| Eligibility |
Common inclusion criteria:
1. Age: = 18 years old and = 65 years old, male or female;
2. The functions of important organs meet the following requirements:
1. Bone marrow hematopoietic function needs to meet: a. White blood cell count = 3 x
10^9/L b. Neutrophil count = 1 x 10^9/L (no colony-stimulating factor treatment within
2 weeks before examination); c. Hemoglobin =60g/L;
2. Liver function:ALT = 3 x ULN,AST=3 x ULN, TBIL=1.5 x ULN(excluding Gilbert syndrome,
total bilirubin = 3.0 x ULN) (No requirements for conditions caused by the disease
itself);
3. Renal function: creatinine clearance rate (CrCl) = 60 ml/minute(Cockcroft/Fault
formula);
4. Coagulation function: International standardized ratio (INR) < 1.5 x ULN,prothrombin
time(PT) < 1.5 x ULN;
5. Cardiac function: Good hemodynamic stability. 3. Female subjects of childbearing
potential and male subjects whose partner is a female of childbearing potential are
required to use medically approved contraception or abstain from sex for at least 6
months during and at least 6 months after the end of the study treatment period;
female subjects of childbearing potential have had a negative serum HCG test within 7
days prior to study enrollment and are not lactating; 4. Voluntarily participate in
this clinical study, sign an informed consent form, have good compliance, and
cooperate with follow-up.
Inclusion Criteria for Relapsing refractory dry syndrome:
1. Meets 2002 AECG criteria or 2016 ACR/EULAR classification criteria for primary dry
syndrome (pSS);
2. Definition of disease activity: investigator-assessed disease ESSDAI score of 5 or
higher;
3. Ineffective conventional treatment or relapse of disease activity after remission.
Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and
cyclophosphamide, as well as any of the following immunomodulatory drugs for more than
6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine,
mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab
and tetracycline;
Inclusion criteria for Systemic Sclerosis:
1. Meets 2013 ACR classification criteria for systemic sclerosis;
2. If combined with interstitial pneumonia, interstitial changes suggestive of
ground-glass exudates on chest HRCT and FVC or DLCO <70% predictive value on pulmonary
function tests;
3. Ineffective conventional treatment or relapse of disease activity after remission.
Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and
cyclophosphamide, as well as any of the following immunomodulatory drugs for more than
6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine,
mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab
and tetracycline;
4. Definition of progressiveness; 1) Definition of cutaneous progression: increase in
mRSS >10%; 2) Definition of lung disease progression: 10% decrease in FVC or 5%
decrease in FVC with 15% decrease in DLCO (OMERACT progression).
Inclusion criteria for Recurrent refractory idiopathic inflammatory myopathy:
1. Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR
(including DM, PM, ASS, and NM);
2. For those with muscle involvement, the MMT-8 score is lower than 142 and at least two
abnormalities are found in the following five core measurements (PhGA, PtGA, or
extramuscular disease activity score = 2 points; total HAQ score = 0.25; muscle enzyme
levels are 1.5 times the upper limit of the normal range);
3. Positive myositis antibodies;
4. Ineffective conventional treatment or relapse of disease activity after remission.
Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and
cyclophosphamide, as well as any of the following immunomodulatory drugs for more than
6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine,
mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab
and tetracycline.
Inclusion criteria for relapsing refractory rheumatoid arthritis:
1. Meets the diagnostic criteria of the 2010 ACR/EULAR classification. Diagnosis of
moderately or severely active rheumatoid arthritis with a previous diagnosis of
rheumatoid arthritis = 6 months;
2. A swollen joint count of = 6 (based on 66 joint counts) and a tender joint count of =
6 (based on 68 joint counts) during the Screening Period;
3. C-reactive protein (CRP) = 10 mg/L or erythrocyte sedimentation rate (ESR) = 28 mm/h
during the Screening Period;
4. EULAR definition of refractory rheumatoid arthritis:
1. Failure of treatment according to EULAR recommended guidelines and failure of
treatment with =2 b/tsDMARDs despite failure of treatment with csDMARDs. (i) unless
treatment with bDMARDs/tsDMARDs is limited due to socioeconomic factors; and (ii) if
treatment with csDMARDs is contraindicated, then failure of treatment with =2
b/tsDMARDs of different mechanisms also fulfills the condition);
2. Symptom management of RA is considered problematic by both the patient and the
physician;
3. Signs suggestive of active or progressive disease if at least 1 of the following 5
items is met
1. At least moderate disease activity (DAS28-ESR >3.2 or CDAI >10);
2. Signs and/or symptoms suggestive of active disease;
3. Inability to reduce glucocorticoids to less than 7.5 mg/day prednisone or
equivalent;
4. Rapid imaging progression (1-year increase of =5 points in van der Heijde
modified Sharp score);
5. Decreased quality of life due to RA, although RA is well controlled;
6. Refractory rheumatoid arthritis is diagnosed if three of the above criteria are
met.
Common exclusion criteria:
1. Subjects with known severe allergic reactions, hypersensitivity, contraindication to any
medications during the trial (cyclophosphamide, fludarabine, tozumabs), or subjects with a
history of severe allergic reactions; 2. Existence or suspicion of uncontrollable or
treatable fungal, bacterial, viral or other infections; 3. Subjects with central nervous
system disorders due to autoimmune diseases or non-autoimmune diseases(including epilepsy,
psychosis, organic encephalopathy syndromes, cerebrovascular accidents, encephalitis,
central nervous system vasculitis); 4. Subjects with relatively serious heart diseases,
such as angina pectoris, myocardial infarction, heart failure, and arrhythmia; 5. Subjects
with congenital immunodeficiency diseases; 6. Subjects with malignant tumors (except for
non-melanoma skin cancer and in situ cervical, bladder, and breast cancers that have been
disease-free for more than 5 years); 7. Subjects with end-stage renal failure; 8. Subjects
with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and
HBV DNA titer in peripheral blood higher than the upper limit of detection; Patients with
positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; People
who are positive for human immunodeficiency virus (HIV) antibodies; Those who have tested
positive for syphilis; 9. Subjects with mental illness and severe cognitive impairment; 10.
Subjects who have received other clinical trial treatment within 3 months; 11. Pregnant or
intending to conceive women; 12. In the opinion of the investigator, there are other
reasons why subjects cannot be included in this study.
Exclusion criteria for relapsing refractory dry syndrome:
1. Combined cirrhosis of the liver;
2. Combination of aplastic anemia (AA), myelodysplastic syndrome (MDS), or other
myeloproliferative disease (MPD).
Exclusion criteria for recurrent refractory idiopathic inflammatory myopathies:
1. Drug-induced myositis;
2. Inclusion body myositis;
3. Tumor-associated myositis (myositis occurring within 2 years of tumor diagnosis).
Exclusion criteria for relapsed refractory rheumatoid arthritis:
Functional status of rheumatoid arthritis graded at level 4 according to ACR.
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