Evaluation of RNase therapy in systemic lupus erythematosus: a randomised phase 2a clinical trial of RSLV-132.

BACKGROUND: Circulating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132 is a catalytically active human RNase molecule fused to human IgG1 Fc designed to digest RNA and thereby decrease the chronic inflammation associated with SLE. The drug was evaluated in a cohort of patients with SLE with moderate-severe cutaneous disease activity and the presence of RNA immune complexes. The primary objective of the study was the assessment of the impact of 13 doses of 10 mg/kg RSLV-132 over 6 months on the mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score. METHODS: Sixty-five patients meeting the entry criteria of a baseline CLASI score of 10 or greater and positivity of at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were randomly assigned (2:1) to receive 13 doses of RSLV-132 10 mg/kg or placebo, respectively. Participants received study drug for 24 weeks on days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141 and 155 with an end-of-treatment visit on day 169 and a follow-up visit at the end of the study on day 215. The primary objective was assessed on days 85 and 169. Secondary objectives included assessment of systemic disease activity using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group 2004 Index and the Physician's Global Assessment. Data from these instruments were used to calculate the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) scores. RESULTS: The mean CLASI score change from baseline at day 169 was -5.7 (±7.0) in the placebo group and -6.2 (±8.5) in the RSLV-132 group. A subgroup of participants with moderate-severe systemic disease activity and high baseline SLEDAI scores (≥9) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high SLEDAI subgroup had a greater percentage of BICLA responses (62% vs 44%) and SRI-4 responses (23% vs 11%) as compared with placebo. A second subgroup of participants with high baseline CLASI scores (≥21) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high CLASI subgroup had a greater percentage of BICLA responses (28% vs 8%) and SRI-4 responses (39% vs 8%) as compared with placebo. CONCLUSIONS: Six months of RSLV-132 therapy consisting of a weekly loading dose of RSLV-132 for 1 month, followed by 5 months of biweekly administrations did not significantly improve the mean CLASI score relative to placebo in this cohort of patients with SLE. The study entry criteria selected patients with moderate-severe cutaneous disease activity and no minimum SLEDAI score, which resulted in a wide range of systemic disease activity from inactive to severe as measured by SLEDAI. When the participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. The results warrant further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease are most likely to benefit from RNase therapy.

Anifrolumab for Adolescent Discoid Lupus Erythematosus.

This case series describes the outcomes among adolescent patients with systemic lupus erythematosus and refractory discoid lupus erythematosus treated with anifrolumab.

Open-Label Phase 2 Pilot Study of Oral Tofacitinib in Adult Subjects With Discoid Lupus Erythematosus (DLE).

CITATION: Alsukait S, Learned C, Rosmarin D. Open-label phase 2 pilot study of oral tofacitinib in adult subjects with Discoid Lupus Erythematosus (DLE). J Drugs Dermatol. 2023;22(4): 425-427. doi:10.36849/JDD.7098.

Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers.

BACKGROUND: Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus erythematosus (CLE) in systemic lupus erythematosus (SLE), especially discoid lupus erythematosus (DLE). Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE, but efficacy for cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and it is unknown which of these are critical to therapeutic response. OBJECTIVES: We evaluated clinical efficacy and quality-of-life impact of type-I interferon-blockade in: (i) rituximab-refractory CLE; (ii) DLE and other morphologies and (iii) transcriptomic and flow cytometric biomarkers. METHODS: We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLE Disease Area and Severity Index (CLASI) activity score, health-related quality of life, 96-probe TaqMan® gene expression analysis capturing key SLE blood transcriptome signatures, and eight-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. RESULTS: Seven patients [DLE (n = 5), chilblain lupus erythematosus (n = 1), subacute CLE (n = 1)] were evaluated. The median number of prior therapies was six (range 3-15), including rituximab in six of seven patients. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (P = 0.016) at 1 month and 0 (P < 0.001) by 3 months. The median percentage reduction in CLASI-A at 3 months was 60%. Significant improvements were observed in Dermatology Life Quality Index scores (P < 0.001), EuroQol 5D visual analogue scale (P = 0.002) and LupusQoL fatigue, image and planning domains (P ≤ 0.05). One patient discontinued treatment owing to severe herpes zoster. Clinical responses paralleled discrete suppression of interferon-stimulated genes (ISGs) from SLE blood transcriptome module M1.2 with more varied downregulation in other interferon modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy (P = 0.014), while other flow subsets showed no substantive changes. CONCLUSIONS: These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.

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).

Assessment of Clinical Response to Anifrolumab in Patients With Refractory Discoid Lupus Erythematosus.

This case series examines the efficacy of anifrolumab as a therapeutic option for patients with lupus erythematosus.

Topical niacinamide (Nicotinamide) treatment for discoid lupus erythematosus (DLE): A prospective pilot study.

BACKGROUND: Cutaneous lupus erythematosus is an umbrella term for a group of autoimmune connective tissue disorders affecting the skin. Discoid lupus erythematosus (DLE) is the chronic condition and most common form of cutaneous lupus erythematosus. AIMS: Current therapies of DLE are challenging and not completely satisfactory, highly expensive, off-label, or poorly available (like antimalarials due to COVID-19 outbreaks). Nicotinamide, also called niacinamide, is a water-soluble form of vitamin B3 (niacin). Its multiple effects let us think that nicotinamide could be a therapy for lupus-associated skin lesions. METHODS: We performed a prospective randomized double-blind clinical trial on 60 subjects diagnosed with Discoid lupus erythematosus using topical Nicotinamide 2% and 4% preparations in form of cream and gel on skin and scalp lesions. Control group was included using only cream/gel base as placebo control. RESULTS: Obtained data showed that topical Nicotinamide can be used for the treatment of DLE as adjuvant to other treatment regimens with good cosmetic results and minimal side effects. Topical 4% Nicotinamide is superior to 2% preparation in response but associated with a higher incidence of irritation. CONCLUSION: Topical Nicotinamide can be used for the treatment of DLE as an adjuvant to other treatment regimens with good cosmetic results and minimal side effects. Further trials with long-term therapy, follow-up period, and bigger sample sizes are required.

Comedogenic lupus: a rare variant of chronic cutaneous lupus erythematosus - case series.

BACKGROUND: Comedogenic lupus is an uncommon variant of cutaneous lupus, clinically characterized by the presence of comedones, papules and erythematous-infiltrated plaques, cysts and scars in photo-exposed areas, mimicking acne vulgaris and acneiform eruptions. OBJECTIVES: To report clinicopathological characteristics of patients with comedogenic lupus in a tertiary dermatology service over a 15-year period and review cases described in the literature. METHODS: Retrospective study of patients with clinical and histopathological diagnoses of comedogenic lupus between the years 2006 and 2021. The literature search was carried out in the PubMed and VHL Regional Portal databases, using the terms: "comedogenic lupus" and "acneiform lupus" in Portuguese and English. RESULTS: Five patients were diagnosed during the described period, all female, with a mean age of 56.6 years. Smoking was observed in three cases, as well as pruritus. The most affected site was the face, especially the pre-auricular, malar and chin regions. Follicular plugs, epidermal thinning and liquefaction degeneration of the basal layer were predominant histopathological findings. Hydroxychloroquine was used as the first-line treatment; however, other medications were used, such as dapsone, methotrexate, tretinoin cream, and topical corticosteroids. The literature search identified 17 cases, with a mean age of 38.9 years, 82% of which were women. Only 23% had a diagnosis of systemic lupus erythematosus. Hydroxychloroquine was the most recommended systemic medication. STUDY LIMITATIONS: Retrospective, single-center study. The literature search was carried out in two databases. CONCLUSIONS: Dermatologists should be aware of acneiform conditions with poor response to the usual treatment. Early diagnosis and treatment reduce the risk of unaesthetic scars.

Effective treatment of canine chronic cutaneous lupus erythematosus variants with oclacitinib: Seven cases.

BACKGROUND: The treatment of canine chronic cutaneous lupus erythematosus (CCLE) variants generally requires immunosuppression, which often results in potentially severe adverse effects. Janus kinase inhibitors, like oclacitinib, might be a valuable treatment option due to their rapid inhibition of the action of interferons known to be relevant in the pathogenesis of CCLE. OBJECTIVES: To report the efficacy and safety of oral oclacitinib for the treatment of canine CCLE variants. ANIMALS: Seven dogs were diagnosed with CCLE based on clinical signs and compatible histopathological findings. MATERIALS AND METHODS: Oclacitinib was administered at the induction dosage of 0.45 mg/kg twice daily to 1.8 mg/kg once daily. The response to treatment was graded as 'good' when there was ≥50% lesion reduction, or as 'complete remission' if all active lesions had resolved. Complete blood counts were performed at variable intervals. RESULTS: A complete remission of all lesions was obtained in the dog with exfoliative cutaneous lupus erythematosus, both dogs with mucocutaneous lupus erythematosus and three of four dogs with facial discoid lupus erythematosus (FDLE); a good response was seen in the remaining dog with FDLE. The first visible improvement of signs was seen within 2-to-3 weeks, while the time to complete remission was around 2 months. Clinical adverse effects were not seen, and haematological parameters remained within the reference range. CONCLUSIONS AND CLINICAL RELEVANCE: Oclacitinib may be considered an effective treatment option for different variants of canine CCLE.

Treatment With Anifrolumab for Discoid Lupus Erythematosus.

This case report describes 2 women with severe and refractory discoid lupus erythematosus that was treated with anifrolumab.

Melanotic lupus erythematosus: A review of a newly described clinical form of chronic cutaneous lupus erythematosus.

Melanotic lupus erythematosus (LE) is a rare and newly described form of chronic cutaneous LE. In this review, we have synthesized existing data on the epidemiologic, clinical, histologic, and immunologic features of melanotic LE. We performed a systematic review using PubMed to identify eligible publications. Eight contributions fulfilled the eligibility criteria and were included in the qualitative synthesis. Twenty-eight patients with a mean age of 57.7 years were included. All patients had medium to dark skin phototypes. The lesions presented either as solitary and localized, poorly limited, round, or oval patches (50%) or as a more diffuse or generalized, sometimes reticulated, hyperpigmentation (50%). Patients diagnosed with systemic LE accounted for 14% of included cases. Antinuclear antibodies were positive in 10.7% of cases. Hydroxychloroquine and topical steroids were the most commonly used treatments. Complete resolution of the lesions was noted in 27.27% of cases. No patient experienced atrophy, destruction, or deformity of the skin. Melanotic LE appears to affect mainly patients with dark phototypes. It is characterized by late age at the onset of disease and an overall good prognosis.

Discoid lupus.

THE COMPARISON A Multicolored (pink, brown, and white) indurated plaques in a butterfly distribution on the face of a 30-year-old woman with a darker skin tone. B Pink, elevated, indurated plaques with hypopigmentation in a butterfly distribution on the face of a 19-year-old woman with a lighter skin tone.

Acitretin treatment in antimalarial-refractory/intolerant discoid lupus erythematosus: A prospective, open-label, uncontrolled study.

BACKGROUND: The treatment of discoid lupus erythematosus (DLE) is often challenging, especially in patients who are refractory or intolerant to topical treatments and first-line systemic drugs, specifically antimalarial drugs. Although acitretin has been shown to be effective in patients with DLE in a few studies, there is no published study describing the long-term efficacy of acitretin with a validated score. OBJECTIVES: To evaluate the efficacy and safety of acitretin in patients with antimalarial-refractory/intolerant DLE. METHODS: A prospective, open-label, uncontrolled study was conducted in patients with antimalarial-refractory/intolerant DLE. All patients were treated with an initial dosage of 10 mg acitretin daily. Clinical response was assessed using the Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) at weeks 4, 8, 12, and 24. Acitretin was increased to 25 mg daily unless an adequate response was achieved at week 8. RESULTS: Fourteen patients were recruited. Of these, 10 were antimalarial-refractory and four were antimalarial-intolerant. The acitretin therapy was discontinued in one patient after 20 weeks of treatment because of active systemic disease. Of the 13 remaining patients, the mean RCLASI activity scores declined from 21 ± 9 at baseline to 9 ± 4 at week 24. A significant reduction in RCLASI was initially observed at week four and consistently noted at each follow-up visit (p ≤ 0.01). At the end of the study, a marked response was achieved in approximately 80% of patients. There were no statistically significant differences in the clinical response or in the requirement of the up-dosing of acitretin between the refractory and intolerance groups (p = 0.88 and p = 0.326, respectively). Age ≥50 years old, female sex, and generalized DLE were the favorable prognostic factors. No serious adverse events were noted. CONCLUSIONS: Acitretin appears to be an effective treatment with acceptable safety profiles for antimalarial-refractory/intolerant DLE.