Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.

Highlights Targeted anti-cytokine agents, tocilizumab and anakinra, used to treat COVID-19 related cytokine storm, yield mixed results Early identification of cytokine storm using laboratory abnormalities can detect patients prior to mechanical ventilation Early identification and treatment of cytokine storm with anakinra and corticosteroids led to improved outcomes compared to initiating tocilizumab shortly after mechanical ventilation. Early identification and treatment of cytokine storm may be more important than which anti-inflammatory treatment is chosen Our results provide additional support for the use of corticosteroid treatment of COVID19 cytokine storm

BackgroundAlthough the combination of cyclophosphamide and rituximab has been utilized in case reports, there are no previous reports of the long term outcome of SLE treated systematically with this regimen. We report a pilot study to evaluate the efficacy of a systematically administered course of rituximab and cyclophosphamide over an eighteen month period to provide sustained improvement in childhood onset systemic lupus erythematosus (SLE).FindingsTwelve patients with childhood onset lupus nephritis or corticosteroid resistant SLE received systematic treatment with a combination of rituximab (750 mg/M2 up to 1 gram) and cyclophosphamide (750 mg/M2: no patient exceeded 1.8 M2). Two administrations of rituximab and cyclophosphamide, two weeks apart, were administered at the start of study, six months later, and eighteen months later. Clinical data were collected and analyzed after sixty months of follow up. There was sustained improvement in all clinical parameters with a dramatic reduction in both mean SLEDAI score (10.1 to 1 at one year and 0 at five years p<0.005) and mean daily prednisone dosage (29.7 mg/day to 12.7 by one year and 7.0 mg/day at five years p<0.005), with sustained improvement in mean C3 (55.5 mg/ml to 113 at one year and 107.5 at five years p<0.001) which was maintained through sixty months of follow up. Serum immunoglobulin levels were transiently depressed but mean values were within the normal range for both IgG and IgM at one and five years. Few complications were observed (two episodes of febrile neutropenia during the first year of treatment were the only serious adverse events) and patients routinely reported sustained wellbeing.ConclusionsThis pilot study demonstrates that a systematically administered course of rituximab and cyclophosphamide over an eighteen month period provided sustained relief for patients with childhood onset SLE which was maintained over a sixty month period, while minimizing the need for corticosteroids, without excessive toxicity.

Objective. Transition from pediatric to adult care is a complex process and can negatively impact patients with chronic disease. We describe the transition experience of patients with pediatric-onset systemic lupus erythematosus (SLE) and its associated outcomes in adulthood. Methods. A telephone survey of 41 pediatric-onset SLE patients was conducted following their transition to adult care. Data on medical and social outcomes during and after the transition were collected. Health status was compared to retrospectively collected baseline data at pediatric discharge.Results. The mean 6 SD followup interval was 5 6 3.7 years; the mean 6 SD age at followup was 24 6 4.2 years. More than half of patients (22 of 41) experienced transition difficulties, primarily due to loss of insurance and emotional readjustment, which were associated with poor symptom control (P 5 0.03) and multiple organ system involvement (P 5 0.05) at followup. After the transition, most patients (35 of 41) were followed by an adult-care rheumatologist, and the majority (37 of 41) reported recent symptoms of active disease; 41% (13 of 29) had developed symptoms suggestive of new renal manifestations following transition. One-third (15 of 41) reported new or ongoing neuropsychiatric symptoms. Both renal and neuropsychiatric manifestations were associated with unemployment (P < 0.05). Direct referral by a pediatric rheumatologist was associated with fewer hospitalizations following transition (P 5 0.04). Conclusion. The majority of patients transitioned successfully to adult rheumatologic care. Major challenges were loss of insurance and attachment to pediatric providers, highlighting the importance of a structured transition process that focuses on providing emotional and financial guidance. Disease activity in pediatric-onset SLE remains high throughout adulthood, with morbidity primarily related to renal and neuropsychiatric manifestations.