This critical disease secondary to lupus, the experts' diagnosis and treatment ideas are too incisive!

*For medical professionals only

Fever, abdominal pain, anuria, what kind of wolf?

Written by Gui Zhi

Recently, the "Friendship Rheumatology Big Coffee to Ward Rounds Season 2" held by Beijing Friendship Hospital affiliated to Capital Medical University brought 1 complex case, Dr.
Wang Tianqi from the Department of Rheumatology of Friendship Hospital gave a wonderful sharing of this case, and Professor Zhao Jiuliang of the Department of Rheumatology and Immunology of Peking Union Medical College Hospital and Professor Zhang Yao of the Department of Neurology commented, let's follow the big coffee to learn wonderful diagnosis and treatment ideas~

Medical record data

The patient is a 27-year-old woman, a staff member, with Raynaud's phenomenon in both hands for 1 year, multiple mouth ulcers for half a year, fever and abdominal pain for more than 20 days
.

● Denial of history of hypertension, heart disease, diabetes, cerebrovascular disease;

● Denial of drug or food allergy history; no history of toxic exposure; Born in Shanxi Province, he has lived in Beijing since 2018;

● No epidemic area, history of contact with infected water;

● Denial of smoking or drinking history;

● Unmarried and childless, menarche 15 years old, 5 days of menstruation, 28 days of menstrual cycle, menstrual disorder in the past half year, last menstruation2022.
05.
15
.

● Parents are alive, 3 siblings, no history of
similar diseases, genetic diseases, or infectious diseases.

Figure 1.
History of present illness

After admission, there is still intermittent fever, the highest body temperature is 39.
2 °C, accompanied by chills, no chills, oliguria, oliguria(300-500ml/d), intermittent wheezing, dyspnea, and progressive aggravation
of systemic edema.
A sudden limb twitch and loss of consciousness lasted about 3 minutes and relieved
after static pushing of diazepam.

Physical examination:

T 37.
6°C, P 136 times/min, R 41 times/min, BP 130/88mmHg, clear mind, indifferent expression; Lip rupture, reticulated bruise on the skin of the right upper extremity, and bruising in the right groin; palpable lymphadenopathy in both armpits, groin, neck; bilateral middle and upper lung breath sounds are coarse, a small number of crackles can be heard, and both lower lung breath sounds are low; Heart rate 136 beats per minute, rhythmic; bloating, mid-epigastric tenderness, no rebound tenderness, muscle tension, positive mobile dullness; negative neurological examination; Severe pitting edema
of the limbs and low-hanging parts of the body.

Figure 2.
Patient-mucocutaneous manifestations

Ancillary examinations:

● Blood routine: WBC 19.
43×10 9/L, GR% 80.
2%, HGB 72g/L, PLT 25×10⁹/L, reticulocyte count and proportion are normal;

● Peripheral blood smear: significantly increased fragmented red blood cells, and the proportion of broken red blood cells was 5.
6%;

● Urine sediment: occult blood 3+, protein 2+
.
24h UTP 0.
46g（500ml）
。 Poop routine + OB normal;

● Biochemical total: liver enzymes, cholangiase normal, ALB 23.
2g/L, GLB 44.
4g/L, T-Bil/D-Bil/I-Bil 32.
65/9.
69/22.
96umol/L, Cr 122.
0μmol/L, AMY, LPS normal;

● Muscle enzymes: LDH 553U/L, TNI 0.
36ng/ml, TNT 0.
042ng/ml;

●Coagulation: PT 16.
6s, PTA 52.
5 percent, APTT 43.
6s, FDP 5.
29 g/L, D-Dimer 57.
64 ug/L;

● Cardiac function: NTproBNP 7480.
0pg/ml
.

Inflammatory indicators, infection indicators, and immune indicators can be abnormal

●ESR 23mm/h, CRP 187.
85mg/L, ferritin 396.
1ug/L, PCT 47.
87ng/ml, CA125 517U/ml;

● Chlamydia pneumoniae/Mycoplasma pneumoniae antibody, Aimee B propylene infection project, T-SPOT, fungal G test, CMV, EBV, blood culture were all negative;

● ANA 1:80 (cytoplasm, spot), enzyme-free dsDNA 332.
62IU/ml (normal range< 300IU/ml); Anti-ENA and ANCA are negative, anti-phospholipid antibodies are negative, Coombs are negative;

● C3 40.
9mg/dl、C4 7.
53mg/dl；

● Routine and biochemical findings of pleural ascites transudate, and all others are negative and normal
.

● Chest CT showed that there were multiple lesions in both lungs, considering the possibility of pulmonary edema, excluding pneumonia; bilateral pleural and pericardial effusion, exudation of the subcutaneous fat layer of the chest wall; bilateral multiple clockwork opacities, considering localized pulmonary insufficiency; Benign small nodules
in the upper lobe of the left lung.

● Abdominal pelvic CT plain scan: changes after appendix surgery, diffuse peritoneal exudation signs, blurred posterior edge of the pancreas, thickening of the anterior fascia of the left kidney; Increased density and multiple enlarged lymph nodes in the abdominal cavity and retroperitoneal space, and enlarged lymph nodes in the bilateral inguinal area, considering the possibility of reactive proliferative lymph nodes; The left adrenal gland is full, and the subcutaneous fat layer of the abdominal pelvic wall oozes
.

● Non-contrast head CT scan showed no obvious abnormalities
.

● Echocardiography shows a small effusion of pericardial effusion, slightly thicker pulmonary arteries, and moderate pulmonary hypertension (SPAP 59.
55 mmHg).

● Pathological examination: bone marrow aspiration cells showed granuloreactive hyperplasia, active erythroid hyperplasia, megakaryotic maturation disorder, increased proportion of monocytes, and occasionally hemophagogy
.
Bone marrow biopsy showed active myeloproliferation, megakaryocyte hyperplasia was obvious, platelet production was seen around it, and no lymphoma
was seen.

● Genetic tests showed that ADAMTS13 activity was 16.
82%, and ADAMTS13 inhibitory antibody was negative
.

The diagnosis is clear, but .
.
.

From the medical records, the patient was first diagnosed with systemic lupus erythematosus (SLE), and its fever, mouth ulcers, thrombocytopenia, positive urine protein, decreased C3 and C4, positive anti-dsDNA and suspected seizures all pointed to SLE, and the SLEDAI-2K score was as high as 19 points
.

Secondly, patients with anemia, a large number of broken red blood cells seen in the peripheral blood smear, negative Coombs test, elevated lactate dehydrogenase, elevated indirect bilirubin, decreased platelets, renal damage, and suspected epilepsy, decreased ADAMTS13 activity, and thrombotic microangiopathy (TMA) secondary to SLE were also diagnosed
.
In addition, macrophage activation syndrome must be differentiated, but the patient does not have hypofibrinogen or hypertriglyceridemia, and elevated leukocytes and mildly elevated serum ferritin levels do not support this diagnosis
.

Final diagnosis:

●Systemic lupus erythematosus

Lupus nephritis?

Neuropsychiatric lupus?

Lupus cardiomyopathy

●Thrombotic microangiopathy

●After appendectomy

Treatment has twists and turns

After back-treatment, the patient began to enter the emergency department on May 29, received anti-infection treatment and rehydration therapy, the patient's oliguriatic status did not improve, and the condition of volume overload was further aggravated (hypertension, uncorrectable cardiac insufficiency and edema), and the patient had a seizure on June 1, and was transferred to the ICU
for intensive supportive treatment.
Considering the patient's primary disease, hormonal therapy was given to control the disease, and plasma exchange was given to SLE and TMA
.

Because it was impossible to rule out whether the patient's seizures were lupus encephalopathy, hormonal shock therapy was given, and the patient's body temperature peak decreased after the shock, but the kidney function and platelet decline did not improve
.
After sequential methotolone combined with immunosuppressants, the condition did not improve significantly, and the second hormone shock therapy was launched, this time the patient's body temperature was normal, the anti-dsDNA was normal, and the complement gradually recovered
.
However, platelet improvement was not satisfactory, and cyclophosphamide was discontinued to exclude myelosuppression of cyclophosphamide
.

After 1 week of treatment, the patient had disorientation, memory loss, and significant decrease in tetraglue muscle strength, and head CT and MRI reported cerebral infarction.

After continuing treatment for 2 weeks, the patient's new vision and hearing decreased significantly, the answer was irrelevant, and the fundus examination showed bilateral retinal hemorrhage, so the third hormone shock therapy
was given.
At the same time, plasma exchange, bedside hemofiltration, intermittent transfusion of red blood cells, and platelets also run through the entire treatment process
of patients.

Figure 3.
Main treatment process

During treatment, the patient's anti-dsDNA antibody turned negative, and other indicators changed as follows:

Figure 4.
Changes in platelets, hemoglobin, and complement during treatment

Figure 5.
Changes in lactate dehydrogenase and myocardial enzymes during treatment

Figure 6.
Changes in creatinine during treatment

Figure 7.
Changes in urine output during treatment

In addition, the changes in the patient's head during treatment were as follows, among which there were no abnormal changes on CT seizures on June 1:

■ June 20 cranial CT: bilateral interfrontal patchy slightly low-density opacities;

■ Plain MRI scan of the head on June 23: multiple small infarcts in the center of bilateral frontal, parietal lobes and hemiovale, embolism? thickening of the mucous membrane of the right maxillary sinus;

■ Cranial CT on July 4: Compared with 2022-06-20, the bilateral frontal lobes showed patchy slightly low-density shadows, which were smaller and blurred than before;

Charging time: What kind of monster is TMA secondary to SLE?

TMA is a rare complication of SLE and antiphospholipid syndrome (APS) that can be life-threatening
.
There is no high-level evidence for treatment recommendations for TMA secondary to SLE and APS, and most are case reports and expert opinions
.
However, interventions for such TMAs lack immediate efficacy, and therapies targeting the complement pathway may be a good choice because complement activation plays a key role in the pathogenesis of TMA secondary to SLE ^[1].

In the case series, such patients have a poor response to hormonal and immunosuppressive therapy, and eculizumab is more effective in these patients
.

The big coffees came to comment, and the doctor of the Union said so.
.
.

The patient is a young woman, chronic course, subacute onset, with "fever, abdominal pain, oliguria" as the first manifestation, with non-immune hemolytic anemia and thrombocytopenia
.
In terms of auxiliary examination, positive antinuclear antibodies, increased dsDNA, decreased C3 and C4, and complications such as epilepsy, polyserous effusion, cerebral infarction, and vision and hearing loss can be seen
.
In the treatment, the response to hormone combined with gammabules, immunosuppressants, and plasmapheresis therapy was not good, and it was a difficult and critical rheumatic immune case
.
During the treatment, the patient's kidneys, blood and nerves all recovered temporarily, but subsequent new changes worsened these indicators
.

Professor Zhao Jiuliang, Department of Rheumatology and Immunology of Peking Union Medical College Hospital, believes that returning to the disease itself, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) in TMA are life-threatening critical diseases, which require timely differential diagnosis and early diagnosis and treatment to improve the prognosis
of patients 。 However, for such patients, referring to the consultation opinion of Professor Zhu Tienan of the Department of Hematology of Union Medical College Hospital, it is not necessary to distinguish it as TTP or HUS, because SLE itself is a systemic autoimmune disease that combines multiple complex factors, so it may not be a simple TTP or HUS
for TMA secondary to SLE.
At the same time, combined with the treatment response, although the ADAMTS13 enzyme activity in this patient decreased, suggesting TTP, the response to plasmapheresis therapy was not ideal, and it supported atypical HUS
.
Therefore, such patients may be considered collectively referred to as "lupus-associated TMA.
"
The key to the treatment of these diseases is to initiate plasma exchange as early as possible, rather than necessarily after ADAMTS13-related test results, which may miss the best time
for intervention.

For such patients, the initial snowflake may be just a snowflake, but if the timely intervention is not done, it can cause an unstoppable avalanche disaster
.
Disease has become medicine, chaos has become and then cured, thirst has been pierced through the well, fighting and casting a cone—it's
too late.
Therefore, when patients are at high suspicion of TMA, treatment should be initiated while waiting for the diagnosis, the cascade of disease occurs very quickly, and early intervention may bring unexpected benefits
.

At the same time, such patients have multiple organ involvement, so the etiology is not completely monistic, and may not be a single choice question, but needs to be considered
.
For example, in this case, intestinal edema cannot be determined to be associated with a history of appendicitis, hypoproteinemia, or SLE disease activity, and it is necessary to intensify primary treatment
while fighting infection + correcting hypoalbuminemia.
At the same time, the patient's nervous system has been temporarily improved, and the subsequent exacerbation can be considered whether it is a central nervous system infection, etc.
, not still similar to the initial lupus encephalopathy, and the peripheral nerve symptoms that occur in the later stage of the patient are also unexplained
.
Therefore, etiology analysis is important and multidirectional, taking into account the development of
the disease due to multiple etiologies.

In addition, the patient underwent 3 rounds of hormonal shocks, which are needed to control the primary condition, but severe infection may not be avoidable
.
Patients with acute hematopoietic arrest in late treatment had to be maintained by blood transfusions, and it is not known that the cause of functional arrest is immunosuppressant use, severe infection, or aplastic anemia
.
Therefore, as the course of the patient's disease increases, it is necessary to have a "balanced" cognition, that is, to avoid complications as much as possible when solving the main contradiction, and individualized tightrope walking diagnosis and treatment may be an increasingly easy situation
.
Finally, drugs targeting the complement pathway are currently on the market, but how to use them to achieve the efficacy in case reports is still a big problem
for clinicians.
Professor Zhao Jiuliang believes that early intervention must also provide more benefits
.

Professor Zhang Yao from the Department of Neurology of Union Medical College Hospital commented on the case from the perspective of neurology, and when Professor Zhang Yao and his colleagues evaluated the patient, they found that his later visual changes were more closely related to fundus hemorrhage, and the correlation with optic neuropathy was relatively small, and the cause of his hearing loss is currently unknown, pending ENT related consultation
.
The patient's seizures improved and seizures did not occur
after drug control.
However, in the follow-up treatment, the patient once showed delirium, and the consciousness disorder was progressively aggravated
.
Bedside neurological examination reveals that the patient has eye movement impairment and has a resolution
of consciousness with vitamin supplementation.
After that, even in the conscious state, except for the grasping action of the left hand, the muscle strength of the limbs was almost 0-1, and there was no voluntary activity
.

In addition, the results of multiple lumbar punctures also showed protein-cell separation
.
At the same time, although the MRI of the patient's head showed abnormal infarct foci, the infarct focus was only subcortical white matter, and did not involve the cortex, so it could not explain the patient's consciousness disorder and epilepsy
.
After the patient developed symptoms of delirium, the patient's MRI showed abnormal signals on the dorsal and perimedeal medulla
oblongata.
From the analysis of clinical features such as epilepsy, impaired consciousness and impaired eye movement, the neurology department believes that the patient has extensive cerebral cortex involvement
.
Combined with a history of decreased or even absent tendon reflexes and weakness of the extremities, consider that the patient also has peripheral nerve and even nerve root involvement
.

Patients with initial fever, seizures, and impaired consciousness can be explained by lupus encephalopathy or TMA, and cerebrospinal fluid examination at that time also supports this conclusion
.
These symptoms have also improved
with aggressive treatment of the primary condition.
However, subsequent delirium, deepening of consciousness, and unstable vital signs were considered by MRI as Wernicke's encephalopathy (encephalopathy, eye movement disorder, and gait disorder are the classic triad), and the corresponding symptoms improved
after supplementation of vitamin_B1 deficiency.

It is worth adding that brainstem lesions in patients with lupus must be differentiated
from demyelinating diseases such as neuromyelitis optica concomitant with lupus.
In addition, in this case, the patient has persistent symptoms of limb weakness, and neurologists often consider the limb weakness in critically ill patients to be critical illness-related myopathy or peripheral neuropathy with myopathy, which may be related to nerve damage due to oxidative stress or systemic reactions, such as axonal degeneration
.
In this patient, later manifestations tend to be radiculopathy and Guillain-Barré syndrome cannot be excluded, and lumbar puncture protein levels decrease after nutritional nerve therapy, suggesting peripheral neuropathy
.