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:
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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. Definition of relapsed and refractory disease: 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. IDefinition of relapsed and refractory disease: ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: use of glucocorticoids and one or more immunomodulatory drugs for more than 6 months, including antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, and tetanuscept;
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:
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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. Subjects with active or suspected fungal, bacterial, viral, or other infections that are uncontrolled or require treatment; 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. SSubjects 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; subjects with positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; subjects with positive human immunodeficiency virus (HIV) antibodies; subjects with positive for syphili; 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.
