th17 cells.

The paper also summarises other RA trials. Autologous bone marrow MSCs lowered Th17 cells at 12 months with no adverse events. Allogeneic adipose MSCs given three times intravenously were acceptable over 6 months, although 3 serious events were reported (a lacunar stroke judged dose-limiting, a peroneal nerve palsy and a fever). Umbilical cord MSCs (40 million cells) combined with standard drugs gave clinical improvement over 3 years with a favourable safety profile.