Schnitzler syndrome

Abstract

A woman in her late 40s with a history of psoriatic arthritis presented to us with fever, migratory rash, cervical and axillary lymphadenopathy, and generalised myalgia. Her symptoms did not improve with steroids and her inflammatory markers were in the range of 2000 mg/dL for C-reactive protein, erythrocyte sedimentation rate of 71 mm/hour and ferritin of 4000 ng/mL. Infectious workup was negative. Haematological malignancy and autoimmune conditions were among the top differentials, and she was eventually diagnosed with Schnitzler syndrome. A multidisciplinary team consisting of internal medicine, rheumatology, infectious disease and haematology-oncology specialists was involved in the care of this patient. We highlight the diagnostic schema that was followed for this rare and unique constellation of symptoms.

Background

Schnitzler syndrome is a very rare diagnosis with only 200 cases reported since 1972.¹ The syndrome comprises chronic urticaria associated with IgM kappa monoclonal gammopathy along with bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy and intermittent fevers.¹ There are no pathognomonic findings for the diagnosis to date. This disease falls under the range of monoclonal gammopathies.¹ The Strasbourg criteria as described in box 1 include monoclonal IgG or IgM and urticarial rash as the major criteria with recurrent fever >38ºC, abnormal bone remodelling with or without bone pain, neutrophilic dermal infiltrate on skin biopsy, leucocytosis and elevated CRP constituting the minor criteria.² Definite diagnosis is made with two major criteria and two minor criteria if IgM positive and three minor criteria if IgG present.² When bone marrow biopsy is completed, there is minimal or no lymphoplasmacytic infiltration seen on pathology.² As a caveat to the use of diagnostic criteria in a rare disease such as Schnitzler syndrome, the clinician must also thoroughly exclude other potential diagnoses.

Box 1. Strasbourg criteria².

Obligate criteria

• Chronic urticarial rash+.

• Monoclonal IgM or IgG.

Minor criteria

• Recurrent fever.

• Objective findings of abnormal bone remodelling with or without bone pain.

• A neutrophilic dermal infiltrate on skin biopsy.

• Leucocytosis and/or elevated CRP.

Definite diagnosis if

Two obligate criteria and at least two minor criteria if IgM, and three minor criteria if IgG.

Probable diagnosis if

Two obligate criteria and at least one minor criterion if IgM, and two minor criteria if IgG.

Case presentation

A woman in her late 40s with a history of psoriatic arthritis (diagnosed in 2017, currently on methotrexate) presented as an outside hospital transfer. She presented to an outside facility for submandibular swelling and tenderness, fever of 39.4ºC, fatigue, generalised myalgias, polyarticular arthralgia and headache. She then developed a non-pruritic maculopapular rash that started on her thighs and later spread to her chest and upper extremities as shown in figures 1 and 2. Her CRP was 277.5 mg/L (normal: 0.3–1 mg/L) and CT head revealed non-necrotic non-specific cervical and axillary lymphadenopathy (figure 3) for which she received intravenous methylprednisolone 125 mg and intravenous ampicillin–sulbactam. She was discharged with a course of amoxicillin–clavulanate with subsequent progression of her rash following 2 days of therapy. She presented to the same facility again for worsening symptoms 2 days later and was found to have an ESR of 71 mm/hr, CRP 200 mg/L, white cell count 17.6 k/uL and antineutrophilic cytoplasmic antibody (ANCA) negative. She received doses of vancomycin, ceftriaxone, acyclovir, azithromycin, doxycycline and dexamethasone for possible meningitis given the complaint of headache. However, the patient left the facility and presented to our institution for further care.

Figure 1.

The rash was maculopapular and appearance in her arms.

Figure 2.

The maculopapular rash as seen in thigh with the skin biopsy site marked A.

Figure 3.

Diffuse cervical lymphadenopathy seen in this patient with Schnitzler syndrome on her CT neck.

Investigations

She had a fever of 38.4^οC with a neutrophilic leucocytosis of 24.51 k/uL, CRP of 243 mg/L and a creatine kinase of 23 U/L. She was initially treated empirically with vancomycin and cefepime during her infectious evaluation which was notable for a negative monospot test and a history of consuming venison prepared by her husband as well recently visiting a state with high rates of tick-borne illnesses. Therefore, she was switched to doxycycline and ceftriaxone to cover Bartonella, Brucellosis and Q fever, and also to cover infective endocarditis given the very high fevers. Despite antibiotic therapy, she continued to be intermittently febrile up to 39.3^οC with migratory rash, generalised myalgias, and diffuse arthralgias worse in her metacarpophalangeal joints, wrists and ankles. Skin biopsy of the rash involving the left thigh revealed lymphohistiocytic infiltrate, mast cells and numerous neutrophils in the dermis consistent with chronic urticaria.

Her infectious workup including blood cultures, fungal battery, Epstein–Barr virus, Bartonella, Trichinella, Whipple disease, universal fungal PCR, Coxsackie, universal bacterial PCR, Parvovirus, Herpes simplex virus, Q fever, rocky mountain spotted, tuberculosis, syphilis, hepatitis, cytomegalovirus, HIV, cryptococcus, blood parasites and west nile were all negative. Throughout her course, her leucocytosis improved, but she developed new thrombocytopenia to 97 k/uL, anaemia to 10.6 g/dL, mildly elevated liver enzymes with aspartate transaminase (AST) peaking at 83 U/L and alanine transaminase (ALT) peaking at 101 U/L, ferritin increasing from 4000 to 45 000 ng/mL and lactate dehydrogenase (LDH) at 450 U/L as seen in Box 1. Her serum protein electrophoresis showed an M protein concentration of 0.29 g/dL and a poorly defined region of IgG.

Bone marrow and lymph node biopsy were pursued for this reason, and were negative for infections and lymphoproliferative malignancies. The investigations pursued are summarised in a pictorial format as shown in figure 4.

Figure 4.

Pictorial representation of the different investigations pursued.

Differential diagnosis

Her exposure to deer meat and recent travel prompted a comprehensive infectious workup which was additionally warranted in the setting of high, recurrent fevers. As such, infectious aetiologies should be excluded prior to the diagnosis of an autoinflammatory syndrome. The persistence of elevated inflammatory markers in the absence of a clear infectious aetiology and despite broad antibiotic therapies suggested an underlying malignancy or autoimmune/autoinflammatory process. The rate of change of ferritin, the lack of splenomegaly and normal triglycerides was not consistent with haemophagocytic lymphohistiocytosis. The flow cytometry and the pathology were negative for lymphoproliferative disorders. Her constellation of symptoms after this extensive workup was most consistent with Schnitzler syndrome with features including: chronic urticarial rash, poorly defined region of restricted mobility in the IgG and lambda lanes, recurrent fever >38^οC, a neutrophilic infiltrate on skin biopsy, leucocytosis >10 000 k/uL and elevated CRP >30 mg/L.

Treatment

She was given anakinra 100 mg subcutaneous injection once daily for a total of two doses with resolution of her fever, generalised myalgia and rash. Anakinra was chosen due to availability in the inpatient setting and also to evaluate the patient’s response to the short-acting agent. She was also started on a steroid taper with prednisone 40 mg for a week followed by a 10 mg decrease in the dose per week.

Outcome and follow-up

She was seen on follow-up 8 days post discharge. She had no new rashes, fever, with improving lymphadenopathy and myalgia. She has returned to daily activity and is only limited by her steroid dose affecting her sleep. With initiation of this regimen, her most recent CRP is 3.1 mg/dL, ferritin of 2701 ng/mL, ESR of 60 mm/hr with a white cell count of 11.51 k/uL, haemoglobin of 95 g/dL and platelets of 607 k/uLDefinitive treatment with interleukin 1 (IL-1) inhibitor therapy has been delayed by insurance.

Discussion

Schnitzler syndrome falls under the umbrella of cryopyrin-associated periodic syndromes (CAPSs) which is an autoinflammatory state caused by activating mutations in the NLRP3 gene. Increased levels of IL-1B and IL-6 were noted for these patients compared with healthy controls which points to increased inflammasome activity and innate immune system activation as seen in other autoimmune diseases.³ Lymphoproliferative disorders and amyloidosis can happen concurrently in these patients in about 15%–20% of cases.³ In a systemic review, it was noticed that the age of onset is around 50 years with a male predominance.³ A missense mutation of MyD88 L256P was found in one-third of patients with this syndrome on literature review.³ This genetic mutation is also linked to lymphoproliferative malignancies and this disease might represent a continuum.³ This syndrome needs to be differentiated from CAPS which is linked to activating mutations in the NLRP3 (nucleotide-binding oligomerisation domain leucine-rich repeats containing pyrin domain gene which is more frequent in a paediatric age range with neurological manifestations unlike Schnitzler). Hepatosplenomegaly and neuropathy are uncommon in Schnitzler syndrome and were not present in our patient.³

Other syndromes that can present similarly to Schnitzler syndrome include pyoderma gangrenosum (PG), polyarteritis nodosa (PN), CAPSs, tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF).

PG occurs due to upregulation of the innate immune system and differs from Schnitzler syndrome given the lack of rash and fever which are the predominant features of Schnitzler syndrome.⁴ PN occurs due to immune complex deposition in the arterial wall of the medium-sized arteries.⁵ It has many other symptoms including neuropathy, cutaneous vessel involvement, gastroenterology related symptoms and medium vessel vasculitis, which often manifests as renal artery aneurysms with biopsy finding of thickening of the aneurysmal vessel.⁵

CAPSs is an umbrella terminology for three other disease processes, all three of which are tied to a mutation of the gene NLRP3 (nacht domain-, leucine-rich repeat- and pyrin domain-containing protein 3).⁶ This leads to the formation of mutated cryopyrin which leads to over activation of the innate immune system. Familial cold autoinflammatory syndrome, which falls under CAPS, is commonly seen in the first year of life and is characterised by a systemic inflammatory response to cold air including fever, urticarial rash, conjunctival injection and arthralgia.⁶ Neonatal-onset multisystem inflammatory disease is the most severe syndrome under the CAPS umbrella and is characterised by fever, urticarial rash, abnormal facies with frontal bossing, protruding eyes, saddle-shaped nose, hearing loss, uveitis, aseptic meningitis and hepatosplenomegaly unlike Schnitzler syndrome.⁶ It is also marked by neutrophilic infiltrate on biopsy.⁶ The presence of a clear trigger, such as cold air, and the presence of conjunctival injection, which are both seen in familial cold autoinflammatory syndrome, are not seen in Schnitzler syndrome.⁷ However, the histology of familial cold autoinflammatory syndrome is similar to Schnitzler syndrome with neutrophilic infiltrate. Muckle–Wells syndrome, also under the CAPS umbrella, is characterised by fever, urticarial rash, hearing loss and secondary amyloidosis unlike Schnitzler syndrome.⁸ These symptoms are very different from Schnitzler syndrome; however, neutrophilic infiltrate is commonly seen on biopsy.⁸

TRAPS occurs due to increasing amount of soluble tumour necrosis factor (TNF) due to the inability of the mutant TNF receptor to bind soluble TNF in addition to impaired TNF-driven apoptosis.⁹ It has unique symptoms like abdominal pain, conjunctivitis, pleuritic chest pain, periorbital oedema, pharyngitis along with fever and urticarial rash similar to Schnitzler syndrome.⁹ However, unlike Schnitzler syndrome, the biopsy will reveal infiltration by lymphocytes and monocytes.⁹

FMF occurs due to mutation of the gene Mediterranean fever (MEFV) gene which encodes a protein called pyrin.¹⁰ Mutated pyrin leads to dysregulation of the innate immune system leading to fever, rash, abdominal pain and pleuritic chest pain unlike Schnitzler syndrome.¹⁰ These differences are also represented in table 1.

Table 1.

Features of Schnitzler syndrome, pyoderma gangrenosum (PG), polyarteritis nodosa (PN), cryopyrin-associated periodic syndrome (CAPS), tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF)^7–13

	Schnitzler syndrome	PG	PAN	CAPS	TRAPS	FMF
Skin feature	Migratory maculopapular rash	Inflammatory papule, pustule, bullae or plaque	Purpura, livedo reticularis and ulcers	Urticarial rash	Migratory rash	Erysipelas-like skin lesion
Clinical features	Fever, lymphadenopathy, diffuse myalgia	Fever	Medium vessel vasculitis, renal artery aneurysms, mononeuropathy, GI symptoms (abdominal pain and diarrhoea)	Familial cold autoinflammatory syndrome—fever, conjunctival injection, arthralgia. Muckle–Wells syndrome—headache, fever, joint pain, hearing loss, secondary AA amyloidosis. Neonatal-onset multisystem inflammatory disease—hearing loss, musculoskeletal symptoms, aseptic meningitis, skeletal abnormalities.	Migratory myalgias, lymphadenopathy, headache, conjunctivitis, GI symptoms, periorbital oedema	Fever, abdominal pain, pleuritic chest pain, joint pain
Biopsy	Lymphocytic and neutrophilic	Neutrophilic	Diffuse inflammation of the adventitia and thickening of the inner layers by loose connective tissue when biopsy taken from areas of aneurysm	Neutrophilic infiltrate	Superficial and deep infiltration by lymphocytes and monocytes	Non-specific
Specific markers	IgM kappa>IgM lambda	None	None	Mutations in IL1RN gene	TNFRSF1A genotype	Two pathogenic mutations in the MEFV gene
Associated with	Haematological malignancy	Inflammatory bowel disease, inflammatory arthritis	Hepatitis B Virus/Hepatitis C Virus infection	None	None	Also associations with inflammatory bowel disease in some literature

Anti-IL1 agents such as canakinumab are the mainstay of treatment for Schnitzler syndrome, CAPS, TRAPS, mevalonate kinase deficiency and FMF.^11–13 It has been associated with complete clinical response on day 7 compared with placebo in a randomised control trial.^11–13 Tocilizumab, which is anti-IL6 agent, can be an alternative in patients when anti-IL1 therapy is ineffective or cost-prohibitive.¹³

Learning points.

• This a rare disorder which falls under the umbrella of cryopyrin-associated periodic syndromes and is an autoinflammatory state.

• There is a male predominance with age of onset at 50 years.

• Schnitzler syndrome comprises chronic urticaria associated with IgM kappa monoclonal gammopathy along with bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy and intermittent fevers.

• Some patients with this syndrome have mutations that predisposes patients to lymphoproliferative malignancies.

• Anti-IL1 (canakinumab) and anti-IL6 (tocilizumab) agents are the mainstay of treatment.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).