Dan Lipsker

The Schnitzler syndrome. Four new cases and review of the literature.

The Schnitzler syndrome is characterized by a chronic urticarial eruption with a monoclonal IgM gammopathy. The other signs of the syndrome include intermittent elevated fever, joint and/or bone pain with radiologic evidence of osteosclerosis, palpable lymph nodes, enlarged liver and/or spleen, elevated erythrocyte sedimentation rate, and leukocytosis. The mean delay to diagnosis is more than 5 years, and this syndrome is of concern to internists and many medical specialists. Patients with this syndrome are often initially considered to have lymphoma or adult-onset Still disease, which are the main differential diagnoses. However, hypocomplementic urticarial vasculitis, systemic lupus erythematosus, cryoglobulinemia, acquired C1 inhibitor deficiency, hyper IgD syndrome, chronic infantile neurologic cutaneous and articular (CINCA) syndrome, and Muckle-Wells syndrome should also be excluded, because diagnosis relies on a combination of clinical and biologic signs and there is no specific marker of the disease. The disease pursues a chronic course, and no remissions have yet been reported. Disabling skin rash, fever, and musculoskeletal involvement are the most frequent complications. Severe anemia of chronic disease is another serious complication. The most harmful complication, however, is evolution to an authentic lymphoplasmacytic malignancy, which occurs in at least 15% of patients. This hematologic transformation can occur more than 20 years after the first signs of the disease, thus patients deserve long-term follow-up. Treatment is symptomatic and unsatisfactory. The skin rash is unresponsive to treatment, and nonsteroidal antiinflammatory drugs, antihistamines, dapsone, colchicine, and psoralens and ultraviolet A (PUVA) therapy give inconstant results. Fever, arthralgia, and bone pain often respond to nonsteroidal antiinflammatory drugs. In some patients, these symptoms and/or the presence of severe inflammatory anemia require steroids and/or immunosuppressive treatment, which ameliorate inflammatory symptoms but do not change the course of the skin rash.

Trends in melanoma epidemiology suggest three different types of melanoma

Background It has been suggested that the incidence of thin melanomas but not of thick tumours is rising in fair‐skinned populations, although the reason for this discrepancy is not understood.

The Schnitzler syndrome

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. 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.In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed.

Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis

radiotherapy, particularly at high doses. However, subcutaneous calcification is rare. Chest wall calcification has been described following fractionated radiotherapy in the chest wall and anterior supraclavicular fields as an additional treatment following surgery for breast cancer. Calcification over the sacrum has been described following radical radiotherapy in addition to surgery for cervical cancer. All cases described a radiation field overlap, thus magnifying the existing high dose of radiation to the skin. Also, as in our patient, this complication became clinically apparent many years after the initial radiotherapy, in some cases over 20 years later. The mechanism is most likely to represent the model of dystrophic calcification secondary to local trauma. Radiation causes cell membrane damage, leading to a massive influx of calcium. The calcium then crystallizes in the mitochondria, leading to failure of cell respiration and further cell necrosis. It is still unclear why this process takes many years to become clinically apparent, although chronic hypoxia from damage to blood vessels may play a role. The only study of treatment for localized dystrophic calcification, by Meline et al. in 1975, looked at the clinical course and treatment of three patients with subcutaneous calcification on the leg, one following a burn injury, and two others following voluntary injection of essence of turpentine. Tentative surgical removal led to recurrence and subsequent ulceration of the areas. Therefore complete surgical resection of the calcified area was recommended if the area had become ulcerated, suggesting that symptoms should be severe before such treatment be considered. In our patient we feel that despite the risks associated with extensive resection of the calcified area, she has had a good cosmetic and functional outcome from previous similar surgery. Therefore, increasing discomfort affecting her everyday activities and quality of life are good reasons for proceeding with additional surgery, and she is currently awaiting further surgical intervention. The long latency of this complication of radiotherapy in a cohort of patients who received high doses of radiation in the 1970s may prompt more to consult dermatologists over the next few years with similar symptoms. As the condition is known to progress to skin ulceration and increasing discomfort, we would suggest that surgical intervention should be considered for patients presenting in a similar manner, perhaps at an earlier stage than when ulcerated, as previously recommended.

Schnitzler's syndrome: diagnosis, treatment, and follow-up

Schnitzlers syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long‐term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzlers syndrome be suspected? How should the diagnosis of Schnitzlers syndrome be established? How should a patient with Schnitzlers syndrome be treated? How should a patient with Schnitzlers syndrome be followed up?. A diagnosis of Schnitzlers syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First‐line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow‐up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.

Low Blood Concentration of Hydroxychloroquine in Patients With Refractory Cutaneous Lupus Erythematosus: A French Multicenter Prospective Study

OBJECTIVE To study the relation between blood concentration of hydroxychloroquine and the clinical efficacy of hydroxychloroquine sulfate in a series of patients with cutaneous lupus erythematosus (CLE). DESIGN Prospective multicenter study. A staff dermatologist blinded to blood hydroxychloroquine concentrations performed a standardized review of medical records and assessment of hydroxychloroquine efficacy in the following 3 categories: complete remission, partial remission (clearing of >50% of skin lesions), or treatment failure. Whole-blood samples were collected for measurement of blood hydroxychloroquine concentration. SETTING Fourteen French university hospitals. PATIENTS Three hundred consecutive patients with subacute or chronic CLE who had been treated with hydroxychloroquine for at least 3 months. MAIN OUTCOME MEASURES The statistical significance of correlation between blood hydroxychloroquine concentration and efficacy of hydroxychloroquine and the statistical associations in univariate and multivariate analyses of complete remission with several variables. RESULTS The study included 300 patients with discoid lupus erythematosus (n = 160), subacute CLE (n = 86), lupus erythematosus tumidus (n = 52), chilblain lupus (n = 26), and lupus panniculitis (n = 16); 38 of these patients had 2 or more associated forms. Median blood hydroxychloroquine concentration was significantly higher in patients with complete remission (910 [range, <50 to 3057] ng/mL) compared with partial remission (692 [<50 to 2843] ng/mL) and treatment failure (569 [<50 to 2242] ng/mL) (P = .007). In the multivariate analysis, complete remission was associated with higher blood hydroxychloroquine concentrations (P = .005) and the absence of discoid lesions (P = .004). Thirty patients (10.0%) had very low blood hydroxychloroquine concentrations (<200 ng/mL) and may be considered nonadherent to the treatment regimen. CONCLUSION Monitoring hydroxychloroquine blood concentrations might improve the management of refractory CLE.

Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is recognized mostly by cutaneous spreading, or not having a leukaemic component. The prognosis is very poor.

Could Jessner’s Lymphocytic Infiltrate of the Skin Be a Dermal Variant of Lupus Erythematosus? An Analysis of 210 Cases

Background and Objective: The objective of this study was to evaluate the relationship between Jessner’s lymphocytic infiltration of the skin (JLI) and lupus erythematosus (LE), which has been the subject of debate since its initial description in 1953. Material and Methods: This is a retrospective study including all patients with a histopathologically ascertained diagnosis of JLI performed at the Laboratoire d’Histopathologie Cutanée of the Strasbourg University Hospital between 1993 and 2003. Information about patient characteristics and follow-up data were retrieved between 2004 and 2005. Special attention was paid to features indicative of LE. Results: 210 consecutive patients (102 women and 108 men) with a mean age 42 years were diagnosed with JLI in the reference period. 175 patients (83%) had multiple lesions and 32 patients (15%) had only a single lesion at the time of diagnosis (data not available in 3 patients). The head, neck and upper part of the thorax were involved in 171 patients (81%). An annular or arciform configuration and/or arrangement were present in 111 patients (53%). Lesions consisted of red (100%) papules or plaques (98%). Mean follow-up was 4 years. Sixteen patients (7.6%) had proven LE. Only 2 patients (1%) developed >4 ACR criteria of systemic LE. Furthermore, 1 patient had antiphospholipid antibody syndrome and 2 patients had rheumatoid arthritis. Conclusions: This high frequency of patients with typical features of LE strongly argues that JLI could be a dermal variant of LE and not an autonomous entity. It might be the cutaneous marker of a subset of LE patients with excellent prognosis.

The combination of complement deficiency and cigarette smoking as risk factor for cutaneous lupus erythematosus in men; a focus on combined C2/C4 deficiency

Background  Although deficiencies in the early components of the complement system were among the first identified genetic risk factors for systemic lupus erythematosus (SLE), only a few studies addressed their significance in patients with cutaneous LE (CLE). Among environmental factors, it was postulated that cigarette smoking might intervene in the pathogenesis of LE.

Long-term prognosis of patients treated for erythema migrans in France

Summary Background The long‐term prognosis of patients treated for erythema migrans has only rarely been assessed.