Urticarial rash,fever, and arthritis: A case of refractory Adult‐onset Still's disease with good response to tocilizumab

Adult‐onset Still's disease (AOSD) is a rare, systemic inflammatory disorder of not completely understood etiology. Aberrant activation of the innate immune system and overproduction of several pro‐inflammatory mediators are considered a critical component in disease pathogenesis. AOSD still poses a challenge due to the broad range of differential diagnoses and no specific biomarkers. Four cardinal symptoms are quotidian spiking fever, joint involvement, evanescent salmon pink‐rash rash, and leukocytosis with neutrophilia. We present a case of a 61‐year‐old female with a recurrent urticarial rash accompanied by attacks of high fever, tender joints, sore throat, enlarged liver, elevated inflammatory reactants, and hyperferritinemia. After an extensive workup, the patient fulfilled the criteria of AOSD. She was refractory to the glucocorticosteroids and disease‐modifying anti‐rheumatic drugs (DMARDs). Finally, after several unsuccessful attempts to achieve disease control with traditional DMAR's administration of Tocilizumab (TCZ), a humanized anti‐IL‐6 receptor antagonist resulted in substantial disease improvement. Since skin manifestations are a common feature of AOSD, it should be among differential diagnoses in patients with skin lesions and constitutional symptoms. Biologic agents represent a significant therapeutic advance in patients with AOSD refractory to conventional therapy.     

Clinical follow‐up study of adult‐onset Still’s disease

Eighteen patients with adult‐onset Still’s disease have been followed up for 3–22 years in our department. Initial manifestations were fever with skin rash in 14 patients, fever, skin rash and sore throat in two, skin rash in one and arthralgia in one. During the follow‐up period, typical skin rash was seen in all patients, of them five patients (29%) revealed atypical skin rash simultaneously. Atypical rash included persistent erythema with pigmentation in two, persistent plaques and papules with linear erythema in two and edema of the eyelids mimicking dermatomyositis in one. Persistent papules and plaques revealed histologically characteristic features, such as dyskeratotic keratinocyte and liquefaction degeneration as well as a sparse superficial dermal infiltrate containing scattered neutrophils. In patients of chronic articular type and polycyclic systemic type, atypical skin rash, lymphadenopathy and hyperferritinemia were noted to be significantly higher than those of monocyclic type. These factors might be prognostic factors of adult‐onset Still’s disease in our study.     

Persistent pruritic papules and plaques: a characteristic histopathologic presentation seen in a subset of patients with adult‐onset and juvenile Still's disease

Background: ‘Persistent pruritic papules and plaques' of Still's disease represents a recently described eruption seen in a subset of patients. Most cases reported in the literature to date have been associated with adult‐onset Still's disease. Methods: We present the clinical and histopathologic examinations of three female patients ranging in age from 15 to 54 years. Results: Our three patients each presented with clinical findings consistent with Still's disease. The youngest patient suffered from the juvenile form of Still's disease (systemic‐onset juvenile rheumatoid arthritis). Each patient had a persistent, pruritic eruption with histopathologic findings of dyskeratosis confined to the upper layers of the epidermis as well as a sparse superficial dermal infiltrate containing scattered neutrophils. Conclusions: These cases confirm the characteristic clinical and histopathologic findings of ‘persistent papules and plaques of Still's disease’ and show the potential for this eruption in both the adult and juvenile age groups. Fortna RR, Gudjonsson JE, Seidel G, DiCostanzo D, Jacobson M, Kopelman M, Patel RM. Persistent pruritic papules and plaques: a characteristic histopathologic presentation seen in a subset of patients with adult‐onset and juvenile Still's disease.     

Refractory macrophage activation syndrome in the setting of adult‐onset Still disease with hemophagocytic lymphohistiocytosis detected on skin biopsy treated with canakinumab and tacrolimus

A 19‐year‐old Caucasian female with adult‐onset Still disease (AOSD) presented for evaluation of an acute clinical decompensation and atypical annular papules and plaques with purpura on the lower extremities. A punch biopsy demonstrated histiocytes with engulfed degenerated erythrocytes and lymphocytes, consistent with hemophagocytic lymphohistiocytosis (HLH). HLH, clinically referred to as macrophage activation syndrome, is a rare complication of AOSD and is life‐threatening. Relevant clinical, laboratory, and histologic features of this diagnosis are reviewed.     

Serum soluble CD163 and proinflammatory chemokines may be biomarkers of the onset of adverse events in dabrafenib plus trametinib combination therapy for advanced melanoma

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon‐inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune‐related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.     

Three cases of pigmented cosmetic dermatitis‐like eruptions associated with primary Sjögren's syndrome or anti‐SSA antibody

Pigmented cosmetic dermatitis‐like (Riehl's melanosis‐like) pigmentation was reported in three of 27 patients with primary Sjögren's syndrome. But case reports of such eruptions are rare. We describe three cases of such eruptions associated with primary Sjögren's syndrome or anti‐SSA antibody and possible associations with specific types of human leukocyte antigen (HLA) and infiltrating lymphocytes. These middle‐aged Japanese women had reticular facial pigmentation and histopathological examination revealed interface dermatitis, melanophages, and dense lymphocytic infiltration around hair follicles and sweat ducts. HLA typing revealed common antigenic equivalents or genetic typing of HLA‐A2, DR52, DPA1(02:02) and DPB1(05:01). Immunohistochemical staining revealed major subsets of T cells to be CD8 and CD45RO. Some Foxp3‐ and few IL17‐positive cells were found in strong contrast to the major CD4 subset of infiltrated T cells in annular erythema associated with Sjögren's syndrome. Apparently, our patients' pigmentation represented a specific etiology associated with primary Sjögren's syndrome or anti‐SSA antibody.     

In‐transit recurrence of Merkel cell carcinoma associated with Bowen's disease: The first reported case successfully treated by avelumab

A 65‐year‐old Japanese man presented with a dome‐shaped nodule, the base of which was contiguous with a dull brown plaque, on the left leg. After local excision of the cutaneous lesion and left inguinal lymph node dissection, several dermal and subcutaneous nodules developed successively on the left lower extremity. Hematoxylin–eosin staining of the primary cutaneous lesion demonstrated uniform neoplastic cells arranged in a trabecular pattern extending from the dermis to subcutis. Mitotic figures were abundant. Although the overlying epidermis was substantially intact, the Merkel cells had invaded the epidermis, resulting in Pautrier‐like microabscesses. The hyperplastic epidermis adjacent to the nodule consisted of abnormally growing atypical keratinocytes. The enlarged left inguinal lymph node and successive secondary nodules contained Merkel cells similar to those in the primary nodule. Immunohistochemically, most tumor cells were positive for CAM5.2, synaptophysin, chromogranin A, CD56 and vimentin. The tumor cells in the left inguinal lymph node were positive for CAM5.2, synaptophysin and cytokeratin 20 but negative for CM2B4, and less than 1% of the cells expressed programmed cell death ligand 1. The patient was treated with avelumab, which showed significant efficacy against the in‐transit recurrence. Two months later, all nodules had disappeared completely. We describe a case of in‐transit recurrence of Merkel cell carcinoma that was associated histologically with Bowen's disease and was successfully treated with avelumab. Although accumulation of additional cases is needed, avelumab therapy may be a useful treatment for in‐transit recurrence of Merkel cell carcinoma.     

Treatment of pigmented purpuric dermatoses with Narrow‐band UVB: a report of six cases

Background Pigmented purpuric dermatoses (PPD) are a group of chronic disorders that pose a therapeutic challenge. Objective In this study, we evaluated the effectiveness of narrow band ultraviolet B (NB UVB) in the treatment of PPD. Patients and methods Six patients of PPD were treated with NB UVB: one patient had Majocchi's purpura and five had Schamberg's disease. NB UVB was given on three weekly basis till clearance, then maintenance treatments were scheduled as twice weekly for 3 weeks and once weekly for another 3 weeks. The patients were followed up to 1 year. Results Successful treatment was achieved in all treatment patients after 24–28 NB UVB treatments and maintenance of nine treatments. Only two patients showed flare of their lesions after stoppage of NB UVB and efficiently controlled with further 14 NB UVB treatments. Conclusion NB UVB is effective in the treatment of PPD and should be considered as a treatment option for PPD.     

Cutis laxa for diagnosis of γ1‐heavy‐chain deposition disease: Report of four cases

Heavy‐chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy‐chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1‐HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ‐HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.     

Successful TS‐1 monotherapy as the second‐line treatment for advanced extramammary Paget's disease: A report of two cases

There is no standard chemotherapeutic treatment for advanced extramammary Paget's disease, though the effectiveness of some chemotherapy regimens, including docetaxel, has been reported. In this report, we report that TS‐1 monotherapy was effective in two patients with advanced extramammary Paget's disease after docetaxel treatment failure. TS‐1 monotherapy may be useful as the second‐line treatment for patients with advanced extramammary Paget's disease.     

High‐risk human papillomavirus in a child with digital pigmented Bowen's disease: Case report and dermoscopic findings

Squamous cell carcinoma in situ, also known as Bowen's disease (BD), is a skin malignancy most commonly seen in middle‐aged and elderly adults. Pediatric BD is rare and can be a diagnostic challenge for physicians. Digital BD has largely been associated with human papilloma virus. We report an immunocompetent 11‐year‐old girl with periungual pigmented BD induced by high‐risk human papilloma virus.     

Relationship between dermoscopy and pathology in a case of clonal‐type pigmented Bowen's disease: Observation with vertical‐view dermoscopy

Pigmented Bowen's disease (pBD) is a subtype of Bowen's disease, which presents clinically as a well‐circumscribed, hyperpigmented plaque. Its clinical manifestations are not fully characterized, and differential diagnoses include various pigmented skin lesions. Dermoscopy could be useful for the diagnosis, although nothing has been reported on the dermoscopic features of clonal‐type pBD. We herein report a first case of clonal‐type pBD on the sole and its dermoscopic features. Dermoscopy showed brown to blue‐gray dots/globules and focally anastomosing lines on the non‐weight‐bearing area, while the weight‐bearing area had a brown to blue‐gray fibrillar‐like pattern. To investigate the relationship between dermoscopy and histopathology, we focused on the melanin distribution in the horny layer of the epidermis, and used vertical dermoscopy observation. We investigated the relationship between dermoscopy and pathology by melanin depth estimation using a color lightness value.     

Congenital “self‐healing” Langerhans cell histiocytosis (Hashimoto‐Pritzker disease): A report of two cases with the same cutaneous manifestations but different clinical course

Congenital self‐healing Langerhans cell histiocytosis or Hashimoto‐Pritzker disease is a rare condition present at birth or in the neonatal period characterized by small reddish‐brown crusted papulonodular lesions. In most cases these lesions are not accompanied by systemic findings and tend to involute spontaneously within weeks or months, but in other cases there may be extracutaneous involvement and/or recurrence of the disease. This emphasizes that the clinical course is variable and a long‐term follow‐up is mandatory in order to reveal possible systemic involvement. We describe two cases of congenital self‐healing Langerhans cell histiocytosis with widespread and very similar cutaneous manifestations but different clinical course. The first patient had multisystemic disease (with lymph nodes, bones, liver and lungs affected) that required systemic therapy. The second patient had cutaneous and bony lesions that resolved spontaneously. We think that the adjective “self‐healing” is misleading and should be abandoned. We stress the importance of a complete systemic evaluation and the necessity of a long‐term follow‐up.     

Clinical significance of serum soluble T‐cell immunoglobulin and mucin domain 3 levels in systemic sclerosis: Association with disease severity

T‐cell immunoglobulin and mucin domain 3 (TIM‐3) has been thought to play a crucial role in the negative regulation of immune responses. Here, we examined the levels of serum soluble TIM‐3 (sTIM‐3) in patients with systemic sclerosis (SSc) and evaluated the results with respect to the clinical features of the disease. Patients with diffuse cutaneous SSc (dcSSc) had higher levels of sTIM‐3 than those with limited cutaneous SSc and healthy individuals. Serum sTIM‐3 levels were positively correlated with the severity of skin sclerosis in early phase dcSSc. Moreover, serum sTIM‐3 levels were increased more often in patients with renal crisis and cardiac involvement than in those with normal sTIM‐3 levels. These results suggest that serum sTIM‐3 levels may be increased in patients with early phase dcSSc and associated with cardiac involvement and renal crisis. Measurement of serum sTIM‐3 may be useful for risk stratification in the early stage of the disease.     

Analysis of incomplete excisions of basal‐cell carcinomas after breadloaf microscopy compared with 3D‐microscopy: a prospective randomized and blinded study

Basal‐cell carcinomas may show irregular, asymmetric subclinical growth. This study analyzed the efficacy of ‘breadloaf’ microscopy (serial sectioning) and three‐dimensional (3D) microscopy in detecting positive tumor margins. Two hundred eighty‐three (283) tumors (51.2%) were put into the breadloaf microscopy group; 270 tumors (48.8%) into the 3D microscopy group. The position of any detected tumor outgrowths was identified in clock face fashion. The time required for cutting and embedding the specimens and the examination of the microscopic slides was measured. Patient/tumor characteristics and surgical margins did not differ significantly. Tumor outgrowths at the excision margin were found in 62 of 283 cases (21.9%) in the breadloaf microscopy group and in 115 of 270 cases (42.6%) in the 3D microscopy group, constituting a highly significant difference (p < 0.001). This difference held true with incomplete excision of fibrosing (infiltrative/sclerosing/morpheaform) tumors [32.9% in the breadloaf microscopy group and 57.5% in the 3D microscopy group (p = 0.003)] and also with solid (nodular) tumors [16.1 and 34.2%, respectively (p < 0.001)]. The mean overall examination time required showed no important difference. In summary, for detection of tumor outgrowths, 3D microscopy has almost twice the sensitivity of breadloaf microscopy, particularly in the situation of aggressive/infiltrative carcinomas.     

Oral lichenoid reaction showing multiple ulcers associated with anti‐programmed death cell receptor‐1 treatment: A report of two cases and published work review

Anti‐programmed cell death receptor‐1 (PD‐1) antibodies represent an effective treatment opinion for advanced melanoma and non‐small‐cell lung cancer, as well as other cancerous entities. Immune checkpoint inhibitors such as anti‐PD‐1 antibody result in a unique side‐effect profile, commonly described as immune‐related adverse events (irAE). These irAE affect the skin, gastrointestinal tract, liver, endocrine system and other organ systems. We report two cases of oral lichenoid reaction showing multiple ulcers associated with nivolumab treatment. Both patients presented with multiple ulcers covered with fibrinous plaque over the entire oral mucosa, lips and tongue. Histopathological examination of ulceration showed epithelial necrosis and subepidermal clefts with dense band‐like layers of lymphohistiocytic infiltrate within the upper dermis. Nivolumab was interrupted in both cases. Case 1 responded well to topical corticosteroids. Case 2 required oral corticosteroids, however, nivolumab could be restarted without recurrence of oral ulcers. We provide a comprehensive review of reported cases of lichenoid reaction showing multiple oral ulcers associated with anti‐PD‐1 therapy to date. Early recognition and management may improve treatment, avoid discontinuation of life‐saving therapy and maintain quality of life in these patients.