This disease is extremely easy to distinguish from 4 types of rheumatism! But the director saw through it at a glance...

*For medical professionals only

Rheumatologists should be vigilant!

Recently, the director of a hospital received a female patient in her 20s, this patient has been bloated and tired for several days, lymph node biopsy shows that lymphatic hyperplasia is obvious, so how does the director finally determine the cause, let's

Case data

Physical examination: no fever, no tenderness in the lymph nodes anterior and posterior to the neck; Right lung base percussion dullness; Tachycardia, heart rate 134 beats / min, normal rhythm; Bulging of the abdomen, diffuse tenderness, positive for fluid wave tremor; There is no skin damage, hair loss, oral/nasal ulcers, arthralgia, arthritis, neurological symptoms, and lower extremity edema

Laboratory tests:

• Complete blood count: WBC count 11.

  
  

• Blood biochemistry: creatinine 1.

  
  

• Serological antibodies: positive for antinucleant antigen (ANA) in titers of 1:2560 (normal <1:40), anti-SS-A/Ro antibodies >8.

  
  

• Imaging results show: pleural effusion, moderate ascites, hepatomegaly

  
  

• PET/CT: multi-site fluorodeoxyglucose (FDG) lymphadenopathy (supraphragm and subphragm), with hepatomegaly and ascites

  
  

 

Figure 1: PET/CT image

• Intraperitoneal puncture: lymphocyte exudative ascites
  .
  
  Gram staining and culture, fungal and acid-antacid staining, interferon-γ release test for tuberculosis, epstein-barr virus, cytomegalovirus (CMV), HIV tests are negative
  .
  

• Diagnostic laparoscopy: ascites are brown and cloudy in nature, but no peritoneal surface masses are found, suggesting tuberculous peritonitis
  .
  
  

• Lymph node biopsy: lymphoproliferative and pronounced interveolar plasmacytosis
  .
  
  

 

Figure 2: Lymph node biopsy results

• Renal biopsy: thrombotic microvascular lesions with diffuse glomerular endothelial injury, however, immunostaining shows "full of bright" immunoglobulins and complement staining (-).
  
  
  

Figure 3: Renal biopsy

Based on the history and examination results, the director first ruled out infectious diseases
such as tuberculosis, Epstein-Barr virus, HIV, syphilis and HHV-8.

Since lymph node biopsy suggests significant interveolar plasmacytosis, experienced directors immediately thought of the possibility
of idiopathic polycentric Castleman disease (MCD).

Of course, this patient may also be diagnosed with autoimmune or autoinflammatory systemic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), adult Still disease (AOSD), autoimmune lymphoproliferative syndrome (ALPS), IgG4-related diseases, and so on
.

How can we rule out these diseases?

Differentiation of Castleman's disease from other rheumatisms

▌ Autoimmune connective tissue diseases: SLE and RA

One study showed that 5 out of 33 patients with SLE (15%) had features of MCD, such as systemic or local lymphadenopathy
.

On the other hand, patients with MCD may also have SLE manifestations, such as arthritis, skin manifestations, or kidney disease, which may lead to misdiagnosis
.

The American Rheumatological Society's criteria for diagnosing SLE are shown in Table 1, and to diagnose SLE, at least 4 of the 11 criteria must be met
.

Table 1: American Rheumatological Society's SLE Diagnostic Criteria

Although this case satisfies 4 of the above criteria, due to:

(1) Renal biopsy immunofluorescence does not prove immune complex-mediated glomerulonephritis and does not support the diagnosis of lupus nephritis;

(2) SLE lymph node lesions are characterized by different degrees of coagulant necrosis with hematoxylin bodies or reactive follicular hyperplasia, but the case of cervical lymph node biopsy shows lymphoproliferation and significant interverolar plasmacytosis, which is the characteristic of
MCD.

So, the director ruled out an SLE diagnosis
.

Coincidentally, lymphadenopathy is often associated
with RA.

RA is more common in the clinic and is diagnosed as follows:

1.
Clinical manifestations: RA is most likely to cause joint involvement, especially small joints, such as fingers, wrists, elbows, knees and toe joints, etc.
, which are manifested as pain, swelling, and joint inflammation
.

In addition to small joint involvement, symmetrical joint involvement and multi-articular involvement are common manifestations
of RA.

In addition, patients will have morning stiffness, which is manifested by tight joints after getting up, wrinkled, sticky, and inflexible, which is slowly relieved
after a period of exercise.

Morning stiffness for more than 1 hour, helpful for diagnosis;

2.
Serological examination: autoantibody detection such as rheumatoid factor, anticyclic citrullin peptide antibody, etc.
, which is helpful for the early diagnosis of RA;

3.
Imaging examination: such as ultrasound, magnetic resonance and X-ray and other imaging tests, can early detection of inflammation of the joint, which is helpful
for the diagnosis of RA.

Clinicians combine clinical findings, haematological tests, and imaging to determine the diagnosis
of RA.

However, in this case, neither the history nor the serological antibody test found any clear evidence of RA and was not considered
.

▌AOSD

AOSD is a systemic autoinflammatory disease similar to systemic adolescent idiopathic arthritis, but only in adulthood
.

Clinically, AOSD is sometimes more similar to MCD, especially if arthritis occurs before other MCD manifestations and is easily misdiagnosed
.

At present, there is no specific diagnostic method for AOSD, and there is no uniform diagnostic standard
.

For suspected patients, the recommendation is more to use the Japanese Yamaguchi standard or the American Cush standard for an exclusionary diagnosis
.

The prerequisites for the US Cush standard are:

(1) Fever ≥ 39 °C; (2) Arthralgia or arthritis; (3) Rheumatoid factor < 1:80; (4) ANA < 1:100;

In addition, you must have any 2 of the following:

(1) Blood leukocyte ≥ 15x10⁹g/L; (2) Rash; (3) Pleurisy or pericarditis; (4) Hepatomegaly, splenomegaly or lymphadenopathy
.

In addition, according to the 2022 MCD Diagnostic Guidelines, lymph node biopsy can help differentiate MCD from AOSD
.

In this case, the patient's serositis, elevated blood picture, elevated inflammatory indicators and other manifestations are very similar to AOSD, but the patient does not have fever and arthritis, ANA is also positive, plus the lymph node biopsy of AOSD is characterized by chronic nonspecific inflammation or reactive hyperplasia, which is inconsistent with this case, so the director rejected the diagnosis
of AOSD.

▌ALPS

ALPS is a rare non-malignant lymphoproliferative disorder whose exact cause has not been elaborated
.

Clinical manifestations of ALPS include lymphadenopathy, splenomegaly, and autoimmune cytopenia, which is caused by
impaired Apoptosis of T cells leading to uncontrolled lymphocyte proliferation.

Its histopathological features may be similar
to those of MCD.

The diagnostic criteria for ALPS were developed by consensus in 1999 and revised
in 2010.

The consensus holds that lymphoproliferation (with/without asplenia and/or lymphadenopathy) is the most important clinical manifestation of
ALPS.

In addition, the joint detection of two indicators of dual-negative T cells and in vitro apoptosis function is most beneficial
for identifying all types of PATIENTS.

Although this case has lymphoproliferatives, lymph node biopsy is more importantly characterized by plasmacytosis between follicles, which is more appropriate for the diagnosis
of MCD.

▌IgG4-related diseases

IgG4-related disease is a chronic, progressive inflammatory disorder
with fibrosis.

Although it was not widely recognized until the 21st century, it has actually existed for a long time in human history and is not clinically uncommon
.

The first to pay attention to IgG4 were gastroenterologists, who found that there is an autoimmune pancreatitis closely related to IgG4, and imaging often diagnoses pancreatic cancer, but pathological biopsy can not find cancer cells
.

A few years later, doctors in various disciplines also found that changes such as swelling, inflammation, and fibrosis of various tissues and organs were related
to IgG4.

In February 2015, the New England Journal of Medicine defined such diseases as lgG4-related diseases
.

According to the MCD guidelines, the criteria for distinguishing MCD from IgG4-related diseases are shown in Table 2:

Table 2: Differentiation of MCD and IgG4-related diseases

According to Table 2, this case is more likely to be diagnosed as MCD
than to IgG4-related diseases.

brief summary

At the end of the article, a summary of the diagnostic criteria for MCD is provided, and the diagnosis of MCD needs to meet the following main criteria and at least 2 of the 11 secondary criteria
.

Table 3: Diagnostic criteria for MCD

At this point, there is basically no doubt about the diagnosis of MCD in
this case.

The follow-up treatment given by the director was first hormone therapy, and after the disease was controlled, it was changed to anti-IL-6 monoclonal antibody therapy, which improved
significantly.

Having met MCD in the clinic, do you still confuse it with rheumatism?

References:

[1] Farrukh L, Lightle A, Peredo-Wende R, Murawski S.
Case of idiopathic multicentric Castleman’s disease：the master mimicker.
BMJ Case Rep.
2022; 15：e250706.

[2] González García A, Fernández-Martín J, Robles Marhuenda Á.
Idiopathic multicentric Castleman disease and associated autoimmune and autoinflammatory conditions：practical guidance for diagnosis [published online ahead of print, 2022 Aug 23].
Rheumatology（Oxford）.
2022; keac481.
doi：10.
1093/rheumatology/keac481

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