Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

Corymbiform cutaneous disorders in pediatric dermatology: Exploring this pattern of presentation beyond secondary syphilis.

"Corymbiform" is a term found in medical literature as early as 1876 to describe a central larger lesion with smaller surrounding lesions, leading to the appearance of an irregular border. While the term in current medical literature most often describes a possible morphology of secondary syphilis, the authors have noted this pattern presenting in other cutaneous conditions. We present a commentary on the corymbiform pattern in dermatology including a series of photographs of cutaneous disorders presenting in a corymbiform morphology in pediatric patients. While the term corymbiform is not commonly used in the present-day dermatologic literature, increased recognition and use of this term may aid in the recognition of various dermatologic diagnoses presenting in a less common morphology and may also lend to increased fluidity of dermatologic descriptions in the literature.

Cross-Comparison of Inflammatory Skin Disease Transcriptomics Identifies PTEN as a Pathogenic Disease Classifier in Cutaneous Lupus Erythematosus.

Tissue transcriptomics is used to uncover molecular dysregulations underlying diseases. However, the majority of transcriptomics studies focus on single diseases with limited relevance for understanding the molecular relationship between diseases or for identifying disease-specific markers. In this study, we used a normalization approach to compare gene expression across nine inflammatory skin diseases. The normalized datasets were found to retain differential expression signals that allowed unsupervised disease clustering and identification of disease-specific gene signatures. Using the NS-Forest algorithm, we identified a minimal set of biomarkers and validated their use as diagnostic disease classifier. Among them, PTEN was identified as being a specific marker for cutaneous lupus erythematosus and found to be strongly expressed by lesional keratinocytes in association with pathogenic type I IFNs. In fact, PTEN facilitated the expression of IFN-ß and IFN-κ in keratinocytes by promoting activation and nuclear translocation of IRF3. Thus, cross-comparison of tissue transcriptomics is a valid strategy to establish a molecular disease classification and to identify pathogenic disease biomarkers.

IL-1ß and IL-17 in cutaneous lupus erythematous skin biopsies: could immunohistochemicals indicate a tendency towards systemic involvement?

BACKGROUND: Only a fraction of patients with cutaneous lupus erythematosus (CLE) will eventually progress toward systemic disease (SLE). OBJECTIVE: To find inflammatory biomarkers which could predict the progression of cutaneous lupus erythematosus (CLE) into systemic lupus erythematosus (SLE) using immunohistochemical (IHC) assays. METHODS: Immunohistochemical markers for cytotoxic, inflammatory, and anti-inflammatory responses and morphometric methods were applied to routine paraffin sections of skin biopsies, taken from lesions of 59 patients with discoid lupus, subacute lupus, and lupus tumidus. For the diagnosis of SLE, patients were classified by both the American College of Rheumatology (ACR-82) and the Systemic Lupus International Collaborating Clinics (SLICC-12) systems. RESULTS: Skin samples from CLE/SLE+patients presented higher expression of IL-1ß (ARC-82: p=0.024; SLICC-12: p=0.0143) and a significantly higher number of cells marked with granzyme B and perforin (ARC: p=0.0097; SLICC-12: p=0.0148). Biopsies from CLE/SLE- individuals had higher expression of IL-17 (ARC-82: p=0.0003; SLICC-12: p=0.0351) and presented a positive correlation between the density of granzyme A+and FoxP3+ cells (ARC-82: p=0.0257; SLICC-12: p=0.0285) and CD8+ cells (ARC-82: p=0.0075; SLICC-12: p=0.0102), as well as between granulysin-positive and CD8+ cells (ARC-82: p=0.0024; SLICC-12: p=0.0116). STUDY LIMITATIONS: Patients were evaluated at a specific point in their evolution and according to the presence or not of systemic disease. The authors cannot predict how many more, from each group, would have evolved towards SLE in the following years. CONCLUSIONS: In this cohort, immunohistochemical findings suggested that patients with a tendency to systemic disease will show strong reactivity for IL-1ß, while those with purely cutaneous involvement will tend to express IL-17 more intensely.

A rare case of cutaneous lupus erythematosus presenting with periorbital erythema and edema.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease that can manifest itself with a variety of skin symptoms. Periorbital erythema, a rare variant of CLE, presents challenges in terms of diagnosis and treatment. Here, we report a case of CLE presenting with periorbital erythema and edema. A 42-year-old female patient presented with complaints of erythema, edema, and scaling on the right eyelid that started four months ago. A skin biopsy was performed on the lesioned skin of the eyelid to differentiate dermatomyositis, cutaneous lupus erythematosus, sarcoidosis, lupus vulgaris, and cutaneous lymphoma. Histopathological examination revealed focal hyperkeratosis and parakeratosis on the surface of the epidermis, vacuolar degeneration in the basal layer of the epidermis, lymphocyte exocytosis with necrotic keratinocytes, edema in the dermis, melanophages, and perivascular, periadnexal lymphocytic reaction. Laboratory tests showed negative antinuclear antibody and anti-dsDNA, but positivity for anti-Ro-52. In the absence of any other complaints, the patient was diagnosed with cutaneous lupus erythematosus presenting with periorbital erythema based on clinical, histopathological, and laboratory findings. Hydroxychloroquine 200 mg/day, topical corticosteroid, and topical tacrolimus were administered. Two months later, significant improvement in the lesions was observed. In conclusion, it should be kept in mind that periorbital erythema can develop as a rare variant of CLE and can be misdiagnosed as contact dermatitis, dermatomyositis, sarcoidosis, or cutaneous lymphoma. Additionally, the ANA and anti-dsDNA antibodies are often found to be negative in these cases. In establishing the diagnosis, firstly considering the disease, followed by histopathological examinations and laboratory tests, is crucial.

Off-Label Use of Janus Kinase Inhibitors in Inflammatory Cutaneous Diseases.

Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders. Oral JAK inhibitors, upadacitinib, tofacitinib, and baricitinib targeting JAK 1 and JAK 1/3, respectively, are currently US Food and Drug Administration (FDA)-approved for several rheumatic conditions. However, studies have shown that JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions. As a result, for recalcitrant diseases, JAK inhibitors are potential alternative therapies due to their broad targeted inhibitory mechanisms. In this case series, we present the successful off-label treatment of 6 cases across dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease, which failed conventional therapies with upadacitinib or tofacitinib. In the 3 dermatomyositis cases, use of upadacitinib or tofacitinib demonstrated positive clinical outcomes, with no recurrent symptoms in cases where upadacitinib was used. In treatment-resistant hidradenitis suppurativa, upadacitinib demonstrated reduced systemic flares and moderate cutaneous symptom improvement. In the case of cutaneous Crohn’s disease, upadacitinib resulted in reduced cutaneous symptoms without new flares. Tofacitinib resulted in completed resolution of cutaneous symptoms in our patient’s case of cutaneous lupus erythematosus. JAK inhibitors upadacitinib and tofacitinib may be potential drug candidates in patients with treatment-resistant disease, especially in cases of inflammatory cutaneous conditions such as dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease. Further studies with larger sample sizes among these conditions are warranted to assess potential broader applicability of the positive results demonstrated in our patient cases. J Drugs Dermatol. 2023;22(12):1183-1190. doi:10.36849/JDD.7500.

Manifestation of subacute cutaneous lupus erythematosus during treatment with anti-PD-1 antibody cemiplimab - a case report.

Introduction: The anti-programmed cell death protein 1 (PD-1) antibody cemiplimab has shown promising results in the treatment of unresectable or metastatic squamous cell carcinoma, however, frequently leads to immune-related adverse events limiting therapy efficacy. Although cutaneous side effects are common, only very few cases of cutaneous lupus erythematosus have been reported under anti-PD-1 immunotherapy. So far, no case of cutaneous lupus has been described under treatment with cemiplimab. Case report: For the first time, we report the case of a patient with advanced squamous cell carcinoma, who developed clinical and histological findings in sun-exposed skin that were consistent with anti-SS-A/Ro antibody-positive subacute cutaneous lupus erythematosus (SCLE) under treatment with cemiplimab. Additionally, laboratory chemical analyses revealed a severe immune-related hepatitis without clinical symptoms. Both, the SCLE and the hepatitis, resolved after the administration of topical and systemic steroids and the discontinuation of anti-PD-1 therapy. Conclusion: Treatment with cemiplimab can be associated with the appearance of cutaneous lupus erythematosus in sun-exposed areas. Application of topical and systemic glucocorticoids can lead to a rapid resolution of the skin eruptions. Moreover, our case illustrates the possibility of simultaneously occurring severe immune-related adverse events. This highlights the importance of additional diagnostics to avoid overlooking additional immune-related adverse events.

Subacute cutaneous lupus erythematosus following ribociclib therapy for metastatic breast cancer.

INTRODUCTION: Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) has been associated with drugs with different mechanisms of action, including anti-hypertensives, tumour necrosis factor-α inhibitors and even some chemotherapy medicines. In the last years, a few reports have been described in patients treated with cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib. CASE REPORT: Here, we describe a case of DI-SCLE in association with ribociclib and exemestane in a woman diagnosed with metastatic breast cancer. MANAGEMENT AND OUTCOME: Topical mometasone was prescribed for two weeks with complete resolution of lesions, also abemaciclib was substituted for ribociclib, and the patient had stable disease with no relapse of DI-SCLE. DISCUSSION: To our knowledge, this is the first report of ribociclib-induced SCLE but based on the DI-SCLE reported cases associated others CDK4/6 inhibitors, the role of this family of drugs in dermatopathology must be further investigated.

A case of reactive granulomatous dermatitis associated with neonatal lupus erythematosus.

Neonatal lupus erythematosus (NLE) is an uncommon disorder affecting approximately one out of 20 000 live births in the United States. Common manifestations of NLE include cutaneous eruptions and cardiac involvement. The typical rash of NLE most closely resembles the rash of subacute cutaneous lupus erythematosus both clinically and histopathologically. We present a case of reactive granulomatous dermatitis (RGD) associated with NLE in a 3-month-old male in whom the initial histopathology and immunohistochemistry were concerning for hematologic malignancy. RGD is a unifying term used to describe cutaneous granulomatous eruptions that occur in response to a variety of stimuli, including autoimmune connective tissue diseases. Our case demonstrates the range of histopathological findings that may be present in the setting of NLE.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions.

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.

Comedonic lupus, a rare variant of chronic cutaneous lupus erythematosus (CCLE): case series and literature review.

BACKGROUND: Cutaneous lupus erythematosus (CLE) is an autoimmune disease with several clinical presentations. The chronic form predominantly presents as discoid rashes but may present with less common morphological findings that can sometimes make diagnosis difficult. Comedonic lupus is a rare and underdiagnosed variant, with unknown etiology and still poorly defined treatment. METHODS: The report illustrates a series of five cases of patients diagnosed with comedonic lupus, and it reviews 18 cases previously published in the literature. RESULTS: The clinical presentation is of comedonal lesions, mostly located on the face, making a differential diagnosis with other benign conditions such as acne vulgaris, Favre-Racouchot syndrome, and syringoma, emphasizing the importance of clinical practice and histopathology for diagnostic confirmation. CONCLUSIONS: There is scarcity in the literature regarding the condition and therapeutic possibilities for these cases of comedonic lupus.

A 30-Year-Old Woman with a History of Autoimmune Hyperthyroidism Presenting with Fever and Oral Ulcers, Diagnosed with Discoid Lupus Erythematosus.

BACKGROUND Lupus erythematosus (LE) is mainly clinically divided into cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) depending on the presence of multi-system manifestations. The most common subtype of CLE is discoid lupus erythematosus (DLE). Graves' disease (GD) is immunologically characterized by lymphocytic infiltration of the thyroid gland and the presence of thyroid-stimulating hormone (TSH) receptor antibodies (TSH-R-Ab), and is the most common autoimmune pathogenic cause of hyperthyroidism. Autoimmune thyroid dysfunction has been widely described in association with rheumatic diseases. A certain rate of coexistence of GD with LE, mainly SLE, has been reported in the literature. Herein, we present a rare case of Graves' hyperthyroidism complicated with DLE. CASE REPORT A 30-year-old female patient, with a history of hyperthyroidism and discontinued methimazole treatment, initially presented with symptoms of infection and oral ulcers. Thyroid hormone, thyroid-stimulating hormone receptor antibody, and immunological tests were consistent with a diagnosis of Graves' hyperthyroidism-associated DLE. Corticosteroids and radioactive iodine (RAI) were used to treat DLE and GD, respectively. Post-treatment evaluation suggested the remission of her hyperthyroidism and active DLE. CONCLUSIONS Autoimmune thyroid diseases have been previously described in association with rheumatic diseases. This association shows the importance of prompt awareness of the increased risk of DLE when evaluating autoimmune thyroid dysfunction, especially under certain conditions, such as after treatment with anti-thyroid drugs (ATDs), or in the absence of multiple organ damage manifestations of SLE.

[Dermoscopy of granulomatous and autoimmune skin diseases]. / Dermatoskopie von granulomatösen und Autoimmunerkrankungen der Haut.

Dermoscopy is an easily accessible, noninvasive diagnostic tool, originally used in the differentiation of benign and malignant skin tumors. Other structures beside pigment content observed by dermoscopy, e.g., scaling, follicles, or vessels, may present in a specific pattern in different dermatoses. Recognition of these patterns may aid the diagnosis of inflammatory and infectious dermatological conditions. The aim of this article is to review the distinct dermoscopic features of granulomatous and autoimmune skin diseases. Diagnosis of granulomatous skin disorders is based on the histopathological examination. The dermoscopic picture of these diseases (cutaneous sarcoidosis, granuloma annulare, necrobiosis lipoidica, and granulomatous rosacea) show many similarities; however, there are some differences to note between the dermatoses, mainly in granuloma annulare. The cornerstones of the diagnostic process of autoimmune skin diseases (morphea, systemic sclerosis, dermatomyositis, cutaneous lupus erythematosus) include the clinical picture, immunoserology, and histology; however, dermoscopy may aid the diagnostic process and follow-up of the patients. For those diseases, where vascular abnormalities play an important role in the pathogenesis, videocapillaroscopy is used for examination of the microcirculation at the nailfold capillaries. Dermoscopy can be an easy-to-use everyday diagnostic tool in clinical practice regarding granulomatous and autoimmune skin diseases. Although punch biopsy is inevitable in many cases, the distinct dermoscopic structures can aid the diagnostic process.

Autoimmune Skin Conditions: Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is a spectrum of autoimmune skin conditions associated with systemic lupus erythematosus (SLE). CLE and SLE may exist concurrently or independently. Accurate recognition of CLE is crucial because it may herald systemic disease onset. Lupus-specific skin conditions include acute cutaneous lupus erythematosus (ACLE) which manifests as a malar or butterfly rash; subacute cutaneous lupus erythematosus (SCLE); and chronic cutaneous lupus erythematosus, which includes discoid lupus erythematosus (DLE). All three types of CLE present as pink-violet macules or plaques with unique morphology, in areas of sun-exposed skin. Association with SLE differs: ACLE is most closely associated, with SCLE in the middle, and DLE the least so. All types of CLE are pruritic, sting, and burn, and DLE can result in disfiguring scarring. All CLE is exacerbated by UV light exposure and smoking. Diagnosis combines clinical evaluation with skin biopsy. Management focuses on mitigating modifiable risk factors and using pharmacotherapy. UV protection includes use of sun protective factor (SPF) 60 or higher sunscreens containing zinc oxide or titanium dioxide, avoidance of sun exposure, and use of physical barrier clothing. Topical therapies and antimalarial drugs are first-line, followed by systemic therapies (eg, disease-modifying antirheumatic drugs, biologic therapies [eg, anifrolumab, belimumab], or other advanced systemic drugs).

Neonatal lupus erythematosus presenting as a non-bullous histiocytoid neutrophilic dermatosis.

Histopathologic findings in neonatal lupus erythematosus (NLE) are usually congruent with those of subacute cutaneous lupus erythematosus. However, neutrophilic dermatosis-type histopathologic features are being increasingly recognized in the literature including rare cases with variant histiocytoid morphology. We report the case of a 7-week-old male presenting with figurate erythema. His mother was found to have elevated anti-nuclear antibodies and was positive for anti-SSA/Ro, anti-SSB/La antibodies and Ro52 autoantibodies. The infant had a similar serological profile. Skin biopsy showed a histiocytoid interstitial infiltrate with mild lichenoid features, sparse neutrophils and mild leukocytoclasis. The histiocytoid infiltrate showed prominent CD68, CD163, and myeloperoxidase expression. Isolated clusters of CD123+ histiocytes were also present. This case highlights the rare finding of non-bullous neutrophilic dermatosis with histiocytoid change in neonatal lupus. In neonates presenting with figurate erythemas with morphological histiocytic change on biopsy, NLE should be considered as a differential diagnosis and investigated for accordingly.