Atypical bortezomib-induced neutrophilic dermatosis

Image: Understanding Velcade, Velcade (bortezomib) for Injection. Accessed 16/11/18.

In 12% of cases, Sweet’s syndrome, otherwise known as acute febrile neutrophilic dermatosis, can be triggered by medication, and this is known as drug-induced Sweet’s syndrome. This is case of a 76-year-old man developing a Sweet’s syndrome-like condition secondary to the chemotherapy drug, bortezomib (trade names: Velcade, Chemobort or Bortecad).

Case-study.

A 76-year-old man was treated with prednisone-melphalan and subcutaneous injections of bortezomib for an IgG kappa multiple myeloma (Lescoat et al, 2018). On day 25 of the first chemotherapy cycle, he developed painless red-to-purple swollen, large blister-like, ulcerated, and haemorrhagic plaques (skin lesions), involving the forehead, top side of fingers, and both ankles. A blood test called a full blood count or FBC was normal. Skin biopsy revealed white blood cells called neutrophils in the skin, but no vasculitis – swelling of the small blood vessels. There was also an absence of dermal oedema – no fluid in the dermal skin layer. Based on these findings, a diagnosis of bortezomib-induced neutrophilic dermatosis (ND) was given.

Bortezomib is a chemotherapy drug and proteasome inhibitor which causes a build up of unwanted proteins in cancer cells, which makes the cells die. In up to 24% of patients receiving this treatment adverse events affecting the skin occur, most commonly papules and nodules during the third or fourth treatment cycle. Bortezomib-induced Sweet’s syndrome and Sweet-like lesions have also been reported, generally appearing during the first or second cycle of chemotherapy.

Bortezomib-induced Sweet’s syndrome causes fever, weakness and lack of energy, painful round reddened and swollen skin plaques on the head, neck, or trunk. Skin biopsy tends to show immature or mature neutrophils in the tissues (Ibid). Walker and Cohen proposed five criteria for typical drug-induced Sweet’s syndrome: (1) sudden onset of painful erythematous plaques or nodules; (2) neutrophils in the dermal skin layer, but no vasculitis; (3) fever above 38 °C; (4) symptoms developing quite quickly after starting a medication, or recurrence after medication is stopped and restarted (rechallenge); (5) skin lesions settling down after the drug has been stopped or treatment with systemic steroids (Lescoat et al, 2018; Walker and Cohen, 1996). Although this case meets 3 of these 5 criteria, it differs from previously reported bortezomib-induced ND on account of the lack of other symptoms and the painless, ulcerated, haemorrhagic lesions, and their unusual localization, being confined to the extremities and forehead, sparing the trunk (Lescoat et al, 2018). Neutrophils in the tissues are characteristic of ND, but the absence of dermal oedema rules out Sweet’s syndrome, while no vasculitis excludes the ND, erythema elevatum diutinum. As a result of this, the spectrum of bortezomib-induced ND needs to be broadened. Also, bortezomib-induced ND remains poorly understood, but may occur because of the bortezomib causing an imbalance of proinflammatory cytokines – molecular messengers that promote inflammation – leading to the migration of neutrophils toward the skin. Treatment included stopping the bortezomib, and the steroid, prednisone, was started at 1 mg/kg/day, leading to the skin lesions completely settling down. Prednisone-melphalan was continued without reappearance of the lesions.

References.

Lescoat, A., Dupuy, A., Belhomme, N., Stock, N., Sebillot, M., Decaux. O. and Jégo, P. (2018) Atypical bortezomib-induced neutrophilic dermatosis. Annals of Hematology, Oct 12 (Springer Berlin Heidelberg).

Walker, D. and Cohen, P. (1996) Trimethoprim-sulafamethoxaole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. Journal of the American Academy of Dermatology, May;34(5 Pt 2):918-23 (PubMed).

2012-present, Sweet’s Syndrome UK

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Sweet’s syndrome associated with infection due to adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

Image: Talaromyces marneffei, Mycology Online, The University of Adelaide. Accessed 23/09/18.

This is the first reported case of Sweet’s syndrome associated with the fungal infectionTalaromyces marneffei, and the bacterial infection, Mycobacterium abscessus, due to adult-onset immunodeficiency with anti-interferon-gamma autoantibodies (Xu et al, 2018).

What is adult-onset immunodeficiency with anti-interferon-gamma autoantibodies?

Adult-onset immunodeficiency with anti-interferon-gamma autoantibodies is an immunodeficiency disorder mainly found in Southeast Asians that were previously healthy. The exact cause for this disorder is unknown, but may be linked to the genes HLA-DR and HLA-DQ (Chan et al, 2016). It causes the body to produce higher amounts of anti-interferon-gamma autoantibodies – specific immune system proteins that mistakenly target a person’s own tissues – and prevents immune cells called T-lymphocytes (T1) from responding properly (Chan et al, 2016). This weakens the immune system leading to infection. Symptoms commonly include multiple swollen lymph nodes and skin lesions, particularly Sweet’s syndrome and acute generalized exanthematous pustulosis (Phoompoung et al, 2017). There is no standard therapy for adult-onset immunodeficiency with anti-interferon-gamma autoantibodies and treatment depends on what kind of infection is present.

What is Talaromyces marneffei?

In Southeast Asia, T. marneffei is a fungal infection that has been linked to bamboo rats and soil from their burrows, and is most commonly found in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) due to very weakened immune systems (Chan et al, 2016). Fairly recently, it has been associated with adult-onset immunodeficiency with anti-interferon-gamma autoantibodies.

What is Mycobacterium abscessus?

M. abscessus is a bacterium distantly related to the ones that cause tuberculosis and leprosy. It is a nontuberculous mycobacterial (NTM) infection that can be difficult to treat and is often resistant to antibiotics. NTM infection in people who were previously healthy and HIV negative has been associated with adult-onset immunodeficiency with anti-interferon-gamma autoantibodies (Phoompoung et al, 2017).

Case-study.

A 54-year-old Chinese man was admitted to hospital with a 2 month history of recurrent fever and a 1 month history of multiple swollen lymph nodes. There was nothing unusual about his history, apart from eating bamboo rats a year before. He went on to develop painful skin lesions on the face, back of hands, lower legs and feet. The antifungal, fluconazole, and the antibiotic, levofloxacin, were started to treat infection. The patient was also given the steroid, methylprednisone, and thalidomide to treat Sweet’s syndrome. His skin lesions eventually healed, but a new painful lesion developed under the left side of his jaw. He then had a recurrent fever and enlarging neck lymph nodes with swelling and flushing over his neck. These symptoms improved after levofloxacin was replaced with the antibiotic clarithromycin.

On admission, blood tests had shown raised white blood cell count, raised neutrophil (type of white blood cell) count, elevated erythrocyte sedimentation and C-reactive protein (two tests that can show increased levels of inflammation in the body). Test for HIV was negative, but anti-interferon gamma autoantibodies were positive. Bone marrow biopsy was normal. Blood and sputum cultures showed no fungal or bacterial infection. Biopsy of a skin lesion showed lots of neutrophils in the tissues and fluid in the dermal skin layer (uppermost part of dermis), these findings being consistent with Sweet’s syndrome. Biopsy of a lymph node from the right groin showed a yeast/fungal-like organism under microscope. Biopsy of the jaw lesion showed both yeast/fungal-like organisms and acid-fast rods, the latter indicating myobacterial infection. A diagnosis of deep mycosis (fungal infection in deeper tissues) caused by T. marneffei was given, and the mycobacterial infection was identified as M. abscessus.

References.

Chan, JF., Lau, SK., Yuen, KY. and Woo, PC. (2016) Talaromyces (Penicillium) marneffei infection in non-HIV-infected patients. Emerging Microbes & Infections, Mar 9;5:e19 (PMC).

Phoompoung, P., Ankasekwinai, N., Pithukpakorn, M., Foongladda, S., Umrod, P., Suktitipat, B., Mahasirimongkol, S., Kiertiburanakul, S. and Suputtamongkol, Y. (2017) Factors associated with acquired Anti IFN- γ autoantibody in patients with nontuberculous mycobacterial infection. PLos One, Apr 24;12(4):e0176342 (PMC).

Xu, H., Liu, D., He, X., Zheng, D. and Deng, Y. (2018) Sweet’s Syndrome Associated with Talaromyces marneffei and Mycobacterium abscessus Infection Due to Anti-interferon-gamma Autoantibodies. Indian Journal of Dermatology, Sep-Oct;63(5):428-430 (PMC).

2012-present, Sweet’s Syndrome UK

Raccoon eyes as a newly reported sign of Sweet’s syndrome

Raccoon eyes sign (RES) is a newly reported sign of Sweet’s syndrome in two male patients, a 27-year-old man with a 10 day history of upper respiratory tract infection and a 52-year-old man with acute myeloid leukaemia and a history of testicular cancer (Salman et al, 2018). Both cases were successfully treated with methylprednisolone.

What is raccoon eyes sign?

RES (also known as owl eyes or panda eyes) or periorbital ecchymosis is a sign of basal skull fracture as a result of traumatic periorbital haemorrhage, periorbital referring to the area around the eye. It can also be caused by systemic amyloidosis, neuroblastoma and other conditions.

Can conditions affecting the skin cause raccoon eyes?

Yes, RES can be a sign of neonatal lupus erythematosus, lichen planus pigmentosus, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE), and Sweet’s syndrome.

What does raccoon eyes look like?

RES describes bruising and discoloration around the eyes that looks like the dark circles around a raccoon’s eyes, and may affect just one eye or both. In Sweet’s syndrome, RES has presented as swollen or haemorrhagic plaques (larger raised, reddened or purple skin lesions) around the eyes (Salman et al, 2018).

What causes raccoon eyes in Sweet’s syndrome?

The exact cause of RES in Sweet’s syndrome is unknown. However, Salman et al argue that it could be caused by secondary damage to blood vessels as a result of white blood cells called neutrophils releasing noxious substances, and the thin skin around the eyes being more sensitive to damage (Ibid). Read more here.

References.

Salman, A., Demir, G., Cinel, L., Oguzsoy, T., Yildizhan, G. And Ergun, T. (2018) Expanding the differential diagnosis of raccoon eyes: Sweet syndrome. Journal of the European Academy of Dermatology and Venereology, May 31|doi: 10.1111/jdv.15104 (Wiley Online).

2012-present, Sweet’s Syndrome UK

28th Feb 2018 is Rare Disease Day. Here’s how you can get involved and spread awareness of Sweet’s syndrome

The 28th February 2018 is the 11th international Rare Disease Day coordinated by EURORDIS (the European Organization for Rare Diseases). On and around this day, hundreds of patient organisations all over the world will be holding awareness-raising activities.

Each year, Rare Disease Day has a theme, and this year continues with the 2017 theme of research.

Here’s how you can get involved and spread awareness of Sweet’s syndrome.

  1. Like our Facebook page.
  2. Join our HealthUnlocked forum and community. It’s free!
  3. Follow this blog.
  4. Follow on twitter @sweetsfiend
  5. Follow on Google +
  6. Share a post from our Facebook page or blog.
  7. Share information about Sweet’s syndrome from a research-based site such as DermNet NZ or the Mayo Clinic.
  8. Talk about Sweet’s syndrome; blog about your experiences; tag a friend; tweet for Sweet’s.
  9. Make a donation to the Autoinflammatory Alliance. This is a US-based non-profit organization that helps children and adults with autoinflammatory conditions, including Sweet’s syndrome.
  10. Visit the Rare Disease Day website and sign up for their updates, download free materials (‘Get Involved’), and follow on social media.
  11. On the Rare Disease Day website, read about how patients can kick start and drive research.

Please BEE Sweet and buzz for Sweet’s. Help us spread the word!

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A Rare Case of Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Neuro-Sweet Disease in Myelodysplastic Syndrome

This is the first documented case of neuro-Sweet’s disease (NSD) in a 66-year-old Japanese woman with a 6 year history of myelodysplastic syndrome (MDS), who developed NSD in association with syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Oka et al, 2017).

What is neuro-Sweet’s disease?

NSD is a rare neurological variant of Sweet’s syndrome (SS) that can affect the brain and spinal cord. Read more here.

What is syndrome of inappropriate antidiuretic hormone secretion?

SIADH is a relatively rare condition where the body makes too much of a hormone called antidiuretic hormone (ADH). ADH is produced in a part of the brain called the hypothalamus, and is then released by the pituitary gland at the base of the brain. ADH helps the kidneys to control the amount of water your body loses through the urine. In SIADH, the body retains too much water, leading to abnormally low levels of sodium in the blood (hyponatraemia). This happens as a result of the excess water diluting the blood and lowering the concentration of sodium.

What causes syndrome of inappropriate antidiuretic hormone secretion?

Common causes for SIADH include medication, hormone treatments, surgery under general anaesthesia, brain conditions, and lung disease. Rare causes include a disease of the hypothalamus or pituitary, cancer, and mental disorders.

Case-study.

A 66-year-old Japanese woman with a 6 year history of MDS, a blood cancer known to trigger SS, developed a fever and skin lesions in the form of a rash over both legs (Oka et al, 2017). A biopsy of a lesion showed lots of white blood cells called neutrophils in the tissues and no inflammation of the blood vessels. These findings were indicative of SS. The patient was given the oral steroid, prednisolone, which is the main form of treatment for SS, and this brought her symptoms under control.

The patient was readmitted to hospital 9 months later with a fever and reduced level of consciousness. Blood tests showed raised C-reactive protein (CRP), indicating increased levels of inflammation in the body. White blood cell count (WBC) was low and neutrophil count was borderline/low, despite being raised in most cases of SS (see ‘Additional notes’). No brain abnormalities were detected on MRI scan. Examination of cerebrospinal fluid (CSF), a clear and colourless fluid found in the brain and spinal cord, showed no neutrophils or white blood cells called lymphocytes, but raised protein levels. Bacterial or viral meningitis were suspected, and intravenous (via a drip in the vein) meropenem and acyclovir were commenced. However, the patient’s fever didn’t improve and her level of consciousness continued to deteriorate.

On day 10 in hospital, the patient was found to be negative for HLA-B51, but positive for HLA-B54. HLA-B51 is a genetic marker associated with a similar condition to SS called Behcet’s syndrome (see ‘Further information’), while HLA-B54 is associated with SS, particularly in Japanese patients (Sweet’s Syndrome UK, 2018). Due to neurological involvement, a diagnosis of NSD instead of SS was suggested (Oka et al, 2017). The intravenous steroid, methylprednisolone, was given. The patient’s condition improved and she was then started on prednisolone.

On day 30, the patient developed a fever and her level of consciousness deteriorated again. Tests revealed a low WBC and neutrophil count; CSF showed no lymphocytes or neutrophils, but raised protein levels; greatly elevated levels of interleukin 6 (IL-6) (see ‘Additional notes’); rapidly falling sodium levels in the blood; no kidney, adrenal or thyroid problems; MRI abnormalities – sagittal T1-weighted MRI showing an absence of high intensity signals in the posterior pituitary lobe. As a result of these findings, a diagnosis of SIADH was given, and the NSD was considered to be the most likely cause for this. Prednisolone and cyclosporine were commenced to treat the NSD, cyclosporine having being found to be useful in SS patients who have developed their condition secondary to low-risk MDS. A 3% sodium chloride intravenous infusion was given for the low sodium levels. The patient’s condition improved, and after discharge from hospital on day 70, she remained stable for a year and there was no recurrence of her symptoms.

Additional notes.

Cytokines are proteins and molecular messengers and part of the body’s immune system. The overproduction or inappropriate production of cytokines, known as cytokine dysregulation, can result in disease. Cytokine dysregulation is a factor in SS, and the cytokine IL-6 plays a role in both NSD and SIADH (Oka et al, 2017). In this case, the patient’s IL-6 levels were greatly elevated, and this activates ADH secretion which can induce SIADH.

IN NSD, blood tests often show a raised WBC, including neutrophil count, and a raised CRP. CSF tends to show a slight increase in protein and an increase in the number of lymphocytes or neutrophils (Oka et al, 2017; Sweet’s Syndrome UK, 2018). However, MDS patients can sometimes have a lack of mature cells or neutrophils, and as a result, blood tests or CSF findings are less likely to clearly indicate NSD.

Further information.

Newson, L. (2016) Hyponatraemia. Patient Info (online). Includes information on SIADH.

Ngan, V. (2002) Behcet Disease. DermNet NZ (online).

References.

Oka, S., Ono, K. And Nohgawa, M. (2017) Successful Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Neuro-Sweet Disease in Myelodysplastic Syndrome. Internal Medicine (Tokyo, Japan), Dec 8th (J-Stage).

Sweet’s Syndrome UK (2018) Neuro-Sweet’s disease: a neurological variant (online).

2012-present, Sweet’s Syndrome UK

Sterile peritonitis as a rare symptom of Sweet’s syndrome

Links checked 30/10/18.

This is the first reported case of sterile peritonitis, a type of peritonitis not caused by infection, as a symptom of Sweet’s syndrome (SS) (Rajjoub et al, 2017). Peritonitis is inflammation of the peritoneum, the thin layer of tissue that lines the inside of the abdomen.

Case-study.

A 37-year-old female patient who had previously been diagnosed with SS in 1998 had been having repeat episodes of peritonitis. On admission to hospital, she had a 48-hour history of right sided abdominal pain and feeling sick, high temperature, fast pulse rate, low blood pressure, and a raised white blood cell count, including neutrophil count. There was no vomiting, problems with bowel movements, urinary symptoms, or vaginal discharge, and the patient reported that she had never been sexually active. One month prior to admission, her SS had also flared up, which was treated with steroid medication.

Click here and here to learn more about the role of neutrophils in SS.

It was in 2000 that the patient had first started experiencing abdominal pain, alongside left groin pain and a high temperature. She was treated with antibiotics, and then had a laparoscopy, otherwise known as abdominal ‘keyhole’ surgery. This is a minimally invasive surgical procedure that allows a surgeon to access the inside of the abdomen, while avoiding large incisions. The laparoscopy showed a large amount of pus in the pelvis and abdomen associated with pelvic adhesions. These are fibrous bands between tissues and organs that occur as a result of inflammation or injury. Due to the complexity of the situation, the laparoscopy was changed to ‘open’ or traditional surgery so that the patient’s abdomen could be more thoroughly examined. Her appendix, although it appeared to be normal, was removed. A sample of the pus was sent for analysis, but showed no bacterial growth, i.e. no signs of infection. It was thought that the absence of infection was due to the patient being given antibiotics before surgery.

On a later admission, the patient had another laparoscopy for ongoing lower abdominal pain. Once again, there was a large amount of pus in the pelvis and abdomen, and a subphrenic abscess. This is a collection of pus between the diaphragm, liver, and spleen. There were also extensive adhesions, and as a result of this finding, the patient was started on antibiotics and initially diagnosed with pelvic inflammatory disease (PID) of unknown cause. PID is an infection of the female upper genital tract, including the womb, fallopian tubes and ovaries, and mostly affects sexually active women aged 15 to 24.

As the patient had reported never being sexually active and having a SS flare-up before admission, it was decided that the PID diagnosis was incorrect, and her peritonitis and pus in the pelvis and abdomen were probably SS-associated. Rajjoub et al have hypothesized that this is because neutrophils have the potential to accumulate in the peritoneal cavity causing a widespread reaction and development of pus and adhesions. It was also hypothesized that steroids may have initially worsened the existing problem, but not caused it, by increasing the movement of white blood cells into the peritoneum.

The patient was eventually discharged from hospital with a pelvic drain in place to drain away any further fluid or pus, and antibiotics to prevent infection.

Further information.

NHS (2018) Pelvic Inflammatory Disease (online). Accessed 30/10/18.

NHS (2017) Peritonitis (online). Accessed 30/10/18.

References.

Rajjoub, Y., Saffaf, N. and Goodman, A. (2017) A rare case report describing the relation between sweet syndrome and spontaneous recurrent peritonitis. International Journal of Surgery Case Reports, Jul 21;39:93-97 (PMC).

2012-present, Sweet’s Syndrome UK