Schnitzler Syndrome Clinical Features

Schnitzlersyn-drome (SS) is a rare acquired spontaneous systemic inflammatory disease characterized by monoclonal immunoglobulin (M-protein)emia and chronic urticaria. First published by Schnitzler in 1972 At present, there are nearly 250 cases reported, including 2 cases reported in China. Repeated fever, myalgia, joint pain, and swollen lymph nodes are also common manifestations. The disease is often missed clinically until the common causes of autoimmune diseases, tumors and infections are excluded. This article reviews the clinical and diagnostic characteristics of Schnitzler syndrome.

1.Etiology and pathogenesis

In 1991, Saurat et al found that high titers of monoclonal anti-IL-1α IgG-type antibodies were present in the serum of SS patients, suggesting that IL-1 plays a role in the pathogenesis of SS. A number of studies have found that the activation of systemic inflammatory disorders characterized by IL-1β synthesis and release disorders caused by multiple pathways such as lipopolysaccharide and ATP also supports IL-1 as the key to the pathogenesis of SS. Monoclonal IL-1 antibodies such as anakinra are effective against SS and also counteract the effects, but whether IL-1 is promoted or not inhibited. Lipopolysaccharide is the main component of the cell wall of G-bacteria. The effect of pefloxacin on some cases can counteract its role in the pathogenesis of some SS. There is also evidence that IL-6, IL-18 may be involved in the pathogenesis. The deposition of M protein around the superficial perivascular layer of the dermis and the lower layer of the dense plate may trigger a local inflammatory reaction and cause urticaria. In 1993, Rybojad et al reported two cases of SS with congenital C4 deficiency, suggesting that C4 is deficient or associated with SS. In 2002, Kuenzli et al reported that SS was given after interferon α-2β, or that interferon alpha could up-regulate the expression level of IL-1 receptor antagonist in vivo. Terpos et al found that the serum VEGF concentration in SS patients was ≥ 3.5 times the upper limit of normal, suggesting that it is involved in the pathogenesis of SS. In addition, mutations in the NLRP3 gene are also associated with the onset of SS.

2.Clinical manifestations

The age of onset of the disease is usually ≥ 40 years old, the average age of diagnosis is 60 years old, male: female is 1.45:1. It is characterized by M proteinemia, chronic urticaria, recurrent fever, bone pain, joint pain, and occasional hepatosplenomegaly and lymphadenopathy. Chronic recurrent urticaria is the first clinical symptom of typical SS. It is often affected by the trunk and limbs, and can also affect the face and neck. The rash is a transient wheal with a diameter of 0.5 to 3.0 cm, which can be completely relieved within 12 to 36 hours. The frequency of seizures varies from one to several times a day. It is non-itching at the beginning of the disease, and about 30% of it can be itchy in the late stage. Studies have also shown that 55% of SS has varying degrees of itching. Cold or hot urticaria can also be seen. 90% of SS can have recurrent hyperthermia with Tmax>40°C, no chills, and good tolerance. There is no correlation between fever and urticaria. 70% of the SS showed bone pain, the pelvis, femur and tibia were often affected, and the spine, clavicle and forearm bones were also affected. At the distal end of the femur and at the proximal end of the humerus, a periosteal reaction with radionuclide concentration is often seen, suggesting focal osteosclerosis. MRI often shows T1 low signal and T2 high signal. Bone biopsy is normal or non-specific inflammatory cell infiltration. 60% of SS can cause inflammatory arthritis with joint pain. In 2010, some scholars reported a severe heterotopic ossification after a total hip arthroplasty in SS, suggesting that SS is active in bone metabolism. In 1994, a scholar reported a case of osteolysis with SS. 50% of SS visible lymph node lesions, axillary and inguinal lymph nodes are often involved, and histopathology is non-specific reactive hyperplasia. About 1/3 of the SS showed hepatosplenomegaly. In addition, clinical manifestations such as sensory and motor-related pain have also been reported. M proteinemia is a serological marker of SS, 90% of which are monoclonal IgM-κ, another IgG-λ, IgG-κ, IgM-κ and IgA-λ mixed type and IgM-κ and IgG-κ mixed type There are reports. However, the pathophysiology between it and clinical manifestations is unknown. It has also been reported that IgE may act on the pathogenesis of SS. In patients with SS, urine is often seen in the urine. Systemic inflammatory markers such as ESR and CRP in SS patients increased, 90% had leukocytosis, and 10% had thrombocytopenia and inflammatory anemia. Consumable hypocomplementemia also occurs, but there are also reports of congenital complement defects.

3.Histopathological findings of skin lesions

The histological manifestations are mainly vascular perivascular and interstitial neutrophilic inflammation in the dermis, also known as neutrophilic dermatophytosis. 37% of SS showed no leukocyte fragmentation vasculitis. Direct immunofluorescence is a manifestation of leukocytic vasculitis, with IgM, IgG, and C3 deposited in dermal vascular deposits or IgM in the basement membrane zone. Immunoelectron microscopy showed that IgM was also deposited in keratinocytes and in the lower layer of dense plates.

4.Diagnosis and differential diagnosis

In 2001, after Lipsker et al. first proposed the SS diagnostic criteria, a number of diagnostic criteria have been proposed and revised, but most of them only consider the presence of IgG variants. Strasbourg diagnostic criteria are the latest revised SS diagnostic criteria, which are based on the original diagnostic criteria, taking into account the clinical manifestations, serology, imaging and pathology of SS, but the diagnostic sensitivity and specificity need further Test, the main diagnostic criteria: 1 chronic urticaria-like rash; 2 monoclonal IgM or IgG. Secondary diagnostic criteria: 1 recurrent fever (Tmax>38 °C); 2 pathological bone remodeling with or without bone pain (bone imaging, MRI, bone-derived ALP); 3 skin biopsy showed dermal neutral granules Cell infiltration (neutrophic urticaria-like skin disease); 4 neutrophils > 10000 / mm 3 and / or CRP > 30 mg / L. The diagnosis needs to meet 2 major criteria and 2 secondary criteria (IgM) or 3 secondary criteria (IgG). The proposed diagnosis needs to meet 2 major criteria and 1 secondary criteria (IgM) or 2 secondary criteria ( IgG). Schnitzler syndrome can be considered in patients with chronic recurrent urticaria with monoclonal M globulinemia, and Schnitzler-like syndrome is considered in patients with rash similar to Schnitzler syndrome. Because the treatment principles of the two are significantly different, it is necessary to make a differential diagnosis. SS needs to be differentiated from various diseases such as systemic lupus erythematosus from urticaria-like lesions and monoclonal M-proteinemia, as shown in Table 1.

5.Treatment

SS treatment to correct systemic inflammatory response and prevent complications. Conventional treatment mainly includes anti-histamine drugs for pruritus and anti-inflammatory and immunosuppressant applications against systemic manifestations, which are poorly effective and toxic. Patients with mild illness who have no significant effect on their lives should first avoid contact with the disease and block the systemic inflammatory response. 25% of patients can be relieved by colchicine 1~2mg per day, hydroxychloroquine (200mg, 2 times) /d) and non-steroidal anti-inflammatory drugs are also available, and pefloxacin is effective in a small number of patients. Clinical efficacy was evaluated after 6 months of treatment. Anakinra, a short-acting IL-1 receptor antagonist, is a first-line treatment for patients with severe medical conditions. The daily dose is 100 mg (subcutaneous administration), which can quickly relieve symptoms, but often Relapsed soon after stopping the drug. Patients with ineffective anakinra treatment should first verify the diagnosis of SS. If the diagnosis is clear, consider increasing the dose of anakinra in parallel with colchicine or pefloxacin. In addition, long-acting IL-1 receptor antagonists such as Canakinumab and Rilonacept may also be used. Cyclosporine, cyclophosphamide, methotrexate, thalidomide, glucocorticoid, interferon alpha-2beta, pamidronate, pefloxacin, anti-CD20 monoclonal antibody rituximab (Rituximab), anti-IL-6 receptor monoclonal antibody tocilizumab (Tocilizumab) and other drugs have also been reported. In 2010, Aikawa et al reported that one case of SS combined with glucocorticoids and adalimumab (Adalimumab, anti-TNF-α monoclonal antibody) showed significant relief, but studies have shown that its therapeutic effect is limited. In 2015, Aouba and other combination of rituximab, cyclophosphamide and glucocorticoid treatment of 1 case of SS achieved complete remission. The patient’s condition can be completely relieved after 2 years, and the drug can be stopped for 2 weeks to evaluate whether the disease persists. Some scholars believe that colchicine can be given immediate treatment for 3 to 6 months after considering withdrawal. White blood cell count and CRP are the main monitoring indicators in the course of treatment. After the indicator returns to normal, it should be continuously tested for 3 months, and then monitored at least twice a year. VEGF is sensitive to treatment and can be used as a secondary diagnostic and follow-up indicator.

6.Prognosis

SS is mostly a benign course, but no spontaneous remission has been reported. After 10 years of illness, 15% to 20% of patients have progressed to the risk of malignant lymphoproliferative diseases such as IgM lymphoma and Waldenstrom’s macroglobulinemia and directly affect the prognosis.