Increased severity and epidermal alterations in persistent versus evanescent skin lesions in adult-onset Still disease

To the Editor: Adult-onset Still disease (AOSD) is characterized by an evanescent salmon-pink maculopapular eruption. Cases of atypical persistent skin eruption (APSE) in AOSD have been reported,1Lee J.Y.-Y. Hsu C.-K. Liu M.-F. Chao S.-C. Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients.Semin Arthritis Rheum. 2012; 42: 317-326Crossref PubMed Scopus (59) Google Scholar possibly associated with more frequent systemic complications and corticosteroid resistance.2Narváez Garcia F.J. Pascual M. López de Recalde M. et al.Adult-onset Still's disease with atypical cutaneous manifestations.Medicine (Baltimore). 2017; 96: e6318Crossref PubMed Scopus (36) Google Scholar We conducted a multicentric retrospective study of 36 patients having AOSD (on the basis of Yamaguchi or Fautrel criteria) with skin involvement. We found higher serum ferritin levels and confirmed an increased resistance to treatment in patients with APSE compared with those with an evanescent rash. Mann-Whitney test and Fisher's exact test were used to compare quantitative and qualitative variables, respectively. The median follow-up was 16 months; 47% of patients (17/36) only had a typical evanescent rash, 28% (10/36) only had an APSE, and 25% (9/36) presented both types of eruptions. APSEs manifested as fixed linear urticaria (7/19, 37%), fixed urticaria (3/19, 16%), fixed maculopapular rash (3/19, 16%), and pigmented papules and plaques (3/19, 16%) (Fig 1, A and B). There were isolated cases of APSE manifesting as erythema of the upper eyelids and dorsal hands (dermatomyositis-like eruption, Fig 1, C and D), lichenoid lesions (Fig 1, E), scaly erythema, pustular eruption, papulonodular rash, and purpura. In total, 19 biopsies of evanescent rash and 20 biopsies of APSE were blindly examined (Drs Battistella and Vignon-Pennamen). AOSD rash histology (typical evanescent rash and APSE) was associated with dermal edema and perivascular and interstitial inflammatory infiltrates composed of lymphocytes and neutrophils. Neutrophilic urticarial dermatosis was observed in 22% of cases (8/36). The following factors were increased in patients with APSE (n = 19) compared with patients without APSE (n = 17) (Table I): face involvement (P = .008), ferritin level >1500 ng/mL (P = .015), and number of lines of treatment to achieve complete remission (P < .05). The epidermal alterations present on histology of APSE biopsies differed from those present on histology of evanescent rash biopsies (P = .02); the alterations included acanthosis, spongiosis, superficial necrotic keratinocytes, and abundant neutrophilic infiltrates (40% vs 21%, not significant) (Fig 1, F).Table IClinical, biologic, and evolutive characteristics of AOSD patients with and without APSECharacteristicAOSD patients with APSEAOSD patients without APSE, evanescent rash only, N = 17P value∗P values compare total AOSD patients with APSE and AOSD patients with evanescent rash only.Total, N = 19APSE only, n = 10APSE + evanescent rash, n = 9Age, y, mean (range)46 (27-80)52 (28-80)48 (27-67)46 (17-74).4Sex, % (N), female:male74 (14/19):26 (5/19)50 (5/10):50 (5/10)100 (9/9):0 (0/9)65 (11/17):35 (6/17).7Delay of diagnosis, month ± SEM10 ± 2.212 ± 2.97 ± 2.86.8 ± 1.6.3Skin eruption distribution, % (N) Limbs84 (16/19)80 (8/10)89 (8/9)100 (17/17).2 Trunk89 (17/19)80 (8/10)100 (9/9)76 (13/17).4 Face47 (9/19)40 (4/10)56 (5/9)6 (1/17).008Pruritus, % (N)63 (12/19)50 (5/10)78 (7/9)53 (9/17).7Arthralgia, % (N)89 (17/19)90 (9/10)89 (8/9)100 (17/17).5Arthritis, % (N)58 (11/19)70 (7/10)44 (4/9)29 (5/17).1Organ involvement, % (N)47 (9/19)30 (3/10)67 (6/9)24 (4/17).18 Elevated liver enzymes47 (9/19)30 (3/10)67 (6/9)18 (3/17).08 Seritis, pleuritis and pericarditis16 (3/19)20 (2/10)11 (1/9)6 (1/17).6 Abdominal pain5 (1/19)10 (1/10)0 (0/9)0 (0/17)1 Neurologic complications5 (1/19)10 (1/10)0 (0/9)6 (1/17)1Complications, % (N)11 (2/19)10 (1/10)11 (1/9)18 (3/17).6 Macrophage activation syndrome11 (2/19)10 (1/10)11 (1/9)12 (2/17)1 Disseminated intravascular coagulation0 (0/19)0 (0/10)0 (0/9)6 (1/17).5Serum ferritin level >1500 ng/mL, % (N)78 (14/18)60 (6/10)89 (8/9)33 (5/15).015CRP, mg/L, mean ± SEM188.5 ± 45.7181.1 ± 42.3196.7 ± 53.8119.4 ± 29.2ESR, mm, mean ± SEM85 ± 34.766 ± 13.3104 ± 7.067.7 ± 19.5.4Skin biopsy, % (N) Neutrophil rate >50%40 (8/20)50 (5/10)30 (3/10)21 (4/19).3 Interstitial distribution45 (9/20)40 (4/10)50 (5/10)53 (10/19).7 Epidermal alterations30 (6/20)40 (4/10)20 (2/10)0 (0/19).02 Necrotic keratinocytes15 (3/20)30 (3/10)0 (0/10)0 (0/19).2 Acanthosis25 (5/20)30 (3/10)20 (2/10)0 (0/19).05 Parakeratotic hyperkeratosis10 (2/20)20 (2/10)0 (0/10)0 (0/19).5 Spongiosis15 (3/20)20 (2/10)10 (1/10)0 (0/19).2 Karyorrhexis60 (12/20)60 (6/10)60 (6/10)37 (7/19).2 Dermal edema70 (14/20)60 (6/10)80 (8/10)74 (14/19)1 Vacuolar interface changes20 (4/20)30 (3/10)10 (1/10)21 (4/19)1 Intravascular neutrophils40 (8/20)40 (4/10)40 (4/10)53 (10/19).5 Neutrophils around the sweat glands50 (10/20)30 (3/10)70 (7/10)47 (9/19)1Treatment Immunosuppressive agents and biologic therapy, % (N)68 (13/19)80 (8/10)55 (5/9)47 (8/17).3 Treatments to achieve complete remission, mean ± SEM2.1 ± 0.52.2 ± 0.42 ± 0.61.2 ± 0.3.045Death, % (N)0 (0/19)0 (0/10)0 (0/9)0 (0/17)1Statistically significant values are in bold.AOSD, Adult-onset Still disease; APSE, atypical persistent skin eruption; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SEM, standard error of the mean.∗ P values compare total AOSD patients with APSE and AOSD patients with evanescent rash only. Open table in a new tab Statistically significant values are in bold. AOSD, Adult-onset Still disease; APSE, atypical persistent skin eruption; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SEM, standard error of the mean. APSE occurred in 14%-78% of patients with an AOSD diagnosis.1Lee J.Y.-Y. Hsu C.-K. Liu M.-F. Chao S.-C. Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients.Semin Arthritis Rheum. 2012; 42: 317-326Crossref PubMed Scopus (59) Google Scholar, 2Narváez Garcia F.J. Pascual M. López de Recalde M. et al.Adult-onset Still's disease with atypical cutaneous manifestations.Medicine (Baltimore). 2017; 96: e6318Crossref PubMed Scopus (36) Google Scholar APSE is usually characterized by linear urticaria, pigmented papules and plaques, and fixed maculopapular rash, and facial involvement is more common in APSE than evanescent rash.1Lee J.Y.-Y. Hsu C.-K. Liu M.-F. Chao S.-C. Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients.Semin Arthritis Rheum. 2012; 42: 317-326Crossref PubMed Scopus (59) Google Scholar Comparisons of APSE and evanescent rash histology revealed more frequent epidermal changes in APSE biopsies, including necrotic keratinocytes in the superficial epidermis and more abundant neutrophilic infiltrates.1Lee J.Y.-Y. Hsu C.-K. Liu M.-F. Chao S.-C. Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients.Semin Arthritis Rheum. 2012; 42: 317-326Crossref PubMed Scopus (59) Google Scholar Some studies have suggested an association between APSE and AOSD severity.2Narváez Garcia F.J. Pascual M. López de Recalde M. et al.Adult-onset Still's disease with atypical cutaneous manifestations.Medicine (Baltimore). 2017; 96: e6318Crossref PubMed Scopus (36) Google Scholar In this work, we show that APSE patients had higher ferritin levels and needed a higher number of line of treatments to achieve complete remission in comparison with patients without APSE, confirming that APSE could be associated with more severe AOSD forms. Dermatomyositis-like APSE, which is very similar to real dermatomyositis cases regarding photodistribution, edema of the upper eyelids, Gottron papules, and vacuolar degeneration of the basal layer, could be a bad prognostic factor in AOSD. Ten cases of dermatomyositis-like eruption have been previously reported in AOSD; these cases were associated with a resistance to corticosteroids, a required immunosuppressive therapy, and a high rate of mortality (40%).1Lee J.Y.-Y. Hsu C.-K. Liu M.-F. Chao S.-C. Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients.Semin Arthritis Rheum. 2012; 42: 317-326Crossref PubMed Scopus (59) Google Scholar, 3Saito A. Sato Y. Miyata M. Nishimaki T. Kasukawa R. Two cases of adult Still's disease with atypical rash [Japanese].Ryumachi. 1998; 38: 516-522Google Scholar, 4Moraites E. Myers D.J. Lloyd R. Longley B.J. A 38-year-old woman with eyelid discoloration. Heliotrope-like manifestation of adult-onset Still disease (AOSD).Arch Dermatol. 2012; 148: 947-952Google Scholar, 5Ohashi M. Moriya C. Kanoh H. et al.Adult-onset Still's disease with dermatomyositis-like eruption.J Dermatol. 2012; 39: 958-960Google Scholar In conclusion, atypical skin features of AOSD might be associated with more severe AOSD forms, and clinicians and pathologist should be able to identify them.