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Dermacademy Challenge – Clinical Case #5 – Pr. Marie-Sylvie Doutre
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Clinical case shared by Pr. Marie-Sylvie Doutre
Clinical Presentation
Mr. M., 67, has had a non-pruriginous skin rash on the chest and arms for 10 months, progressing in flare-ups. He has no history, allergy history in particular, and is not taking any drugs. The diagnosis of spontaneous chronic urticaria is made and 2nd generation anti-H1 treatment (levocetirizine) is prescribed at the dose of 1 tab per day, followed by 4 tabs per day, but which was not effective.
Four months after the rash appeared, he began to experience recurrent fever and shivering episodes considered to be infectious, giving rise to systemic antibiotic treatment twice, but without this ever improving the symptoms. He says he lost 7 kilos during that time. The tests to look for a deep focus of infection (sinus and chest CT-scan, heart ultrasound, quantiféron etc.) and neoplasia (upper GI endoscopy, colonoscopy etc.) were completely normal.
A dermatology consultation was requested as the symptoms had lasted nearly a year.
Social History
Former bank manager
Physical Examination
The examination revealed pinkish, very slightly papular macula (photo 1) on the chest, arms and legs. The patient confirms that the lesions are not pruriginous and last for 12 to 24h.
Laboratory Result
The full blood count revealed 15,700 leukocytes /mm3 of which 13,290 granulocytes; sedimentation rate is 73 in the first hour, CRP 144 mg/l. There is a monoclonal IgM kappa peak at 3.6 g/l.
Biopsy Result
The cutaneous biopsy shows interstitial and perivascular leukocytoclastic neutrophil granulocyte infiltrate, without involvement of the vessel walls (photo 2).
Developments
The appearance of the cutaneous lesions and histological images suggest neutrophilic urticarial dermatosis (NUD).
Diagnosis
In this patient, the clinical characteristics of the rash, the related signs (fever, poor condition), presence of an inflammatory syndrome and monoclonal IgM kappa and the histological images orient the diagnosis towards Schnitzler syndrome.
Management and outcome
Schnitzler syndrome is currently considered to be an acquired autoinflammatory syndrome involving various cytokines, especially IL 1.
Progression is generally long and benign, but as with monoclonal gammopathies of undetermined significance (MGUS), a lymphoplasmocytic malignancy, in particular Waldenstrom’s disease or IgM multiple myeloma, appears in around 15% of cases, years, sometimes 20 years, after the start of the disease.
According to the severity of the symptoms, colchicine, non-steroidal anti-inflammatory drugs and hydroxychloroquine are offered in first intention.In patients with significant and permanent inflammatory syndrome, at risk of long-term complications (amyloidosis) and sometimes seeing a change in their quality-of-life, IL-1beta treatment is recommended or treatment with its receptor. The efficacy of anakinra (anti IL-1R) is spectacular but temporary (rebound common on discontinuation). The efficacy of canakinumab (anti IL-1) is also noted. These treatments do not influence the outcome of the monoclonal gammapathy. However, given the treatment constraints (daily injections in the case of anakinra) and the potential rebound on discontinuation, the benefit/risk balance must be assessed with the patient.
Teaching points
Schnitzler syndrome, the first case of which was published in 1974, combines skin rash, fever, inflammatory arthralgia, sometimes arthritis and bone pain (mainly in the pelvis, femurs, and tibias) which are often debilitating as resistant to standard analgesics. Half of cases include superficial or even deep adenopathies, less often hepatosplenomegaly and always inflammatory syndrome and monoclonal kappa IgM, without lymphoplasmocyctic proliferation. X-rays often show osteosclerosis of the lumbar spine, pelvis and legs. The Tc-99m bone scan can show hyperfixation in the painful areas. The MRI-scan reveals a low signal in T1 and high in T2 in the metaphyses.
Very similar clinical observations are described, related to kappa monoclonal IgG in most cases.
The skin biopsy most often reveals a dermal infiltrate made up of neutrophil granulocytes, without vascularitis. These histological images, associated with cutaneous lesions, effectively represent neutrophilic urticarial dermatosis.
The diagnosis is made based on the Strasbourg criteria: 2 are determining, chronic urticaria rash and monoclonal IgM or IgG. The diagnosis is confirmed if related to at least 2 minor criteria if IgM, 3 if IgG: unexplained recurrent fever >38°, the most often concomitantly with the skin rash, objective bone anomalies, with or without pain, evaluated by bone scan, MRI-scan or elevated bone alkaline phosphatases, dermal neutrophil infiltrate, leukocytosis with neutrophil granulocytes >10 G/l and/or CRP >30 mg/l. The diagnosis is likely if the 2 determining criteria are present and at least 1 minor criterion if IgM, 2 minor criteria if IgG.
Bibliography
- De Koning et al., The role of IL-1 beta in the pathophysiology of Schnitzler’syndrome ;Arthritis Res Th 2015;Jul 22.
- Neel et al., Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler syndrome: a french multicenter study; Autoimmun Rev 2014 ;13 :1035-41.
- Krause et al., Efficacy and safety of canakimumab in Schnitzler syndrome: a multicenter placebo-controlled study; J Allergy Clin Immunol 2017;139:1311-202010 ;40 :828-34.
- Lipsker D, The Schnitzler syndrome Orphanet; J Rare Dis 2010 ;dec 8.
- De Koning et al., Schnitzler’s syndrome: lessons from 281 cases ; Clin Transl Allergy 2014 ;dec 5.
- Simon A et al., Schnitzler’syndrome: diagnosis, treatment and follow-up Allergy 2013; 68:562-8.
- Gusdorf L et al., Schnitzler’syndrome: validation and applicability of diagnosis criteria in real-life patients; Allergy 2017;72:177-82.
