Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.

Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells.

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2-/- mouse recipients. Highly purified follicular B cells transdifferentiated into marginal zone-like B cells when transferred into Rag2-/- lymphopenic hosts but not into wild-type hosts. In lymphopenic spleens, transferred B cells gradually lost their follicular phenotype and acquired characteristics of marginal zone B cells, as judged by cell surface phenotype, expression of integrins and chemokine receptors, positioning close to the marginal sinus, and an ability to rapidly generate functional plasma cells. Initiation of follicular to marginal zone B cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B cells and expression of Delta-like 1 Notch ligands by splenic Ccl19-Cre+ fibroblastic stromal cells. Gene expression analysis showed rapid induction of Notch-regulated transcripts followed by upregulated Myc expression and acquisition of broad transcriptional features of marginal zone B cells. Thus, naive mature B cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.

Reduced risk of mortality associated with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR): A nested case-control analysis.

BACKGROUND: The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood. OBJECTIVE: To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry. METHODS: Nested case-control analyses were performed to estimate mortality risk. Cases were defined as patients who died while participating in the Psoriasis Longitudinal Assessment and Registry. Cases were matched (1:4) with controls by age, race, sex, and geographic region. Evaluated treatments included methotrexate, ustekinumab, and tumor necrosis factor α inhibitors. Exposure was defined as at least 1 dose of treatment within 3 months before death and was stratified by duration of therapy. RESULTS: Among 12,090 patients, 341 deaths occurred, matched to 1364 controls. Biologic treatment within the preceding 3 months was protective against mortality versus no exposure: odds ratio (OR) for exposure of less than 1 year, 0.08 (95% confidence interval [CI], 0.03-0.23); OR for exposure of 1 year or longer, 0.09 (95% CI, 0.06-0.13). Methotrexate was protective against mortality only with exposure for 1 year or longer (OR, 0.08; 95% CI, 0.02-0.28). LIMITATIONS: Observational studies are subject to unmeasured confounding. CONCLUSIONS: Biologic therapy was associated with reduced mortality risk in patients with moderate to severe psoriasis, regardless of treatment duration; methotrexate reduced risk only with exposure for 1 year or longer.

First-in-Human study of JNJ-55920839 in healthy volunteers and patients with systemic lupus erythematosus: a randomised placebo-controlled phase 1 trial.

BACKGROUND: Activation of the type I interferon (IFN) pathway is associated with systemic lupus erythematosus (SLE). We assessed the safety and tolerability of JNJ-55920839, a human monoclonal antibody that selectively neutralises most human IFNα subtypes and IFNω, in healthy participants and those with SLE. METHODS: This was a two-part, first-in-human, phase 1, randomised, double-blind, placebo-controlled, multicentre study of single-ascending intravenous doses of 0·3-15 mg/kg or a single subcutaneous dose of 1 mg/kg JNJ-55920839 administered to healthy participants (part A) and multiple intravenous doses of 10 mg/kg JNJ-55920839 administered to participants with SLE (part B). Healthy men and women (women had to be postmenopausal or surgically sterile) aged 18-55 years; bodyweight of 50-90 kg; and body-mass index (BMI) of 18-30 kg/m2 were eligible for inclusion in part A. Men and women with SLE were recruited to part B, fertile female participants were required to have a negative pregnancy test result before and during the study and be using two highly effective methods of birth control. The inclusion criteria for participants with SLE in part B matched part A, except for bodyweight (40-100 kg). In both parts, participants were randomly assigned (3:1) to receive JNJ-55920839 or placebo; a computer-generated randomisation schedule was used in part A, and randomisation was stratified by racial and ethnic subpopulation and elevated levels of serological disease activity in part B. The primary outcome was evaluation of safety and tolerability of the study regimen assessed using clinical and laboratory tests compared with placebo. This study is registered with ClinicalTrials.gov, NCT02609789. FINDINGS: Between Dec 11, 2015, and Sept 20, 2018, 48 healthy participants from a single site and 28 participants with mild-to-moderate SLE from 19 participating centres in seven countries were enrolled in the study. 12 healthy volunteers in part A and eight participants with SLE in part B received placebo. The most common treatment-emergent adverse events in both part A and B were in the system organ class of infections and infestations with a higher percentage of participants administered JNJ-55920839 with infections (ten [28%] of 36 in part A and nine [50%] of 18 in part B) than those exposed to placebo (two [17%] of 12 in part A and one [13%] of eight in part B). Particpants in part B were permitted to continue on defined ongoing standard of care medications. In two participants with SLE, locally disseminated herpes zoster of the skin was reported. No other clinically significant safety or tolerability issues were identified beyond the infections observed in participants treated with JNJ-55920839. INTERPRETATION: JNJ-55920839 was well tolerated and safe. Additional studies are warranted to determine optimal dosing of patients and further explore safety. FUNDING: Janssen.

Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics.

BACKGROUND: Patients with psoriatic arthritis (PsA) have increased risk of adverse events, including serious infections (SI), compared with psoriasis patients. METHODS: Patients eligible for, or receiving conventional systemic and biologic agents for psoriasis were followed prospectively using PSOLAR. Cohorts included: ustekinumab, tumor necrosis factor (TNF) inhibitors; infliximab; etanercept; adalimumab; non-biologic/methotrexate (MTX) (reference group); and non-biologic/non-MTX. Multivariate analyses using Cox hazard regression were used to identify factors associated with time to first SI. Rates of SI in PSOLAR psoriasis patients with self-reported PsA and possible risks with biologic therapy were evaluated. RESULTS: PSOLAR enrolled 4315 psoriasis patients with self-reported PsA. The overall population (N = 2401) included patients (n): 628 ustekinumab; 1413 TNF inhibitors; 258 infliximab; 481 etanercept; 674 adalimumab; 54 other biologics, 98 non-biologic/MTX; 208 non-biologic/non-MTX. Overall, 138 SI were reported with incidence rates per 100 patient-years as follows: a) ustekinumab: 1.00; b) TNF inhibitors: 2.22; c) infliximab: 2.12; d) etanercept: 2.58; e) adalimumab: 1.99; f) non-biologic/MTX: 3.01; g) and non-biologic/non-MTX: 2.31. Age, time-dependent disease activity Physician's Global Assessment (PGA) of 4, 5, history of infection, and diabetes were associated with increased risk for SI (p < 0.05) in self-reported PsA patients. Biologic groups, other than ustekinumab, had numerically higher rates of SI. CONCLUSIONS: PSOLAR psoriasis patients with self-reported PsA in the TNF inhibitors, infliximab, adalimumab, etanercept, and MTX cohorts had numerically higher SI rates than the ustekinumab cohort, although not statistically significant. Age, PGA 4, 5, history of infection, and diabetes were associated with an increased risk for SI, irrespective of biologic exposure. TRIAL REGISTRATION: NCT00508547; Registered July 30, 2007.

Non-Melanoma Skin Cancer Risk Among Patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR)

To the Editor: Patients with psoriasis are at increased risk of developing non melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).1,2 The risk is especially elevated among those who previously received systemic treatment or phototherapy.2 Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors.3

Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Purpose: To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. Materials and methods: Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined. HZ incident rates were calculated for each therapy cohort and rates between cohorts were compared using hazard ratios (HR) adjusted for potential confounders, in new users and prevalent-exposure patients. Results: A total of 55 HZ events were identified in 10,469 patients in PSOLAR. The adjusted hazard ratio in the overall study population (new user and prevalent-exposed patients) was 2.22 (95% CI: 0.82-5.97; p = .116) for tumor necrosis factor-α (TNF) inhibitors, 2.73 (0.98-7.58; p = .054) for ustekinumab, and 1.04 (0.20-5.41; p = .966) for methotrexate versus reference (combined phototherapy, systemic steroids, topical therapy, and immunomodulators other than methotrexate). Conclusions: Exposure to ustekinumab, TNF-α inhibitors, and methotrexate was not associated with a statistically significant increased risk of HZ. However, HRs were elevated for ustekinumab and TNF-α inhibitors; a larger number of HZ events would be needed to assess the presence or absence of risk.

Gastrointestinal Signs and Symptoms Related to Inflammatory Bowel Disease in Patients With Moderate-to-Severe Psoriasis

Background: Psoriasis (PsO) is a chronic inflammatory skin disorder that may be associated with comorbidities, including inflammatory bowel disease (IBD), given common immunopathogenic mechanisms. Whether PsO patients are more likely to suffer from gastrointestinal (GI) signs and symptoms has not been well-characterized. Understanding their prevalence in PsO patients may inform strategies to evaluate for GI signs and symptoms, screen for those at risk for IBD, and guide choice of therapy. Objective: To assess the prevalence of GI signs and symptoms in patients with moderate-to-severe PsO. Methods: An Internet-based survey was conducted to evaluate GI signs and symptoms in patients with self-reported moderate-to-severe PsO and non-PsO controls. The impact of PsO severity and presence of psoriatic arthritis (PsA) [self-reported and/or screened positive on the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire] on prevalence of GI signs and symptoms was also assessed. The survey included questions about PsO, comorbidities, demographics, and GI signs and symptoms. Questions related to GI signs and symptoms were used to calculate a modified CalproQuest* score to identify patients at increased risk for IBD. Results: Survey responses were collected from 740 PsO patients and 1411 non-PsO controls. With the exception of age, demographics were generally comparable between groups. All six GI signs and symptoms assessed (belly pain, feeling full/bloated, diarrhea, mucus in stool, blood in stool, and unintentional weight loss) were more prevalent in PsO patients compared with non-PsO controls, and a higher proportion of PsO patients also had a positive CalproQuest* result. In addition, both more severe PsO and concomitant PsA were associated with a higher prevalence of GI signs and symptoms and a positive CalproQuest*. Conclusions: This study suggests that PsO patients, including those with PsA, have a higher prevalence of GI signs and symptoms. Physicians should recognize and consider this concern in PsO patient management. J Drugs Dermatol. 2018;17(12):1298-1308.

Effect of Age of Onset of Psoriasis on Clinical Outcomes with Systemic Treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

OBJECTIVE: Our objective was to compare therapeutic response among patients with early-onset psoriasis (EOP) and late-onset psoriasis (LOP) receiving adalimumab, etanercept, infliximab, ustekinumab, or methotrexate in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Patients were grouped by age of onset: EOP (age ≤ 40 years) or LOP (age > 40 years). Repeated-measures analysis with logistic regression was used to calculate the adjusted odds ratio (AOR; adjusted for baseline characteristics) for achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) or a percentage of body surface area involved with psoriasis < 3% (%BSA < 3) or %BSA < 1 for all patients; similar sensitivity analyses were performed for each treatment group. RESULTS: Of 7511 patients, 5479 (72.9%) had EOP. The LOP group had a higher likelihood of achieving PGA 0/1 after treatment than did the EOP group in all patients (AOR 1.14 [95% confidence interval (CI) 1.05-1.25]; p = 0.0019); the same was true in subgroups of etanercept-treated (AOR 1.38 [95% CI 1.14-1.66]; p = 0.0010) and methotrexate-treated (AOR 1.62 [95% CI 1.16-2.26]; p = 0.0049) patients. No significant difference was found between the EOP and LOP groups with regard to the likelihood of achieving %BSA < 3 or %BSA < 1 among all patients. However, LOP patients were more likely than EOP patients to achieve %BSA < 3 or %BSA < 1 in subgroups treated with infliximab (AOR 1.45 [95% CI 1.09-1.93; p = 0.0103] and AOR 1.36 [95% CI 1.03-1.78; p = 0.0290], respectively) and etanercept (AOR 1.30 [95% CI 1.06-1.61; p = 0.0123] and AOR 1.34 [95% CI 1.09-1.64; p = 0.0053], respectively). CONCLUSION: Our real-world data from PSOLAR indicate that there are differences in some patient characteristics between EOP and LOP and that patients with EOP are less likely than those with LOP to respond to certain systemic treatments. (ClinicalTrials.gov identifier: NCT00508547).

Demography, baseline disease characteristics, and treatment history of psoriasis patients with self-reported psoriatic arthritis enrolled in the PSOLAR registry.

BACKGROUND: To evaluate demographics, family history, and previous medication use at enrollment in a subset of psoriasis patients with self-reported psoriatic arthritis (PsA) enrolled in Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is an international, prospective, longitudinal, disease-based registry that collects data in patients receiving, or are eligible to receive, systemic or biologic treatments for psoriasis. Baseline demographic, disease characteristics, medical history, and prior medication use at enrollment were evaluated in PSOLAR psoriasis patients self-reporting PsA (n = 4315); a subset of which had their diagnosis of PsA established by a healthcare provider (HCP; n = 1719); patients with psoriasis only (n = 7775); and the overall PSOLAR population (n = 12,090). RESULTS: At enrollment, demographic characteristics were distinct between psoriasis patients self-reporting PsA and psoriasis only patients. Of the patients with psoriasis self-reporting PsA, 44.4% had cardiovascular disease (CVD), 26.3% had psychiatric illness, and 3.2% had inflammatory bowel disease (IBD), with each more prevalent than among patients with psoriasis only (p < 0.001). Overall, 17.5% of psoriasis patients self-reporting PsA had a family history of PsA, 29.8% had used systemic steroids, 39.5% had used nonsteroidal anti-inflammatory drugs, and 83.5% had used biologics. CONCLUSIONS: Demographics, family history, and previous medication use were generally comparable between "PsA established by a HCP" patients and psoriasis patients self-reporting PsA in the PSOLAR registry, but there were statistical differences compared with the psoriasis only group regarding the prevalence of certain comorbidities (CVD, psychiatric illness, and IBD). These analyses provide important data regarding characteristics of psoriasis patients with self-reported PsA in PSOLAR. TRIAL REGISTRATION: NCT00508547.

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Patients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear. OBJECTIVE: Evaluate the incidence and impact of treatment on depression among patients with moderate-to-severe psoriasis. METHODS: We defined a study population within the Psoriasis Longitudinal Assessment and Registry and measured the incidence of depressive symptoms (Hospital Anxiety and Depression Scale-Depression score ≥8) and adverse events (AEs) of depression within cohorts receiving biologics, conventional systemic therapies, or phototherapy. Patients were evaluated at approximately 6-month intervals. Multivariate modeling determined the impact of treatment on risk. RESULTS: The incidence rates of depressive symptoms were 3.01 per 100 patient-years (PYs) (95% confidence interval [CI], 2.73-3.32), 5.85 per 100 PYs (95% CI, 4.29-7.97), and 5.70 per 100 PYs (95% CI, 4.58-7.10) for biologics, phototherapy, and conventional therapy, respectively. Compared with conventional therapy, biologics reduced the risk for depressive symptoms (hazard ratio, 0.76; 95% CI, 0.59-0.98), whereas phototherapy did not (hazard ratio, 1.05; 95% CI, 0.71-1.54). The incidence rates for AEs of depression were 0.21 per 100 PYs (95% CI, 0.15-0.31) for biologics, 0.55 per 100 PYs (95% CI, 0.21-1.47) for phototherapy, and 0.14 per 100 PYs (95% CI, 0.03-0.55) for conventional therapy; the fact that there were too few events (37 AEs) precluded modeling. LIMITATIONS: Incomplete capture of depression and confounders in the patients on registry. CONCLUSION: Compared with conventional therapy, biologics appear to be associated with a lower incidence of depressive symptoms among patients with psoriasis.

Evaluation of Risk of Major Adverse Cardiovascular Events With Biologic Therapy in Patients With Psoriasis.

BACKGROUND: Psoriasis is associated with increased risk of major adverse cardiovascular events (MACE). OBJECTIVES: Compare MACE risk with biologics vs topical/phototherapy use. METHODS: Psoriasis Longitudinal Assessment Registry (PSOLAR) is an international psoriasis registry of patients eligible to receive biologic/systemic treatments prospectively. MACE is defined as myocardial infarction, stroke, or cardiovascular death. Biologic cohorts, including tumor necrosis factor-alpha (TNF-α) inhibitors (ie, adalimumab, etanercept, and infliximab) and ustekinumab, combined and by class, were compared with a topical/phototherapy cohort. Incidence rates of MACE per 100-patient-years (100PY) with 95% confidence intervals (95% CI) are reported. Multivariate analyses were performed to evaluate the effect of treatment on the risk of MACE adjusting for confounders. RESULTS: Analyses included 7550 patients: 6767 in the combined biologics cohort (3949 and 2818 in the TNF-α inhibitors and ustekinumab cohorts, respectively) and 783 in the topical/phototherapy cohort. Mean duration of exposure was approximately 2.8 years (combined biologics) and 4.1 years (topical/phototherapy). A total of 52 MACE were reported; MACE incidence rates were 0.22/100PY (95% CI: 0.16, 0.30) for the combined biologics cohort (TNF-α inhibitors [0.20/100PY (0.12, 0.31)] and ustekinumab [0.24/100PY (0.15, 0.37]) and 0.34/100PY (0.17, 0.61) for the topical/phototherapy cohort. For the combined biologics (hazard ratio=0.92; 95% CI [0.426, 1.988]), TNF-α inhibitor (0.85 [0.373, 1.928]), and ustekinumab (1.03[0.440, 2.402]) cohorts, treatment was not associated with increased risk of MACE versus the topical/phototherapy cohort. CONCLUSION: Based on data accumulated to date in PSOLAR, treatment with biologics did not have an impact on the risk of MACE in patients with moderate-to-severe psoriasis.

J Drugs Dermatol. 2017;16 (10):1002-1013.

Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry.

BACKGROUND: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood. OBJECTIVE: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy. RESULTS: Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk. LIMITATIONS: Cases and controls could belong to 1 or more therapy categories. CONCLUSIONS: Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis.

Pregnancy-associated morphea: a case report and literature review.

Morphea, also known as localized scleroderma, is arare fibrosing disorder of the skin, the pathogenesisof which is incompletely understood. It is thought,however, to involve interplay of genetic dispositionand triggering environmental factors, such asinfections and autoimmunity. Pregnancy as a potentialtrigger has only been reported in four cases. Herein,we present a patient who developed morphea of thebreasts during pregnancy, which rapidly resolvedwith a normal delivery. Our patient was distinct fromsome of the reported patients because her conditionwas tightly correlated with her pregnancy, as judgingby rapid resolution after delivery. In addition, therewas no apparent infection, history of autoimmunity,or development of autoimmunity during or afterpregnancy. Although the pathogenesis of pregnancyassociatedmorphea is largely unknown, we exploredpotential mechanisms of this condition, which mayinvolve mechanical injury, "microchimerism," andshifts in intrapartum hormones, such as TGF-ß.

Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.

B-Raf(V600E) inhibitors have been suggested to promote tumor regression with the help of host immunity, but this hypothesis has not been examined directly in detail. In this study, we profiled immunologic changes in the tumor microenvironment and tumor-infiltrating lymphocytes (TIL) in a B-RafV600E/Pten-driven murine model of melanoma after administration of the B-Raf(V600E) small molecule inhibitor PLX4720. In this model, we found that as tumors developed, they gradually acquired immunosuppressive features, including accumulation of regulatory T cells (Treg) and CD11b(+)/Gr-1(+) myeloid cells and loss of Th1 effector functions on CD4(+) TILs, such as CD40L and IFNγ expression. PLX4720 administration promoted development of a more immune stimulatory microenvironment associated with a relative increase in CD40L and IFNγ expression on intratumoral CD4(+) TILs and a reduced accumulation of Tregs and CD11b(+)/Gr-1(+) myeloid cells. Strikingly, CD40L or IFNγ blockade compromised the ability of PLX4720 to inhibit melanoma growth. Supporting this result, agonistic CD40 antibody was sufficient to evoke antitumor immunity and suppress tumor growth in tumor-bearing mice. Taken together, our results establish the critical role of immune-related changes, with key contributions for CD40L and IFNγ signaling in the antitumor responses triggered in vivo by B-Raf(V600E) inhibitors.

Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining.

CD123-positive plasmacytoid dendrocytes are prominent in the infiltrate of discoid lupus erythematosus (LE). We hypothesized that these cells would also be present in hypertrophic LE and would aid in the histopathologic distinction from squamous cell carcinoma (SCC) and hypertrophic actinic keratosis (AK). Five cases of hypertrophic LE and 10 cases each of SCC and hypertrophic AK were stained with CD123. A heavy band of CD123-positive cells was present at the epidermal-dermal junction in all cases of hypertrophic LE, and only single or rare scattered clusters of CD123-positive cells were seen in SCC and actinic keratoses. The pattern of CD123 staining can be a useful feature to distinguish hypertrophic LE from SCC and hypertrophic AK.

Generation of peripheral B cells occurs via two spatially and temporally distinct pathways.

We have identified a population of newly formed bone marrow (BM) B cells that shares multiple characteristics with late transitional B cells in the spleen. Both late splenic transitional B cells and cells within this uncharacterized BM population expressed the cell-surface phenotype AA4(+) CD23(+), yet the developmental kinetics and the renewal rate of AA4(+) CD23(+) BM B cells mirrored recently formed BM B cells. Further, unlike the least mature B cells in the BM and spleen, AA4(+) CD23(+) BM B cells expressed the homing receptor CD62L, were dependent on the antiapoptotic cytokine receptor BR3 and the tec family kinase Btk, and proliferated in response to IL-4 plus CD40 stimulation. Finally, frequencies of lambda light chain-positive B cells declined among AA4(+) CD23(+) B cells in both the BM and spleen, suggesting that V-gene selection events correlate with CD23 expression in both compartments. These observations indicate that the first step in B-cell maturation occurs in both the BM and the periphery and suggest that recently formed B cells exit the BM as a heterogeneous pool of immature and semimature B cells.