Our data confirm the predominance of streptococcal infections and sarcoidosis among patients with EN. Tuberculosis has virtually disappeared, since the last case was observed in 1962. Various viral or bacterial diseases are rarely associated with EN, but all patients were not thoroughly investigated. A large and prospective study should be performed in order to determine the true prevalence of associated diseases in EN. In the absence of specific symptoms, exhaustive investigations are not cost-effective.

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.

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The arylpropionic acid derivatives (APADs) ketoprofen and tiaprofenic acid can provoke photoallergic dermatitis. Possible cross-reactivity between APADs is of importance in patients using nonsteroidal anti-inflammatory drugs. Because of the similarities in chemical structures, we investigated patients with photoallergy to ketoprofen or tiaprofenic acid, in order to study cross-reactivity between APADs and a possible pattern of cross-reactivity between benzophenone-containing molecules, so as to determine the molecular basis of photoallergy to ketoprofen or tiaprofenic acid. 10 patients with photoallergy to topical ketoprofen, 2 with photoallergy to oral tiaprofenic acid, and 15 control subjects with no history of contact dermatitis from APADs, nor from benzophenone-containing molecules, were photopatch tested in triplicate with ketoprofen, tiaprofenic acid, other APADs (alminoprofen, fenoprofen, flurbiprofen, ibuprofen and naproxen), benzophenone-containing molecules (fenofibrate, oxybenzone, sulisobenzone), and unsubstituted benzophenone. 1 set was irradiated with UVA light, 1 with solar-simulated irradiation and 1 dark control. Tests were read at 2, 3 and 4 days. Patients reacted to both ketoprofen and tiaprofenic acid (12/12), fenofibrate (8/12), oxybenzone (3/12) and unsubstituted benzophenone (11/12), but not to other APADs, nor to sulisobenzone. Tests remained negative in control patients. Photoallergy is due to the benzophenone moiety of ketoprofen, or to the very similar thiophene-phenylketone of tiaprofenic acid, but not to their arylpropionic function. This induces cross-reactivity to fenofibrate and oxybenzone but not to APADs without a benzophenone moiety, which may therefore probably be used in such patients. Unsubstituted benzophenone should be added to standard phototesting series.

The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.

Partial deficiency of C4, C2 or C4 and C2 is a common finding in patients with CLE. Most male patients with CLE are smokers. It is thus suggested that the combination of cigarette smoking and complement deficiency could be a risk factor for LE in men.

The Schnitzler syndrome is the association of chronic urticaria, intermittent fever, osteosclerotic bone lesions and a monoclonal IgM gammopathy. It is not yet firmly established whether the monoclonal immunoglobulin component plays a part in the pathophysiology of the urticarial lesions. Immunoblotting on epidermal and dermal human skin extracts as well as immunoelectron microscopic (IEM) studies on Lowicryl K4M-embedded skin sections were performed in three patients with the Schnitzler syndrome. Western blotting on epidermal extracts showed the presence of IgM-kappa antiskin autoantibodies in two patients. These antibodies displayed the same isotype as the monoclonal components and recognized a 280-290-kDa antigen in one patient and a 200-kDa antigen in the other patient. IEM studies showed sparse IgM deposits in the epidermis, around the keratinocytes, near the desmosomes in one patient and dense deposits below the lamina densa, in the region of the anchoring fibrils, in another patient. Antiskin IgM autoantibodies of the same isotype as their monoclonal gammopathies can be present in the serum of some patients with the Schnitzler syndrome. These IgM antibodies seem to deposit in vivo in the epidermis and at the dermal-epidermal junction, in the region of the anchoring fibrils. These findings suggest that the monoclonal gammopathy plays a part in the pathophysiology of the skin rash. They also suggest patient heterogeneity both in the skin antigens that are recognized as well as in their localization.