Introduction

Adult onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, characterized by spiking fever, usually exceeding 39 °C, an evanescent cutaneous manifestations, arthralgia or arthritis, and multiorgan involvement. AOSD occurs worldwide, and women seem to be affected more often than men. AOSD usually affects young people, with 75 % of the cases reporting disease onset between 16 and 35 years of age [1]. AOSD may affect several organs and the full constellation of symptoms may not be present at onset, so the evolution of case may take several weeks or months [2]. Fever is a constant feature, associated with cutaneous lesions and arthralgia or arthritis of big joints. Other organs involved are the liver, the cardiopulmonary, and the hematologic systems. There are several sets of classification criteria for AOSD, all developed from retrospective studies, but Yamaguchi’s criteria [3] were shown to be by far the most sensitive (93.5 %) [4]. Cutaneous manifestations are well accepted as a major diagnostic criterion, and, more important, the skin is the most easily accessible site for obtaining histological samples. Despite these well-established diagnostic criteria, delayed diagnosis is still common, and the skin lesions are often misdiagnosed as infectious exanthemas or allergic reactions to drugs. Herein, a case of AOSD is reported that presented with skin lesions which allowed an easy diagnosis. Moreover, the literature has been reviewed for cases of AOSD in whom cutaneous lesions and the corresponding histology had been described in detail.

Clinical case

A 35-year-old man presented with 15-day history of high fever, with evening spike of 40 °C, asthenia, cough, dyspnea, and a sense of tightness in the chest, not responsive to antibiotics (cephalosporin) and anti-inflammatory (ibuprofen) therapy. Laboratory investigations revealed elevated C reactive protein (262 mg/L; n.v. <5 mg/L), alanine amminotransferase (ALT) (167 U/L; n.v. 5–45 U/L), and ferritin (258 μg/L; n.v. 20–200 μg/L) and increased alpha-1 protein (9.6 g/L; n.v. 2.4–5.6 g/L), alpha-2 protein (8 g/L; n.v. 4.8–9.6 g/L), and gamma globulin (17.6 g/L; n.v. 8–16 g/L). Moreover, there was increased creatinine (2.3 mg/dL; n.v. 0.59–1.29 mg/dL) with diuresis reduction (600 mL/day) and normal blood cells count and triglycerides. Echocardiography showed minimal reduction of global function of left and right ventricles (ejection fraction of 33 %), with pericardial effusion referable to acute myopericarditis. Thoracic computed tomography (CT) scan revealed bilateral parenchymal densifications and interstitial thickening, more evident in the right superior lobe. Continuous positive airway pressure (CPAP) was started for respiratory failure. Screening for autoimmune diseases was negative, such as antinuclear antibodies (ANA), extractable nuclear antigens (ENA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-liver and anti-kidney microsomes antibodies (LKM), and rheumatoid factor. All microbiologic tests performed were negatives (research on urine of Streptococcus pneumoniae and Legionella pneumophila antigens, malaria test, research on blood of Aspergillus antigen, Epstein-Barr virus (EBV) DNA, hepatitis C (HCV) RNA, hepatitis B (HBV) DNA, Toxoplasma gondii DNA, serologies for Salmonella typhi, Brucella abortus, Rickettsia conorii, Legionella pneumophila, Coxiella burnetii, Herpes simplex viruses 1–2, adenovirus, coxsackie virus, cytomegalovirus, parvovirus B19, enteroviruses, leptospira, respiratory syncitial virus (RSV), influenza viruses A–B, parainfluenzae viruses 1–3, EBV, West Nile virus, chikungunya virus, dengue virus, Leishmania donovani, Mycoplasman pneumoniae, Chlamydia pneumonie, Borrelia burgdoferi, Quantiferon TB gold test, coproculture). During the fifth day of hospitalization, the patient developed erythematous-edematous plaques on the trunk and upper limbs, confluent in wide areas of erythema, moderately itching (Fig. 1). A skin biopsy taken from the left side of the trunk demonstrated mild epidermal spongiosis and dermal superficial inflammatory infiltrate, consisting of perivascular lymphocytes and histiocytes (Fig. 2a, b). Interstitial and intravascular neutrophils were also evident among the inflammatory cells, confirmed by their positive for anti-CD-15 antibody by immunohistochemistry (Fig. 2c). No hyphae and/or mycotic spore were detected with Alcian-PAS stain. A therapy with intravenous steroids (metilprednisolone 500 mg for 3 days and then 75 mg for 7 days), intravenous immunoglobulins (300 mg for 5 days), and oral antibiotics (ciprofloxacin 500 mg twice a day for 7 days) was started, achieving remission of symptoms (autonomous breathing and stable hemodynamic values) within 2 weeks. Steroids were gradually decreased, and an immunosuppressive therapy with methotrexate 15 mg/week was started. At a 1-month follow-up, the skin was still completely clear from lesions and cardiopulmonary symptoms were resolved.

Fig. 1
figure 1

Erythematous-edematous plaques on the trunk and upper limbs (a), confluent in wide areas of erythema (b)

Fig. 2
figure 2

Mild epidermal spongiosis and dermal superficial inflammatory infiltrate, consisting of perivascular lymphocytes and histiocytes (hematoxylin and eosin, original magnification × 20) (a); interstitial and intravascular neutrophils among the inflammatory cells (hematoxylin and eosin, original magnification × 40, arrows) (b); confirmed by immunohistochemistry positive for CD-15 antibody (original magnification × 20) (c)

Discussion

An accurate review of literature through the PubMed search (1987–2013; terms: adult onset Still’s disease, adult onset Still’s disease and skin, neutrophilic urticarial dermatosis) was performed to retrieve data regarding the cutaneous findings of patients with AOSD. The mean age at diagnosis is 35 years, and the disease affects a slightly larger number of women as compared to men. The fever is usually more than 39 °C, typically quotidian or double quotidian in pattern, with the highest temperatures seen in the late afternoon or early evening; it is transient and its incidence is estimated at about 96 % according to the largest retrospective studies of literature [57]. Arthralgia and arthritis of big joints (oligoarticular and transient but sometimes evolving into a more severe, destructive, symmetrical, and polyarticular form) occur in the majority of patients with AOSD, with incidences ranging from 64 to 100 %, although it is not mandatory for diagnosis in adults [4, 8]. Other manifestations are hepatomegaly and elevation in liver enzymes (50–75 %) [4], sore throat (69 %) [4], cardiopulmonary involvement like pleuritis (26.4 %) or pericarditis (23.8 %) [6, 10], tamponade, myocarditis, pulmonary fibrosis, pleural effusions, and adult respiratory distress syndrome [4]. Laboratory test largely reflects the systemic inflammatory nature of the disease process, and none of the findings are specific for AOSD. An increased sedimentation rate is universal, and there is no association with rheumatoid factor or ANA. Patients frequently have a marked blood neutrophilia, probably secondary to bone marrow granulocyte hyperplasia [4]. According to the largest retrospective studies, the rash occurs in about 80 % of patients [1, 57, 9], being present from the initial onset of the disease in 28 % of patient [9]. The most common cutaneous manifestation is an evanescent salmon-pink or erythematous maculopapular eruption which frequently appears during febrile attacks and is predominantly found on the proximal limbs and trunk with rare involvement of the face and distal limbs [1, 57, 9]. The rash can be mildly itchy or may be associated with burning sensation. In general, it lasts for hours and may change daily, enhancing with the fever spike and fading with the fever down; however in some patients, the duration of skin lesions correlates with the degree of systemic activity and may last for days or weeks without change [1117]. However, other types of cutaneous manifestations have been described. The most frequent are persistent plaques and linear pigmentation [1114], fixed plaques [1520], and urticarial lesions [2124]. The latter are characterized by “atypical wheals,” persistent for more than 24–36 h, with symmetrical distribution [25]. Less common manifestations include angioedema [26], eczematous lesions [10], acne-like lesions [10], pustules on hands and feet [27, 28], persistent generalized erythema [29, 30], and flagellate erythema [31] (Table 1). Histological findings of classic skin lesions show normal epidermis overlying a mixed mild perivascular inflammation of the superficial dermis composed of lymphocytes and neutrophils [32, 33]. Persistent papules and plaques are histologically characterized by necrotic keratinocytes in the upper half of the epidermis with a neutrophilic infiltrate in the papillary dermis [33, 34]. In patients with urticarial lesions, the histopathologic findings show an intense neutrophilic infiltrate around the blood vessels but also with significant interstitial involvement. These elements are mature CD15+ neutrophils and often have a peculiar disposition between the dermal collagen bundles, in single file or “en file indienne.” This type of dermatosis has recently been described as a clinicopathological entity called neutrophilic urticarial dermatosis (NUD) [35]. Leukocytoclasia is present, but blood vessel walls are not damaged and therefore vasculitis can be excluded [35]. NUD has been found also in other diseases such as monogenic autoinflammatory syndromes, Schnitzler syndrome, and neutrophilic diseases like Behçet syndrome and Crohn’s disease [35]. NUD is then considered a cutaneous marker of autoinflammation, which can unify more clinical entities under a common pathogenetic mechanism. Typical Still’s disease rash needs to be differentiated from various other types of maculopapular eruptions, which are often drug- or infection-related. The histopathologic finding of a superficial dermal infiltrate containing neutrophils supports the diagnosis of Still’s disease rash [33]. Eosinophils, which are commonly seen in drug eruption, are consistently absent in AOSD-associated skin lesions. The atypical persistent lesions, on the other hand, need to be differentiated from a variety of disorders that may manifest urticarial papules, erythematous to violaceous or pigmented lichenoid papules, or plaques clinically and necrotic keratinocytes histologically. The unique pattern of dyskeratotic cells, singly or in aggregates, mainly located in the upper epidermis, and the presence of a neutrophilic and lymphocytic infiltrate in the upper dermis appears very distinct and allows relatively easy differentiation from the disorders in which infiltrate is in band at dermo-epidermal junction [33]. Schnitzler’s syndrome is a paradigm of an acquired/late onset autoinflammatory disease which needs to be differentiated from AOSD. The diagnostic criteria include a chronic-relapsing urticarial rash frequently leaving a brown hyperpigmentation and usually not pruritic. Histologically, it manifests with a neutrophilic urticarial dermatosis [8, 25], a monoclonal IgM component, and at least two of the following signs: fever (recurrent and above 40 °C), joint and/or bone pain, lymphadenopathy, spleen and/or liver enlargement, increased ESR, neutrophilia, and abnormal bone imaging findings [36]. The monoclonal IgM component is a defining feature of the syndrome and is present in all patients with Schnitzler’s syndrome. The clinical presentation in our patient fulfilled the Yamaguchi’s criteria for diagnosis of AOSD. The skin lesions were not the first sign of disease, but they prove to be essential for diagnosis. Moreover, exanthematous/urticarial manifestations reflected one of the most common skin patterns of AOSD and clinicopathological correlation allowed the correct diagnosis. Early recognition of AOSD can be particularly helpful during the initial workup when the clinical manifestations do not yet meet the Yamaguchi’s criteria. A careful evaluation of skin lesions and a proper lesion selection for histological examination may be very important for the early diagnosis of AOSD. A clinicopathological correlation is then essential as both clinical and histological features are not pathognomonic.

Table 1 Characteristics of patients with cutaneous involvement in adult onset Still’s disease