Long-term efficacy and safety of baricitinib in patients with severe alopecia areata: 104-week results from BRAVE-AA1 and BRAVE-AA2.

BACKGROUND: Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA. OBJECTIVES: To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. METHODS: Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation. RESULTS: Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase. CONCLUSIONS: Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.

Development of the Scalp Hair Assessment PRO™ measure for alopecia areata.

BACKGROUND: Valid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. OBJECTIVES: To develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™). METHODS: A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. RESULTS: Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. CONCLUSIONS: The Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials.

BACKGROUND: Content-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA). OBJECTIVES: To develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies. METHODS: Qualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA. RESULTS: Expert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss. CONCLUSIONS: We recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study.

BACKGROUND: It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. OBJECTIVES: To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). METHODS: Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. RESULTS: At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). CONCLUSIONS: The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.

Treatment outcomes with ixekizumab in patients with moderate-to-severe psoriasis who have or have not received prior biological therapies: an integrated analysis of two Phase III randomized studies.

BACKGROUND: Biologics are effective for the treatment of psoriasis. However, treatment outcomes may differ among biologic-naive patients and those switched from previous biological therapies. OBJECTIVES: The study's objective was to investigate efficacy and safety of ixekizumab, a high-affinity anti-interleukin-17A antibody, in patients with psoriasis with and without previous exposure to biologics. METHODS: Data were integrated from the 12-week induction phase of two etanercept-controlled Phase III trials. Patients received 80 mg ixekizumab every 2 weeks (IXE Q2W; N = 736) or every 4 weeks (IXE Q4W; N = 733) following a 160-mg starting dose, or placebo (N = 361). Etanercept (50 mg twice weekly; N = 740) was administered as active control. Psoriasis Area and Severity Index (PASI) 75, PASI 90 and PASI 100 response rates at week 12 were evaluated in patients with or without previous exposure to biologics. Treatment effects were analysed with the Cochran-Mantel-Haenszel test stratified by study; missing values were imputed as non-response. RESULTS: Overall, 497 (19.3%) patients had prior exposure to biologics and 2073 (80.7%) were naive to biologic therapy. PASI 75 was achieved by 91.5% of biologic-experienced patients and 87.7% of biologic-naive patients for IXE Q2W, 76.2% and 82.2% for IXE Q4W, respectively, and 34.6% and 50.7%, respectively, for etanercept. Higher response rates favouring each ixekizumab dose over etanercept within subgroups were also seen regarding PASI 90 and PASI 100. CONCLUSIONS: Contrary to etanercept, the efficacy of ixekizumab was similarly high in patients with and without previous exposure to biologics when administered 80 mg every 2 weeks.

Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis.

BACKGROUND: Scalp and nail psoriasis have a major impact on quality of life and are traditionally resistant to therapy. Ixekizumab is a monoclonal antibody that targets IL-17A, a key cytokine in psoriasis pathogenesis. OBJECTIVE: Changes in nail and scalp psoriasis associated with ixekizumab treatment were evaluated in a post hoc analysis of a phase 2 study comprising a 20-week randomized, placebo-controlled (RCT) period and 48 weeks of an open-label extension (OLE) period. METHODS: There were 142 patients with moderate-to-severe plaque psoriasis at baseline of the RCT. Patients were randomized to receive placebo, 10, 25, 75 or 150 mg of ixekizumab injected subcutaneously at weeks 0, 2, 4, 8, 12 and 16. In the OLE, all patients received 120 mg ixekizumab every 4 weeks. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) were used to evaluate nail and scalp psoriasis respectively. Fifty-eight (41.0%) patients had nail psoriasis (NAPSI > 0) and 105 (74.0%) had scalp psoriasis (PSSI > 0) at baseline; these cases were evaluated for the present analyses. RESULTS: At RCT week 20, patients with scalp psoriasis in the 25-, 75- and 150-mg groups had significant mean change and percent improvement from baseline PSSI of -16.3 (75.3%; P = 0.001), -11.6 (83.7%; P = 0.001) and -18.2 (82.2%; P < 0.001) respectively compared to -6.0 (18.8%) in placebo. Patients with nail psoriasis in the 75- and 150-mg groups had significant improvements from baseline NAPSI of -26.3 (63.8%; P = 0.003) and -23.1 (52.6%; P = 0.009) respectively compared to 0.4 (-1.7%) in placebo. By OLE week 48, 78.0% of patients with scalp psoriasis and 51.0% of patients with nail psoriasis experienced complete resolution of lesions (PSSI = 0 or NAPSI = 0). CONCLUSIONS: Ixekizumab monotherapy improved scalp psoriasis quickly with maintenance of clinical response and complete resolution of plaques in the majority of patients. Additionally, over 50.0% of patients with nail psoriasis experienced complete resolution of nail lesions by OLE week 48.

[Pulmonary abscess and Pyoderma gangrenosum]. / Abcès pulmonaire et Pyoderma gangrenosum.

INTRODUCTION: Pyoderma gangrenosum is the ulcerative form of neutrophilic dermatoses. The most frequent extracutaneous localizations are the lungs, joints, and digestive tract. CASE RECORD: We report a case of Pyoderma gangrenosum, which presented first as an aseptic lung abscess. The first cutaneous lesions occurred 9 months later, with skin ulcerations on the thorax and on surgical scars. The histological diagnosis was made on skin biopsies. There was no associated abnormality except for IgA monoclonal gammapathy. Clinical improvement was noted with immunosuppressive treatment. DISCUSSION: This infrequent case report underlines that lung abscesses may be of non-infectious origin, that in Pyoderma gangrenosum, skin lesions may be come several months after extracutaneous manifestations, among which lungs abcesses are the most frequent.

[Infliximab-induced skin reaction with visceral manifestations and high levels of anti-DNA antibodies]. / Toxidermie avec manifestations systémiques et sérologie lupique induites par l'infliximab.

BACKGROUND: Infliximab is a monoclonal anti-Tumor Necrosis Factor alpha-antibody (anti-TNFalpha) that has demonstrated its efficacy in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis. CASE REPORT: We report the case of a 59 year-old woman with a 20-year history of rheumatoid arthritis consulting for an atypical erythematosus rash 18 months after her first infusion of infliximab. The rash was associated with inflammatory syndrome, incipient renal failure and high levels of antinuclear antibodies with the presence of anti-dsDNA antibodies. Lack of specificity in both skin manifestations and histology ruled out a diagnosis of drug-induced lupus. Discontinuation of treatment with infliximab resulted in improvement of all clinical signs together with a significant decrease of antinuclear antibody titers within six months. DISCUSSION: Induction of antinuclear antibodies and/or anti-dsDNA antibodies is often seen in patients treated with TNFalpha inhibitors. Cases of true systemic lupus erythematosus or anti-TNFalpha-related eruption in a context of autoimmunity, as seen in our patient, have been reported only rarely. All cases were reversible upon discontinuation of treatment.

The CD1 family and T cell recognition of lipid antigens.

For many years it was thought that T lymphocytes recognized only peptide antigens presented by MHC class I or class II molecules. Recently, it has become clear that a wide variety of lipids and glycolipids are also targets of the T cell response. This novel form of cell-mediated immune recognition is mediated by a family of lipid binding and presenting molecules known as CD1. The CD1 proteins represent a small to moderate sized family of beta2-microglobulin-associated transmembrane proteins that are distantly related to MHC class I and class II molecules. They are conserved in most or all mammals, and control the development and function of T cell populations that participate in innate and adaptive immune responses through the recognition of self and foreign lipid antigens. Here we review the current state of our understanding of the structure and function of CD1 proteins, and the role of CD1-restricted T cell responses in the immune system.

[Cross-sensitivity between angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonist]. / Toxidermies aux inhibiteurs de l'enzyme de conversion pérennisées par la prise d'inhibiteurs de l'angiotensine II.

BACKGROUND: Cross-sensitivity between angiotensin-converting enzyme inhibitor-induced angioedema and cough, and angiotensin II receptor antagonist has been reported in the literature. Eczema-like skin reactions have never been documented. We report the first two cases. CASE REPORTS: Two patients, aged 79 and 88 years, with a history of hypertension, were treated with angiotensin-converting enzyme inhibitors, which had been discontinued because of an eczematiform rash. In spite of substitution with an angiotensin II receptor antagonist, the patients had developed the same eruption. The outcome was favourable after discontinuation of the angiotensin II receptor antagonist. The pharmacologic study suggested the possibility of a cross-sensitivity reaction between these two drugs. CONCLUSION: We report the first two cases of a cross-sensitivity between angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonist presenting as an eczematiform rash. The exact mechanism is unknown, but clinicians must be aware that angiotensin II receptor antagonist is not a safe alternative in patients who have a history of eczematiform rash secondary to angiotensin-converting enzyme inhibitors, as has been always reported with angioedema.

[Acute osteomyelitis. A rare erysipelas differential diagnosis]. / Ostéomyélite aiguë. Un diagnostic différentiel rare d'érysipèle.

INTRODUCTION: Acute haematogenous osteomyelitis, whose clinical features may mimic erysipelas, is an uncommon disease in adults. OBSERVATION: A 56 year-old man was hospitalized for a suspicion of leg erysipelas. Oral and intravenous antibiotic therapy was inefficient. Magnetic Resonance Imaging (MRI) of the leg revealed osteomyelitis with subperiosteal abscess. Change of antibiotics and surgical debridement improved the patient's condition. DISCUSSION: Erysipela is a common disease which most often responds to anti-streptococcal therapy. Unfavourable evolution under antibiotherapy must lead to consider necrotizing fasciitis but also acute osteomyelitis. In these cases MRI is necessary. In our observation, the leg pain which preceded other signs of local inflammation, suggested the existence of primitive bone infection which further diffused in soft tissues, thus explaining the erysipelatoid aspect.

Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells.

The MHC class I-like protein CD1d is a nonpolymorphic molecule that plays a central role in development and activation of a subset of T cells that coexpress receptors used by NK cells (NK-T cells). Recently, T cells bearing NK receptors were identified in acute and chronic lesions of psoriasis. To determine whether NK-T cells could interact with epidermal cells, we examined the pattern of expression of CD1d in normal skin, psoriasis, and related skin disorders, using a panel of CD1d-specific mAbs. CD1d was expressed by keratinocytes in normal skin, although expression was at a relatively low level and was generally confined to upper level keratinocytes immediately beneath the lipid-rich stratum corneum. In contrast, there was overexpression of CD1d in chronic, active psoriatic plaques. CD1d could be rapidly induced on keratinocytes in normal skin by physical trauma that disrupted barrier function or by application of a potent contact-sensitizing agent. Keratinocytes displayed enhanced CD1d following exposure to IFN-gamma. Combining CD1d-positive keratinocytes with human NK-T cell clones resulted in clustering of NK-T cells, and while no significant proliferation ensued, NK-T cells became activated to produce large amounts of IFN-gamma. We conclude that CD1d can be expressed in a functionally active form by keratinocytes and is up-regulated in psoriasis and other inflammatory dermatoses. The ability of IFN-gamma to enhance keratinocyte CD1d expression and the subsequent ability of CD1d-positive keratinocytes to activate NK-T cells to produce IFN-gamma, could provide a mechanism that contributes to the pathogenesis of psoriasis and other skin disorders.

[Cutaneous manifestations of Yersinia enterocolitica infection]. / Manifestations cutanées d'une infection à Yersinia enterocolitica.

BACKGROUND: Cutaneous manifestations occurring in infections due to Yersinia enterocolitica are usually erythema nodosum, erythema multiforme or cutaneous vasculitis. The association between Yersinia infection and Sweet's syndrome is rare. We describe such a case contributing to the discussion on this association. CASE-REPORT: A 29-year-old woman had a papulo-pustular eruption with fever associated with arthralgia. The results of the infectious laboratory investigations were negative but Yersinia enterocolitica type 0.9 was isolated from a stool culture. The serologic diagnosis of Yersinia enterocolitica using serum agglutinins was negative. The diagnosis of Sweet's syndrome was made on a skin biopsy specimen. Search for hematology disease or underlying neoplasia was negative. The clinical course was rapidly favorable with antibiotic treatment (ciprofloxacin). DISCUSSION: The diagnosis of Yersinia enterocolitica infection is difficult. Microbiologic diagnosis of Yersinia infection is best achieved by isolation of the bacterium from a clinical specimen of involved tissue. The agglutination test is not highly specific or sensitive. Immunoblotting appears to be more sensitive.

[Umbilical cutaneous metastasis (or Sister Mary Joseph's nodule) disclosing an ovarian adenocarcinoma]. / Métastase cutanée ombilicale (ou nodule de Soeur Mary Joseph) révélatrice d'un adénocarcinome ovarien.

In this study, the case is described of an umbilical metastasis as the presenting symptom of an ovarian adenosarcoma. The overall frequency of cutaneous metastases has been estimated at between 5 and 9%. Umbilical metastases are a rare occurrence: it is estimated that between 1 and 3% of patients with abdomino-pelvic disease present with an umbilical nodule. Epidemiological studies have shown the female predominance of this disease. The clinical characteristics of umbilical metastases cannot be visually distinguished from those of primary lesions. The clinical appearance is often that of a nodule of varying size, more or less painful, and sometimes ulcerated or suppurating as in the present case. The nodule may be indicative of cancer, or of cancer recurrence. The most frequently encountered histological type is adenocarcinoma (about 75% of cases), and is more rarely epidermoid, undifferentiated, or carcinoid. Etiological findings have indicated a digestive origin in over 55% of cases (stomach, colon, rectum, pancreas, in decreasing order of frequency), with a clear male predominance; cancers of gynecological origin are the second most frequent etiology, with ovarian cancers being the most common (34% of cases). Sister Mary Joseph nodule accounts for 60% of all malignant umbilical tumors (primary or secondary), and is usually associated with a poor prognosis (mean survival: 10-12 months). However, patient survival time could be lengthened by aggressive therapy, i.e., surgery combined with chemotherapy.