Introduction

Adult onset Still’s disease (AOSD) is a systemic auto-inflammatory condition of unknown etiology, characterized by intermittent spiking high fever, an evanescent, salmon-pink or erythematous maculopapular skin rash, arthralgia or arthritis and leukocytosis with at least 80 % neutrophils [1]. Other common symptoms include sore throat, lymphadenopathy, hepatomegaly, and splenomegaly [2]. High serum ferritin levels, elevated ESR and high CRP levels, absent antinuclear antibody (ANA) and rheumatoid factors (RF) are the most common laboratory findings [3, 4]. We report a case of AOSD in a 31-year-old Brazilian man presenting with both typical Still’s rash and atypical non-evanescent polymorphic cutaneous manifestations.

Case presentation

A 31-year-old Brazilian male presented with high quotidian fever and night sweats, non-productive cough, lower back pain and erythematous rash for two weeks. The fever occurred almost daily and ranged from 39 to 40 °C. The rash started from both hands and was characterized by multiple erythematous confluent roundish macules and papules that coalesced to form large, irregular erythematous plaques (Fig. 1). The rash lasted for a few days and then appeared with a different morphology on the flexor surfaces of his arms as an extensive erythematous linear urticarial eruption (Fig. 2a). Subsequently the rash appeared on his upper and lower trunk as multiple intensely pruritic linear urticarial streaks (Fig. 2b). Ibuprofen has been used intermittently to alleviate back pain as well as the fever with minimal relief. He denied any contacts with sick individuals, insect or animal bites and his last trip was to Brazil 10 months ago. He has been sexually active in a monogamous relationship.

Fig. 1
figure 1

Typical evanescent rash: Multiple non-pruritic confluent erythematous macules and papules on the dorsal surface of both hands that coalesced to form irregular erythematous plaques

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Fig. 2
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Atypical urticarial rash: a linear urticarial eruption on the flexor surface of arms. b Multiple intensely pruritic linear urticarial streaks on the upper and lower trunk

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On admission, his temperature was 39 °C and a persistent pigmented plaque V shaped was evident on his anterior chest extending down the midline to the umbilicus (Fig. 3). Further skin examination revealed a confluent salmon-pink papular eruption on his lower back area and a persistent pigmented plaque on the upper area of his back. Besides mild splenomegaly and a tender right wrist, left second and third proximal interphalangeal joints with no signs of swelling or erythema, the rest of the physical exam was unremarkable. Laboratory profile revealed severe neutrophilic leukocytosis (30,000, normal values 4800–10,800/mcL), and a highly elevated serum ferritin levels (>10,000, normal values 17.90–464.00 ng/mL). Autoantibodies (including ANA, ANCA, RF and anti-CCP) were negative. Blood cultures excluded common viral and bacterial infections and RPR were negative. Serological tests for Hepatitis B and C, HIV, Epstein-Barr and Cytomegalovirus were negative. Borrelia burgdorferi, Bartonella henselae, Rickettsia typhi, RMSF, Typhus and Parvovirus B-19 serologies were negative as well. Parasites for malaria or Babesia microti were undetectable on peripheral blood smear. Transthoracic echocardiogram was negative for vegetations and computed tomography (CT) of the neck, chest and abdomen revealed only borderline mild splenomegaly.

Fig. 3
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Atypical persistent rash: persistent pigmented plaque V shaped on the anterior chest extending down the midline to the umbilicus

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The clinical and laboratory findings were consistent with the diagnosis of AOSD according to Yamaguchi criteria [2]. He was started on 50 mg of prednisone. After 2 weeks of treatment, he returned to our hospital with very high daily spiking fever up to 39.5 °C, perfuse sweating, hypotension, elevated liver enzymes and severe leukocytosis with neutrophil predominance. No new skin lesions were noted. The patient was admitted to intensive care unit due to suspected systemic inflammatory response syndrome and was started on broad-spectrum antibiotics and intravenous fluids. Since the blood cultures were negative, antibiotics were discontinued. Anakinra 100 mg daily subcutaneously was added to 50 mg of prednisone with dramatic resolution of his febrile episodes. The patient was discharged with instructions to gradually taper prednisone.

After 1 week of treatment with Anakinra and while on 40 mg of prednisone the patient remained afebrile but new erythematous plaques appeared on lower abdominal quadrants and a skin biopsy was performed (Fig. 4). Skin biopsy showed a normal epidermis, with an inflammatory infiltrate in the dermis surrounding superficial blood vessels and adnexal structures, and the interstitium as well (Fig. 5a). The inflammatory infiltrate composed of lymphocytes, neutrophils and eosinophils (Fig. 5b). Because of the persistent cutaneous manifestations, the patient was advised to apply on the persistent eruptions of his chest and abdomen triamcinolone cream 0.5 % twice daily. After 1-month follow-up, the skin rash on the above areas almost resolved.

Fig. 4
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Atypical persistent pruritic eruption: edematous erythematous plaques on lower abdominal quadrants. Stich denotes the site of skin biopsy

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Fig. 5
figure 5

a Hematoxylin and eosin (H&E) stain showing periadnexal and perivascular infiltrate of inflammatory cells surrounding blood vessels, hair follicles and the interstitium (in between the vessels and adnexal structures). Original magnification at ×100. b H&E stain showing perivascular inflammatory infiltration of lymphocytes, neutrophils and eosinophils. Original magnification at ×400

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Discussion

Review of literature, via the PubMed search, using the terms adult onset Still’s disease, cutaneous manifestations and eruptions from 1985 to 2014 to retrieve data on the diversity in clinical manifestations and histopathological findings of polymorphic Still’s rash, was performed (Table 1). AOSD is a rare young adult systemic autoimmune disorder with diverse clinical manifestations and occasionally unwanted serious organ damage like acute liver failure, adult respiratory distress syndrome, disseminated intravascular coagulation, and hemophagocytic syndrome [5–10]. Thus, early recognition of AOSD is crucial and should be always considered in the differential diagnosis of a systemic inflammatory syndrome, particularly when extensive microbiological workup is negative.

Table 1 Clinical manifestations and histopathological findings of Still’s disease
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The typical skin rash of AOSD is an evanescent salmon-pink non-pruritic or mildly pruritic maculopapular rash, with nonspecific histologic characteristics comprised of a superficial perivascular lymphocytic and scattered neutrophilic infiltrate in the upper epidermis [11–13]. The lesions often develop on the extremities and over the trunk during the peak of the fever and then resolve. AOSD can also present with various atypical cutaneous manifestations and persistent pruritic eruptions (PPEs) are common [14].

PPEs are polymorphic both in morphology and distribution patterns. The more common patterns include lichenoid, linear and dermographism-like eruptions [14], persistent pruritic coalescent papules and plaques [15–17] with linear pigmentation [18], dermal and mucosal hyperpigmentation [19], amyloidosis-like skin eruption [20], generalized peau d’orange appearance of the skin [21], generalized persistent erythema [22], prurigo pigmentosa-like eruption [23, 24], vesiculopustules [25], urticaria [26, 27] and fixed papular lesions [28]. The latter are characterized by atypical wheals, present for more than 24–36 h, with symmetrical distribution [29, 30]. Pruritic lesions are usually evident with the presence of linear dermographism from scratching, as was evident in our patient. The most common atypical rash manifestation in AOSD includes the persistent pruritic coalescent papules and plaques and linear lesions [31].

In addition to the typical maculopapular evanescent Still’s rash, our patient had also an atypical persistent pigmented eruption manifested with different cutaneous morphology and geographic distribution over his body. The linear urticarial streaky and dermographism-like eruptions on upper extremities and torso sequentially gave place to persistent erythematous plaques on his chest and abdomen. We believe that this type of polymorphic cutaneous eruption may be a predictor of severe systemic inflammatory disease like in our case, and could be associated with activation of macrophages and natural killer cells in addition with increased production of IL-2, interferon-γ and tumor necrosis factor (TNF)- α. High levels of IL-8 were demonstrated in Still’s rash and this cytokine is considered as the inducer of the acute phase of inflammatory cascade in AOSD [32]. We believe that the cutaneous response to Anakinra was slower than the systemic one, since the febrile episodes resolved rapidly after initiation of Anakinra whereas the skin lesions persisted. The introduction of Anakinra therapy in our patient may have slightly exacerbated the pre-existing cutaneous lesions and caused new ones at the initiation of the treatment probably due to its immune modulating effects. Anakinra has been shown to cause interstitial granulomatous drug reaction [33, 34]. The application of topical corticosteroids facilitated the resolution of the cutaneous manifestations.

The histological features of persistent eruptions include parakeratosis [35], necrotic keratinocytes in the upper epidermis and a perivascular and interstitial inflammatory infiltrate of lymphocytes and neutrophils in the upper- and mid-dermis [36–39]. In urticarial lesions the histopathologic findings demonstrate an intense infiltrate of mature CD15+ neutrophils between the dermal collagen bundles. This clinicopathological entity has recently been described as neutrophilic urticarial dermatosis (NUD) [40].

Dyskeratosis and dermal mucinosis represent distinctive cutaneous lesions of AOSD [41, 42]. The presence of fibrin thrombi in the small vessel with scarce inflammatory cell infiltration, suggestive of vasculopathy [25] has also been observed in cases of AOSD. Leukocytoclastic cutaneous vasculitis [43, 44] with mixed cryoglobulinemia [44] in AOSD has been described only rare in the literature.

Eosinophils that are commonly seen in drug-induced eruption are consistently lacking in the AOSD-associated skin lesions [14]. Perez et al. described a case of AOSD-related persistent erythematous rash characterized by papules and plaques in which skin biopsy revealed perivascular infiltration of the small vessels in the dermis by eosinophils, histiocytes and lymphocytes [45]. In our case, the histopathology findings of the new persistent cutaneous eruption included the presence of several perivascular eosinophils not just in the dermis but also in the interstitium. The eosinophilic cutaneous manifestation could be either drug-related (i.e. antibiotics, Anakinra) or AOSD-associated.

Treatment of AOSD has been empirical. Non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids, disease modifying anti-rheumatic drugs (DMARDs), methotrexate (MTX), cyclosporine, azathioprine, sulfasalazine and minocycline have been used to treat this rare disease. Recently effective biologic agents including TNF-a, IL-1 and IL-6 antagonist have been used for steroid-resistant AOSD [46]. Laskari et al. provided evidence that Anakinra monotherapy or in combination with a DMARD, such as MTX may be the treatment of choice for patients with refractory Still’s disease [47]. MTX is recommended in patients with polyarthritis and allows for steroid dose sparing in AOSD [48]. Our patient did not respond to corticosteroid treatment, but showed dramatic response to initiation of Anakinra treatment.

In summary, AOSD can manifest with atypical skin lesions that have highly distinctive but non-pathognomonic pathological features and are usually associated with severe disease. Still’s rash can mimic various disorders with maculopapular, urticarial, linear and lichenoid manifestations and skin biopsy of those atypical cutaneous lesions is strongly recommended before or during the treatment course of AOSD because it allows rheumatologists and pathologists to recognize those specific distinctive histopathological characteristics and put the correct diagnosis.