Cyclophosphamide in the Treatment of Panniculitis Associated Acquired Lipodystrophy Syndrome With Type 1 Diabetes
Phase: NA
Conditions: Lipodystrophy Acquired, Type1diabetes
Sponsor: Children's Hospital of Fudan University

 
 
 
 
 
 
 
Cyclophosphamide in the Treatment of  
Panniculitis Associated Acquired Lipodystrophy Syndrome 
With Type 1 Diabetes 
2019-04-09 
 
 
 

Background 
Lipodystrophy Syndrome is a kind of rare metabolic diseases with a global incidence 
of about 3.07/1,000,000. Patients with lipodystrophy syndrome often have severe 
metabolic syndrome in childhood, which affects the life span and quality of life of 
patients. However, there is no effective treatment for curing this disease at home and 
abroad. 
Panniculitis associated acquired lipodystrophy syndrome leads to severe insulin 
resistance 
Lipodystrophy syndrome is a class of rare metabolic diseases in which there is 
generalized or localized subcutaneous fat deficiency without the absence of nutrients 
or catabolism. Patients with lipodystrophy syndrome are clinically characterized by 
enormous appetite and severe metabolic disorders, including hyperinsulinemia, 
hyperlipidemia, nonalcoholic fatty liver and cirrhosis, and high metabolic rate. 
Insulin resistance is the major feature of lipodystrophy syndrome. Low leptin levels due 
to loss of subcutaneous fat, increased expression of tumor necrosis factor 1 in immature 
adipose tissue, increased levels of free fatty acids in the blood, and deposition of fat in 
the liver and muscle lead to severe insulin resistance and diabetes in patients with 
lipodystrophy syndrome. One study suggested that approximately 70% of patients with 
acquired systemic dystrophy syndrome develop diabetes during the course of the 
disease. Due to early onset, long course of disease, and difficulty in correcting 
metabolic disorders, these patients have early cardiovascular events, especially the high 
risk of developing atherosclerotic cardiovascular disease, which seriously affects the 

life and quality of life of patients. There is currently no effective method for curing 
lipodystrophy syndrome. Patients can only follow blood glucose, blood lipids and 
related complications regularly, and manage blood lipids and blood glucose and 
increase insulin sensitivity through lipid-lowering drugs, metformin, and 
thiazolidinediones as those with hyperlipidemia and diabetes. 
Autoimmune factors may be the common cause of panniculitis associated acquired 
lipodystrophy syndrome and type 1 diabetes 
Acquired lipodystrophy syndrome often onsets in childhood or adulthood and has a 
complex cause. In addition to HIV or drugs associated acquired fatty dystrophy 
syndrome, autoimmune factor is considered to be the leading cause of acquired 
lipodystrophy syndrome. Some patients with acquired lipodystrophy syndrome have 
positive autoantibodies, and about 67% of patients with acquired lipodystrophy 
syndrome have autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid 
arthritis, and hemolytic anemia. More than 1,141 children have been reported to have 
autoimmune diseases in patients with acquired lipodystrophy syndrome. 
Among the patients with acquired lipodystrophy syndrome, a quarter of patients suffer 
from subcutaneous panniculitis, known as panniculitis associated acquired 
lipodystrophy syndrome. Inflammatory infiltration of subcutaneous adipose tissue is 
also a strong evidence of autoimmune response. 
Type 1 diabetes is a type of diabetes characterized by a lack of insulin secretion. Islet 
beta cells are gradually destroyed by chronic autoimmune processes and eventually lead 
to complete insulin deficiency in a short period of time. Islet autoantibodies such as 

ICA, IAA, GADA, and IA-2A can be detected in patients with type 1 diabetes. 
Patients with lipodystrophy syndrome often have type 2 diabetes due to insulin 
resistance, but cases with type 1 diabetes are rare. Three cases of acquired lipodystrophy 
combined with type 1 diabetes have been reported worldwide. Since the autoimmune 
response plays an important role in both of the pathogenesis of panniculitis associated 
acquired lipodystrophy syndrome and type 1 diabetes, we believe that autoimmune 
factors may be the common cause of these two diseases. 
Patients with panniculitis associated acquired lipodystrophy syndrome and type 1 
diabetes have difficulty in managing glucose metabolism due to suffering from 
insulin deficiency and insulin resistance at the same time 
Patients with acquired lipodystrophy syndrome combined with type 1 diabetes have 
severe insulin resistance and absolute insulin deficiency, thus they need to rely on 
insulin several times of that of other common type 1 diabetes patients to control blood 
sugar, but often still cannot get satisfactory results. What’s more, insulin sensitizing 
drugs such as metformin and thiazolidinediones have limited effects in these patients. 
The recombinant human leptin analog, Metreleptin, is currently the only drug that can 
specifically address the metabolic problems of patients with lipodystrophy syndrome. 
Foreign clinical trials have confirmed that Metreleptin can inhibit appetite, lower blood 
lipid levels, improve glucose metabolism and alleviate nonalcoholic fatty liver disease 
in patients with lipodystrophy syndrome. In patients with acquired lipodystrophy 
syndrome and type 1 diabetes, Metreleptin reduces insulin resistance and reduces 
insulin use in some patients. But Metreleptin is not yet available in China and the cost 

is high. At the same time, about one-third of patients experienced different degrees of 
side effects after receiving Metreleptin injection, including headache, hypoglycemia, 
allergic reactions at the injection site, hair loss, fatigue, and T-cell lymphoma. What’s 
more, one study found that more than 80% of patients treated with Metreleptin 
developed leptin antibodies, which may lead to insensitivity to leptin, resulting in 
reduced efficacy and even treatment failure. This raises questions about the long-term 
efficacy of Metreleptin. 
Cytotoxic drugs may improve the glucose metabolism of patients with acquired 
lipodystrophy syndrome and type 1 diabetes, and may even achieve clinical 
remission 
Cyclophosphamide is a commonly used immunosuppressant in patients with 
autoimmune diseases. It is mature in pediatric use and has controllable adverse 
reactions. It is one of the first choices for children with nephrotic syndrome, systemic 
lupus erythematosus and rheumatoid arthritis. It can also be used in patients with 
autoimmune-associated panniculitis who cannot tolerate glucocorticoids. In view of the 
fact that autoimmune factors may be the common cause of panniculitis associated 
acquired lipodystrophy syndrome and type 1 diabetes, immunomodulatory therapy may 
improve the insulin resistance of these patients from the etiology, reduce the amount of 
insulin to use, and even achieves the effect of preventing disease progression and 
clinical cure. 
 
 

Objectives 
To improve the insulin resistance, reduce the daily dosage of insulin and control the 
blood glucose level of patients with panniculitis associated acquired lipodystrophy 
syndrome, we plan to use cyclophosphamide to inhibit the immune response, prevent 
and alleviate the progression of panniculitis and acquired lipodystrophy syndrome, and 
improves insulin resistance caused by subcutaneous fat deficiency. 
Methods 
Participants 
Volunteers will recruit from patients who are diagnosed panniculitis associated acquired 
lipodystrophy syndrome and T1DM in Children’s Hospital of Fudan University. 
Inclusion Criteria include: 1. Meet the diagnostic criteria of type 1 diabetes mellitus: 
clinical manifestations of typical diabetes mellitus include polyphagia, polyuria, weight 
loss, or diabetic ketoacidosis, confirmed by blood sugar level, islet function and 
autoimmune antibody; 2. Meet the diagnostic criteria for panniculitis: fat biopsy 
suggests inflammatory infiltration. 3. Meet the diagnostic criteria for acquired 
lipodystrophy syndrome: childhood onset, clinically no nutritional deficiency or 
catabolism, systemic or partial subcutaneous fat reduction, genetic testing to exclude 
congenital lipodystrophy syndrome; low leptin level and autoantibodies can aid in 
diagnosis. 
Interventions 
The patient meet the diagnosis of panniculitis associated acquired lipodystrophy 
syndrome and T1DM and was rigorously evaluated and discussed. He had the 

indication for the application of cyclophosphamide and no contraindications, and 
informed and signed the informed consent form. The patient will receive 6 cycles of 
cyclophosphamide treatment. Cyclophosphamide was intravenously instilled (500mg 
mg/m2 of BSA). Each treatment interval is 4 weeks. Patients will be carefully assessed 
for contraindications before each treatment. And the daily insulin usage, fast blood 
glucose level, serum C-peptide level, HbA1c and abdominal subcutaneous fat thickness 
will be measured and recorded after each treatment. When finish the total 6 treatment 
cycles, patients will receive long-term follow-up for 3 years. 
 
Flow chart to illustrate the study 
 
 
 
 
 
 
 
 
 
 
 
 
Participants 
recruitment 
Clinical diagnosis of panniculitis associated acquired lipodystrophy 
syndrome: clinical manifestations, genetic analysis, fat biopsy, 
autoantibody, leptin level, and assessment of systemic fat distribution 
Contraindication assessment: terminating this procedure is patients have 
cyclophosphamide contraindications or mental disorders 
Clinical diagnosis of type 1 diabetes: clinical manifestations, antibody, 
islet function and genetic analysis 
Pre-treatment 
evaluation: 
except 
for 
infections 
and 
other 
contraindications 
Cyclophosphamide 
treatment (6 times) 
Evaluation of insulin resistance and glucose metabolism 
Cyclophosphamide treatment (500mg/m2 BSA) (ECG monitoring and 
infection prevention) 
Re-admission after 4 weeks 
Post-treatment 
assessment 
and 
follow-up 
Outpatient 
follow-up: 
glucose 
metabolism, 
subcutaneous 
fat 
distribution, leptin levels, autoantibodies, organ function 

Adverse reactions: 
1. Infection: There may be infections of various organs, including bacteria, fungi, 
viruses and other pathogens, especially lung infections and intracranial infections, 
which can be life-threatening in severe cases. 
2. Important organ damage: There may be damage to important organs, such as heart, 
liver, kidney, lungs, etc. Some damage may not be fully restored even if the drug is 
stopped. 
3. Myelosuppression: anemia which is difficult to correct; thrombocytopenia, bleeding 
such as mucous membrane bleeding, digestive tract, urinary tract bleeding, intracranial 
hemorrhage and other parts of the bleeding; granulocyte reduction, various serious 
infections, septicemia, shock, etc. 
4. Musculoskeletal and nervous system damage: cause muscle weakness, numbness of 
the limbs, headache, blurred vision, etc; may induce epilepsy. Osteoporosis can cause 
femoral head necrosis and fracture deformation in severe cases. 
5. Gastrointestinal reactions. 
6. Phlebitis. 
7. Reproductive system toxicity. 
8. Drug allergies, anaphylactic shock, etc. 
9. Other unforeseen, unpredictable and precautionary situations: Long-term use 
increases the risk of developing a tumor. 
10. There are other unpredictable risks and adverse reactions and consequences that 
may jeopardize the life of the child. 

Risk assessment and contingency plans 
1. Adverse reactions: Regular assessment of organ function, exclusion of potential 
infections before each dose, bedside equipped call system, ECG monitoring, suction 
device and oxygen. Severe cases can be transferred to the laminar flow ward of the 
Department of Critical Care Medicine. 
2. Ineffective in the treatment of cyclophosphamide: closely monitor blood sugar, 
actively adjust the insulin dose, and rationally use oral hypoglycemic drugs to correct 
the children's metabolic disorders. 
3. Primary disease-related complications: Type 1 diabetes patients may have acute 
complications such as ketoacidosis and chronic complications such as retinopathy and 
peripheral 
neuropathy; 
patients 
with 
lipodystrophy 
syndrome 
often 
have 
hyperlipidemia, polycystic ovary syndrome, non-alcoholic fatty liver and so on. 
Children enrolled will receive regular assessments to screen for the occurrence of 
related complications and receive appropriate treatment. 
 
Quality control measures 
1. Strictly grasp the indications of cyclophosphamide. According to the patient's 
condition, the treatment options and other factors, we can make a comprehensive 
judgment and treat the disease scientifically and rationally. 
2. Perform notification and sign informed consent before the implementation of 
cyclophosphamide treatment. 
3. Strict screening for contraindications prior to treatment with cyclophosphamide. 

4. Establish a follow-up system after cyclophosphamide treatment. 
5. Strictly implement the national price policy and charge according to regulations.