A Resident's Breakthrough 住院医师的突破: Schnitzler syndrome

choi

syndrome  症候群
https://en.wikipedia.org/wiki/Syndrome


Lisa Sanders, A Resident's Breakthrough. Like mismatched puzzle pieces, her symptoms just didn't fit. Until one doctor put it all together. New York Times Magazine, Feb 18, 2018.
https://www.nytimes.com/2018/02/ ... t-all-together.html

Quote:

A 68-year-old woman's symptoms: "It started years earlier * * * Almost every night, she would get these crazy fevers. First came bone-rattling, shaking chills; she couldn’t get warm even under a pile of quilts. Then suddenly she would be roasting hot, with sweat pouring off her. Her temperature would spike to 102 or 103. And her whole body would hurt, right down to her bones. * * * Then an hour after the fever hit, she would start to feel sick and throw up until she had nothing left in her. * * * During the day, she felt weak and tired, and her bones hurt. It made any movement painful. * * * She also had a rash. Hives, the doctors told her. It didn't itch * * * she had no appetite * * * She'd [had] lost over 80 pounds this past year.

Her signs and laboratory work: "her [physical] exam was uninformative. * * * the patient had a persistently elevated white-blood-cell count. Normal is under 10[k, or 10,000]; the patient’s was at nearly 20 — and had been for a couple of years. CT scans showed enlarged lymph nodes throughout her body. * * * The patient didn't have multiple myeloma either, though that test, which measures levels of one part of the immune system known as antibodies, was abnormal; one antibody, known as IgM, was high.

Note:
(a) Dr Forest Huls is now a hematopathology fellow with Department of Pathology, University of Michigan.
https://www.pathology.med.umich.edu/news/540
("Hematopathology Fellow Dr Forest Huls Makes NY Times")

(b) "And given her persistent gastrointestinal problems, [internal medicine 内科 resident Jori] May would look for celiac disease."
(i)
(A) It is certain that patients with celiac disease are intolerant to a protein "called gluten found in wheat, rye, and barley. Celiac disease causes damage to the lining of the small intestine and prevents absorption of nutrients."  National Institute of Health (NIH).
(B) "Researchers do not know exactly what triggers celiac disease in people at risk who eat gluten over a long period of time." National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK), NIH, undated.

Basically we do not know why these patients are intolerant to gluten, or why the intolerance causes this disease.
(C) The same institute (NIDDK) estimates that as many as 1% of Americans have celiac disease, though they may not know they have it.
(D) "Since celiac disease is genetic, this means it runs in families." Celiac Disease Foundation, undated.
(E) ONSET of symptoms of celiac disease can be any age (the disease has been there in the patients, bit takes trigger events to make it apparent).  
(F) Diagnosis is through blood tests (for specific antibodies and for two genes), as well as
The causative agent is gluten (main ingredient of 素鸡). The treatment is to avoid gluten; that is why many food labels indicate it (food) contains no gluten.
(ii) celiac (adj; ultimately from Greek koilia cavity, from koilos hollow): "of or relating to the abdominal cavity"
https://www.merriam-webster.com/dictionary/celiac
(iii) coeliac disease
https://en.wikipedia.org/wiki/Coeliac_disease
(also spelt celiac disease; "The term 'coeliac' is from the Greek κοιλιακός (romanization:] koiliakós, 'abdominal') and was introduced in the 19th century in a translation of what is generally regarded as an Ancient Greek description of the disease by Aretaeus of Cappadocia")

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(c)
(i) First of all I want to discuss syphilis: all stages -- primary, secondary and tertiary (last) -- of syphilis, treated or untreated can be tested with blood for antibodies (unlike gonorrhea, which after treatment leaves no trace behind).  
(ii) Mentioned in the second quotation above, multiple myeloma is a malignancy (cancer) of plasma cells.
(A) The disease is so called because plasma cells may aggregate to form multiple masses in the bone marrow [a mass eats a bone, creating blackness within white bone in the X0ray film) or soft tissue
(B) Normally, entry of an antigen (into a human body) causes multiplication of a specific B cell which will mature into plasma cells to secret the right antibody to bind to (and eliminate) the antigen.
(C) In multiple myeloma, a single plasma cell goes rogues and becomes cancerous, secreting a particular immunoglobulin. However, 1-5% of multiple myeloma are "nonsecretory," because their plasma cells do not secret immunoglobuline.

(d) "Schnitzler syndrome [is] a rare and poorly understood immune disorder. * * * The disorder was first described in 1972 by the French dermatologist Liliane Schnitzler"
(i) Liliane Schnitzler was a woman.
(ii) Lillian (name)
https://en.wikipedia.org/wiki/Lillian_(name) (or Lilian, a female given name [in English-speaking world]; "It is Latin, meaning 'Lilium [genus name for lily].' In French, Lilian is the male form of the name, while Liliane is the female form").
(iii) English dictionary:
* Lillian (etymology: generally accepted as a variant of Late Latin [noun neuter] lilium lily): "a female given name. (This is the standard American spelling.)"
https://en.wiktionary.org/wiki/Lillian

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(e) "Huls hadn't heard of Schnitzler syndrome, either. He came upon it by using the database PubMed to look for a disease that matched the patient's symptoms. He made a list of her symptoms and abnormalities. To get the full picture, he combed through her earlier electronic medical records, now archived in an old electronic warehouse, and found that her symptoms had started maybe a decade earlier. * * * It took hours before articles on this strange disorder began to appear [in the PubMed search]."

Pubmed is a rudimentary website operated by National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), NIH. It is akin to Google, but database is made up of abstracts of biomedical reports (all publications voluntarily submit abstracts to this database, without payment from either side -- publishers or US government). One enters search terms, and search is done only on abstract (not the full text) of the reports (latest first).
https://www.ncbi.nlm.nih.gov/pubmed/
(f) "It was an important diagnosis to make, in part because there is now a very effective treatment. When the woman's insurance company refused to pay for the new and very expensive drug, May appealed to the manufacturer, which agreed, after several months, to provide it. Once she started taking it, the shaking chills and fever disappeared. So did the nausea and vomiting, the hives and bone pain."

Swedish Orphan Biovitrum AB (acronym: Sobi; based in Stockholm, Sweden) acquired the right, from Amgen (based in California), to make the drug anakinra (trade name: Kineret). See Sobi Acquires Full Rights for Kineret® and additional clinical data for Kepivance® from Amgen. Sept 9, 2013.
https://globenewswire.com/news-r ... nce-from-Amgen.html

choi

(g) As hinted in (d) above, the cause of the syndrome is unknown. The author of the NYT article ascribes the cause to macrophage. But it is more prudent to say we simply do not know.
(i) Often cause of a disease, though unknown, can be deduced from effective treatment. This syndrome is one example.
(ii) A protein of 17 KD (kilodaltons or kilograms per mol; check Wikipedia for "molar mass"), anakinra is a man-made (read: recombinant) human IL-1 receptor antagonist. Healthy humans secret both IL-1 and "IL-1 receptor antagonist" (maybe in different time or sites), both of which bind to IL-1 receptor -- the former is an agonist (causing effects) but the latter an antagonist (preventing effects). The big molecular weight means anakinra must be injected (can not be taken by mouth; digestive system will reduce the drug to amino acids).
(iii) "Anakinra differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus."  Wikipedia.
(iv) Macrophage secrets interleukin-1 (IL-1), which actually are "two distinct, but distantly related" (quoting Wikipedia; but with similar functions) proteins encoded by two different genes.
(v) IL-1 binds to two similar receptors (encoded by two different genes), of which the main type, IL-1 receptor type I (as opposed to type II), is expressed on the surface of on T cells, fibroblasts and endothelial cells. Science, 241: 585-589 (1988)
(vi) Schnitzler syndrome apparently has overproduction of IL-1, compared to in normal persons. Yet one can not blame it on macrophage alone, which can be cause or effect (some other cells causes macrophage to secret more IL-1).  
(vii) Gouveia AI et al, Schnitzler Syndrome: A Dramatic Response to Anakinra. Heidelberg: Dermatology and Therapy, 6: 299–302 (2016).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906102/
(A) View only Figure 2, whose caption is "Histological features. Mixed inflammatory infiltrate (predominantly of neutrophils) in the dermis with no evidence of vasculitis. a H&E ×10, b H&E ×40."
(B) White blood cells (or leukocytes) "can be divided into the five main types: neutrophils, eosinophils, basophils, lymphocytes, and monocytes."  Wikipedia.
(C) For hematoxylin and eosin (H&E, where H and E are two separate dyes of simple chemicals, both of which are red to naked eyes) stain, see What is H&E?  In The Histology Guide, Faculty of Biological Sciences, University of Leeds, undated.
http://histology.leeds.ac.uk/what-is-histology/H_and_E.php

Both eosinophils and basophils contain large granules inside their cytoplasm, with the former's stained red (eosinophilic ) and the latter's purple (basophilic). Neutrophils have neither, and are so named ("neutro"). Pay attention Figure 2 shows infiltration by neutrophils, but not macrophages.

(h) The (g)(vii) above cited in reference 1 a seminal review:
Dan Lipsker, The Schnitzler syndrome. Orphanet Journal of Rare Diseases, 5: 38 (2010).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018454/

Quote

"It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections. * * * signs recur as soon as the treatment is stopped.

"And indeed, IL-1 inhibition is a very effective treatment modality in patients with CINCA [another disease whose full name is Chronic Infantile Neurological Cutaneous and Articular syndrome]. Since the Schnitzler syndrome shares many features with the CINCA syndrome, anakinra, an IL-1 inhibitor was also tried in the former syndrome. It proved to be the first really efficient treatment of the Schnitzler syndrome.

"mean age of disease onset is 51 years.

* A mean 中间数 is different from an average 平均值.