Case Report

European Journal of Inflammation

Volume 22: 1–6
A 63-year-old Chinese female with mixed © The Author(s) 2024
Article reuse guidelines:
connective tissue disease who suffered from sagepub.com/journals-permissions
DOI: 10.1177/1721727X241249392
journals.sagepub.com/home/eji
renal crisis

Jiasheng Shao1,2 , Jiayan Liu1, Qiang Guo3 and Liou Cao4

Abstract
Mixed connective tissue disease (MCTD) is a rare autoimmune disorder. We present a case of a Chinese female who has
been admitted to our hospital on eight separate occasions. Her initial symptoms involved internal organs including the lung
and heart. Due to the presence of anti-U1RNP antibodies and other clinical features, a diagnosis of MCTD was considered.
Throughout her first to seventh admissions, her serum creatinine levels remained normal. During her eighth hospital-
ization, her renal function deteriorated rapidly, culminating in renal crisis. Chest computed tomography (CT) confirmed
pulmonary edema, necessitating hemodialysis. Her interleukin (IL)-6 level increased significantly during throughout
hospitalizations. The patient responded well to treatment with an IL-6 receptor antagonist (IL-6RA). This case raises the
question of whether IL-6 could serve as a potential biomarker for predicting renal crisis incidence in MCTD patients, a topic
warranting further investigation in the future.

Keywords
mixed connective tissue disease, renal crisis, interleukin-6, interleukin-6 receptor antagonist

Date received: 18 October 2023; accepted: 8 April 2024 1

Department of Immunology and Rheumatology, Jiading District Central
Hospital Affiliated Shanghai University of Medicine & Health Sciences,
Shanghai, China
2
Department of Comparative Pathology, Tulane National Primate
Introduction Research Center, Tulane University School of Medicine, Covington,
LA, USA
Mixed connective tissue disease (MCTD) is an uncommon 3
Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong
autoimmune disease that shares clinically relevance with University School of Medicine, Shanghai, China
4
several other connective tissue diseases. Its diagnosis Department of Nephrology, Molecular Cell Laboratory for Kidney
primarily relies on the presence of high titers of an antibody Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis
and Treatment Center, Renji Hospital, Shanghai Jiao Tong University
to the U1 ribonucleoprotein (U1 RNP).1 However, Renal
School of Medicine, Shanghai, China
crises are exceptionally rare in patients with MCTD.2 In
this case study, we presented a clinical case of MCTD with Corresponding authors:
a renal crisis. Qiang Guo, Department of Rheumatology, Renji Hospital, Shanghai Jiao
Tong University School of Medicine,145 Shan Dong Road (Middle),
Shanghai 200001, China.
Email: [email protected]
Case report Liou Cao, Department of Nephrology, Molecular Cell Laboratory for
A 63-year-old female patient has been experiencing Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia
Diagnosis and Treatment Center, Renji Hospital, Shanghai Jiao Tong
symptoms including cough, dry mouth/eyes, shortness of University School of Medicine, Shan Dong Road (Middle), Shanghai
breath and Raynaud’s phenomenon (RP) for 2 years, which 200127, China.
initially went unnoticed. On October 1, 2021, she noticed Email: [email protected]

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the
SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 European Journal of Inflammation

that these symptoms were worsening. Her left index fin- Table 1. Laboratory data and autoantibodies of the patient were
ger’s skin turned black, and the discoloration began to summarized.
extend to all her fingers and her right toes. Additionally, her Investigation (unit) Result
body temperature reached as high as 38.0°C, and her
C-reactive protein was 52 mg/L (reference range, 0–8). Respiratory virusesa
Consequently, the patient was hospitalized. Her laboratory HIV-1/2
findings and autoantibodies were shown in Table 1. A chest T-spot
computerized tomography (CT) scan indicated both lungs Coombs’s test
had scattered with diffuse airspace opacities and ANA titer 1:1000 (granular pattern)
honeycomb-like lesion, especially in the mid- and lower Anti-CCP
lobes (Figure 1A); doppler echocardiography showed an Anti-U1-nRNP 1:1600
estimated pulmonary artery pressure of 60 mmHg. Anti-smith
She was diagnosed with MCTD, pneumonia, interstitial Anti-SSA (Ro) +
Anti-SSB(La)
lung disease (ILD), vasculitis and pulmonary artery hy-
p-ANCA ±
pertension (PAH). We administered methylprednisolone at
c-ANCA +
a daily dose of 40 mg intravenously for 12 days and
Anti-golgi
changed to prednisone 30 mg/day by mouth. She under-
Anti-LKM
went a 14-day course of intravenous antibiotics for lung Anti-PCNA
infection (Cefoperazone-Sulbactam) to address possible Anti-mitochondrial Ab-M2
hospital-acquired pneumonia (HAP). Aspirin for preven- Anti-mitochondrion
tion of platelet aggregation was also initiated because the Anti-β2 GP1(IgA/IgG/IgM)
patient’s platelet aggregation rate was tested and it was anti-Scl-70
found beyond normal limit, fluctuating between 26% and Anti-dsDNA
40% (reference limit: 10%–25%). On Nov. 1, 2021, she Anti-Pm/Scl
received an initial intravenous dose of 0.8 g of cyclo- Anti-Jo-1
phosphamide (CTX) to suppress autoimmune reactions and Anti-centromere
treat ILD. Pirfenidone, at a dose of 0.2 g, was administered anti-Cardiolipin (IgA/IgG/IgM)
three times daily for antifibrosis. Ambrisentan was pre- Anti-MPO +
scribed to improve PAH, and she was also given Anti-PR3
phosphodiesterase-5 (PDE-5) inhibitors-sildenafil at Anti-smooth muscle
25 mg, three times/day, along with nifedipine at 30 mg/day Anti-nucleosome
to improve Raynaud’s phenomenon.3,4 Hydroxy- Anti-histone
chloroquine at 0.2 g twice/day for immune modulation. She Anti-ribosomal P protein
was discharged after her blood pressure (BP) became RF +
within normal limits and her symptoms were less signif- RNP-III
icant. Her post-discharge medications included prednisone HIV: human immunodeficiency virus; T-spot: Interferon Gamma Release
at 30 mg/day, tapered by 5 mg every week, with a Assays; CCP: cyclic citrullinated peptides; LKM: liver and kidney micro-
maintenance dose of 10 mg, pirfenidone at 0.6 g/day, some; MPO: myeloperoxidase; PR3: proteinase 3; dsDNA: double-
stranded deoxyribonucleic acid (DNA); Scl: scleroderma; p-ANCA:
ambrisentan at 5 mg/day, nifedipine at 30 mg/day, sildenafil perinuclear anti-neutrophil cytoplasmic antibodies; c-ANCA: cytoplasmic
at 25 mg, three times a day, and at aspirin 75 mg/day. anti-neutrophil cytoplasmic antibodies; PCNA: proliferating cell nuclear
From December 25, 2021, to September 20, 2022, the antigen; GP: glycoprotein; RF: rheumatoid factor, RNP-III: RNA poly-
patient was admitted to the hospital 5 times for CTX, with a merase III.
a
Severe acute respiratory syndrome coronavirus-2 (Covid-19), Influenza
total of 4.8 g administered on the following dates: Jan. 6, A, B virus, Syncytial virus, Coxsackie virus were tested by Real-time
2022; March 4, 2022; April 9, 2022; May 9, 2022; and July polymerase chain reaction (RT-PCR) from nasopharyngeal swab.
20, 2022. After the administration of CTX, we attempted to
switch to azathioprine (AZA), cyclosporine (CsA), and
mycophenolate mofetil (MMF) for immunosuppressive 14: 443.26 umol/L; Day 18: 515.31 umol/L; Day 21:
therapy, but had to discontinue them due to nausea and 547.69 umol/L; Day 24: 601.1 umol/L). 5 days after
vomiting. admission, the patient’s BP abruptly increased (peaking
On Dec. 22, 2022, the patient was admitted for the 8th as high as 182/104 mmHg), at which point renal crisis
time due to worsening of orthopnea and dyspnea. During related to MCTD was considered. She was started on
this hospitalization, her renal function deteriorated (Day furosemide and isosorbide mononitrate intravenously for
1: serum creatinine 147.39 umol/L, reference range of controlling BP as captopril (50 mg three times per day)
46–92; Day 6: 217.37 umol/L; Day 10: 357 umol/L; Day proved ineffective. After her BP normalized, a renal
Shao et al. 3

biopsy was performed. Following consultation with a Discussion

nephrologist in our hospital, she was treated with he-
MCTD is a mild overlapping complex of at least two of the
modialysis due to deteriorating kidney function and
following three connective tissue diseases including sys-
diffuse alveolar edema (Figure 1B). Given the elevated
temic sclerosis, systemic lupus erythematosus (SLE), and
Interleukin-6 (IL-6) levels in her blood, she was ad-
polymyositis. It generally results in a good clinical out-
ministered an IL-6 receptor antagonist (IL-6RA) at a come, requiring low-dose of corticosteroid.5 Its initial
dose of 8 mg/kg every 4 weeks to inhibit the systemic clinical features are nonspecific, classifying it as an un-
inflammatory responses. Her serum creatinine and IL-6 deferential connective tissue disease (UCTD).6 The pres-
levels returned to normal 1 week later and she was ence of the anti-U1-ribonucleoprotein (anti-U1-RNP)
discharged after her clinical symptoms and signs sub- antibodies is considered a hallmark of the disease and most
sided. Her condition remained stable during 1- and 2- MCTD patients exhibiting high titer of anti-U1-RNP and
month follow-up assessment by Chest CTs (Figure 1C RP appear not correlate with nephropathy.7,8 An animal
and D). Dynamic changes of laboratory studies during experiment demonstrates that the immunization of mice
hospitalizations for the patient and renal pathology were with RNP antigen induced anti-RNP antibodies and MCTD
indicated in Figures 2A–F, 3A–C, respectively. clinical features, particularly ILD but not kidney disease.9

Figure 1. Dynamic changes of chest computed tomography (CT). (A). Chest CT conducted on Oct. 10, 2021, during the 1st admission.
(B). Chest CT conducted on Jan. 22, 2023, during the 8th admission (Chest CT that indicated bilateral pulmonary infiltrates, most
notable in the whole lung fields with alveolar edema). (C). Chest CT conducted on March 22, 2023, during 1st follow-up. (D). Chest CT
conducted on April 24, 2023, during 2nd follow-up.

Figure 2. Dynamic changes of laboratory findings during hospitalizations for the patient. IL: interleukin; TNF: tumor necrosis factor;
IFN: interferon; Scr: serum creatinine; BUN: blood urea nitrogen; e-GFR: estimated glomerular filtration rate; RBC: red blood cell;
WBC: white blood cell; Hb: hemoglobin; PLT: platelet; CRP: C reactive protein; ESR: erythrocyte sedimentation rate; Ig:
immunoglobulin; C: compliment; BNP: B-type natriuretic peptide; PAP: pulmonary artery pressure.
4 European Journal of Inflammation

Figure 3. Kidney biopsy. Renal biopsy findings: (A) (Periodic-acid Schiff staining, ×400). (B) (Periodic acid-silver methenamine
staining, ×400). 12 glomeruli were found. Most glomerular mesangial cells and stroma are slightly increased, with a few glomeruli
showing segmental capillary hyperplasia, and some glomeruli showing segmental double-track sign. The capillary loops of each
glomerulus are rigid. Mild tubulointerstitial lesions, focal atrophy and degeneration of tubules, visible protein tubular type, interstitial
inflammatory fibrosis, small blood vessels ( ). Immunofluorescent stain indicated IgG+, IgA , IgM±, C3++, C1q+, κ±, λ+. Electronic
microscope findings: The endothelial cells of capillaries are slightly swollen; the capillary loops are open and a few loops contain
monocytes and neutrophils. There was no significant proliferation of epithelial cells in the wall layer of the renal capsule. Basement
membrane: Most of them have no obvious thickening, and a few segments have slight irregular thickening, with a thickness of about
550 nm at the thickening point, resulting in segmental wrinkling. Podocytes: Swelling, vacuolar degeneration and zebra corpuscles can be
seen in individual podocytes. Lymphocytes, monocytes, plasma cells can be observed in the focal renal interstitium.

To the best of our knowledge, the majority of reported and stroma slightly increased, some glomeruli showing
MCTD cases with renal crisis have been among individuals segmental double-track sign. Electronic microscope indi-
of Caucasians and Hispanics descent.10,11 In this case re- cated the swollen endothelial cells of capillaries and
port, we presented the first instance of a Chinese female electron-dense deposits in the subepithelial and endothelial
patient with MCTD experiencing renal crisis, which was space, immunofluorescent stain also revealed some im-
reversed by using IL-6RA. Notably, a prior study showed that mune deposits, findings may suggest the presence of im-
increased and fluctuating levels of IL-10 or TNF-a do not mune complex glomerulonephritis other than renal crisis.
correlate with disease activity in patients with MCTD.12 Farhey et al., considered that renal involvement in patients
However, We observed the serum level of IL-6 for the pa- with MCTD can be in the form of proliferative glomeru-
tient was escalating throughout the treatment course, where lonephritis, membranous glomerulonephritis, amyloidosis
even CTX and prednisone were administered. This intriguing or interstitial nephritis.13 Abdul Mabood Khalil et al. re-
finding raises the question of whether IL-6 could potentially ported a case with MCTD who suffered from renal crisis,
serve as a biomarker for predicting the occurrence of renal the renal biopsy showed onion skin-like vasculopathic
crisis and assessing their prognosis in MCTD patients. Further changes with ischemic wrinkling of glomeruli,10 which
investigations will be necessary to explore this possibility and result from fibro-intimal sclerosis with adventitial fibrosis,
elucidate its clinical implications. develop later in the course of renal crisis. When the disease
The kidney biopsy findings in the case indicated twelve reaches chronic stages, glomerular changes can vary from
glomeruli were found with most glomerular mesangial cells double contour and tram tracking to ischemic glomerular
Shao et al. 5

collapse,14 which is similar to kidney biopsy findings in Ethical statement

lupus nephritis. However, Cheta et al. reported a MCTD Ethical approval
female case with renal crisis. Her renal biopsy indicated
nine available glomeruli with rare intraglomerular thrombi, The study was conducted in accordance with the Declaration of
moderately thickened vessels without onion skinning Helsinki, and approved by the Ethics Committee of Jiading
proliferation.15 District Central Hospital Affiliated Shanghai University of
Medicine & Health Sciences (Ethics approval number: 2023K05).
All information about the patient was anonymized.

Conclusion Informed consent

We reported the case of a Chinese female patient with Written informed consent was obtained from the patient prior to
MCTD who developed a renal crisis and responded well to study initiation and we also had obtained the necessary consent to
IL-6RA treatment. This case should remind clinicians to publish patient information.
consider the possibility of using IL-6 could as a potential
biomarker for predicting renal crisis incidence in MCTD ORCID iD
patients. Early interventions with IL-6RA should be con-
Jiasheng Shao  https://orcid.org/0000-0001-6345-5350
sidered upon detecting elevated IL-6 levels to prevent the
occurrence of renal crises. It is advisable to recommend
renal biopsy for patients with MCTD if their kidney References
function deteriorates, as this may be manifested by various 1. Ferrara CA, La Rocca G, Ielo G, et al. Towards early di-
forms of pathological profiles. agnosis of mixed connective tissue disease: updated per-
spectives. ImmunoTargets Ther 2023; 12: 79–89.
2. Madieh J, Khamayseh I, Hrizat A, et al. Scleroderma renal
Acknowledgements
crisis in a case of mixed connective tissue disease treated
We thank the patient involved in the study and her family. We also successfully with angiotensin-converting enzyme inhibitors.
thank Min Dai, Limin Tan, Manxiang Wang, Guanghui Li for Case Rep Nephrol 2021; 2021: 8862405.
their medical advices and consultations. 3. Maltez N, Maxwell LJ, Rirash F, et al. Phosphodiesterase
5 inhibitors (PDE5i) for the treatment of Raynaud’s phe-
Author contributions nomenon. Cochrane Database Syst Rev 2023; 11(11):
CD014089.
Conceptualization, Jiasheng Shao, Liou Cao; Methodology, Jia-
4. Wigley FM. Treatment of Raynaud phenomenon: initial
sheng Shao; Software, Jiayan Liu; Formal analysis, Jiasheng
management. Waltham, MA: UpToDate, 2023.
Shao, Liou Cao, Qiang Guo; Resources, Liou Cao, Qiang Guo;
5. Ciang NC, Pereira N and Isenberg DA. Mixed connective
Data curation, Jiasheng Shao, Jiayan Liu; Writing-original draft
tissue disease-enigma variations? Rheumatology 2017;
preparation, Jiasheng Shao; Writing-review and editing, Jiasheng
56(3): 326–333.
Shao, Liou Cao; Supervision, Liou Cao, Qiang Guo; Funding
6. Pepmueller PH. Undifferentiated connective tissue disease,
acquisition, Liou Cao, Qiang Guo. All authors have read and
mixed connective tissue disease, and overlap syndromes in
agreed to the published version of the manuscript.
rheumatology. Mo Med 2016; 113(2): 136–140.
7. Kitridou RC, Akmal M, Turkel SB, et al. Renal involvement
Declaration of conflicting interests in mixed connective tissue disease: a longitudinal clinico-
The author(s) declared no potential conflicts of interest with pathologic study. Semin Arthritis Rheum 1986; 16(2):
respect to the research, authorship, and/or publication of this 135–145.
article. 8. Tanaka Y, Kuwana M, Fujii T, et al. 2019 diagnostic criteria
for mixed connective tissue disease (MCTD): from the Japan
research committee of the ministry of health, labor, and
Funding welfare for systemic autoimmune diseases. Mod Rheumatol.
The author(s) disclosed receipt of the following financial 2021;31(1):29-33.
support for the research, authorship, and/or publication of this 9. Greidinger EL, Zang Y, Jaimes K, et al. A murine model of
article: This work was supported by Shanghai University of mixed connective tissue disease induced with U1 small
Medicine and Health Sciences Clinical Research Centre for nuclear RNP autoantigen. Arthritis Rheum 2006; 54(2):
Metabolic Vascular Diseases Project (20MC2020004), the 661–669.
Science and Technology Commission of Jiading District 10. Abdul Mabood Khalil M, Iftikhar N, Hussain SA, et al.
(Grant No. JDKW-2021-0022) and Jiading District Central Scleroderma renal crisis in a newly diagnosed mixed con-
Hospital Project (YJKT202101). nective tissue disease resulting in dialysis-dependent chronic
6 European Journal of Inflammation

kidney disease despite angiotensin-converting enzyme in- 13. Farhey Y and Hess EV. Mixed connective tissue disease.
hibition. CEN Case Rep 2013; 2(1): 41–45. Arthritis Care Res 1997; 10(5): 333–342.
11. Chaigne B, Scire CA, Talarico R, et al. Mixed connective 14. Batal I, Domsic RT, Medsger TA, et al. Scleroderma renal
tissue disease: state of the art on clinical practice guidelines. crisis: a pathology perspective. Internet J Rheumatol 2010;
RMD Open 2018; 4(Suppl 1): e000783. 2010: 543704.
12. Hassan AB, Gunnarsson I, Karlsson G, et al. Longitudinal 15. Cheta J, Rijhwani S and Rust H. Scleroderma renal crisis in
study of interleukin-10, tumor necrosis factor-alpha, anti-U1- mixed connective tissue disease with full renal recovery within
snRNP antibody levels and disease activity in patients with 3 Months: a case report with expanding treatment modalities to
mixed connective tissue disease. Scand J Rheumatol 2001; treat each clinical sign as an independent entity. J Investig Med
30(5): 282–289. High Impact Case Rep 2017; 5(4): 2324709617734012.