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.

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.

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.

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.

Controversies in Systemic Lupus Erythematosus: Are We Treating Our Patients Adequately?

ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by great clinical heterogeneity. The objectives of its management are to make a timely diagnosis and to initiate treatment as promptly as possible so organ damage can be avoided while at the same time exposure to potentially toxic drugs is minimized so that its overall course and outcome improve. In reviewing the current literature, it became quite clear that there are specific topics in which controversies do exist. These include how to treat patients with incomplete lupus erythematosus, the real possibility of abandoning altogether the use of oral glucocorticoids, and the pros and cons of the use of cyclophosphamide and mycophenolate mofetil for the induction treatment of lupus nephritis. Herein we discuss different points of view regarding these still unresolved issues; these comments represent a debate that took place during the PANLAR Virtual Congress (Pan American League of Associations for Rheumatology) and that was organized by the PANLAR Lupus study group, GLADEL (Grupo Latino Americano De Estudio del Lupus) on September 19, 2020.

Combining maintenance therapy with hydroxychloroquine increases LLDAS achievement rates in individuals with stable systemic lupus erythematosus.

BACKGROUND: Hydroxychloroquine (HCQ) has been positioned as an anchor drug for systemic lupus erythematosus (SLE). There is evidence supporting the benefits of HCQ; however, the effect of additional HCQ in maintenance therapy remains unclear. METHODS: Thirty patients with SLE who visited Juntendo University Hospital were receiving maintenance therapy before HCQ treatment and were able to complete more than 104 weeks of HCQ treatment were analyzed. Anti-DNA antibody titers, IgG and CH50 levels, the maintenance dose of corticosteroids, the SLE disease activity index (SLEDAI), and the achievement of the Lupus Low Disease Activity State (LLDAS) were evaluated at baseline and at 12, 24, 52, and 104 weeks after HCQ initiation. RESULTS: We observed improvements in the anti-DNA antibody titers, IgG and CH50 levels, maintenance dose of corticosteroids, and SLEDAI at week 104 relative to baseline. Moreover, the LLDAS achievement rate increased over time from 10% at baseline to 43% and 80% at week 52 and week 104, respectively. CONCLUSION: Two years of continuous HCQ treatment led to improvements in SLE disease activity and corticosteroid dose and an increase in LLDAS achievement, thereby demonstrating the significance of the maintenance dose of HCQ for the management of SLE.

Refractory palmo-plantar discoid lupus erythematosus successfully treated with mycophenolate mofetil: Unusual localization and literature review.

Palmo-plantar lesions in discoid lupus erythematosus (DLE) can be considered a very distinct rarity, generally refractory to conventional treatments. We present a 47-year-old African female patient with a 6-month clinical history of palm and soles erosions. Clinical examination revealed painful multiple, well defined, erosions with an erythematous and scaly central area and peripherical post-inflammatory hyperchromic border bilaterally distributed on the palmo-plantar surfaces. Pterygium inversum unguis involved all nails of both hands. Histological analysis and direct immunofluorescence study confirmed palmo-plantar DLE. Therapy with mycophenolate mofetil (MMF) was initiated with a progressive clearing of palmo-plantar lesions and a drastic reduction of pain. Therapy was well tolerated, neither side effects nor altered laboratory investigations were observed. Our case and literature review confirm that MMF may be an effective approach for the management of refractory palmo-plantar DLE with a safer profile than Azathioprine regarding adverse effects and cutaneous malignancies risk.

Comparison of effectiveness of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05% as an add-on to oral hydroxychloroquine in discoid lupus erythematosus.

In recent years, calcineurin inhibitors have been used as the first line alternative to topical corticosteroids in the treatment of discoid lupus erythematosus (DLE). We aim to evaluate the efficacy and safety of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05% in patients with DLE. This comparative study was carried out in the Department of Dermatology and Venereology, Chittagong Medical College Hospital (CMCH), Bangladesh between the period of July 2018 and June 2019. The change of DLE activity assessed with the cutaneous lupus erythematosus disease area and severity index was used as a primary outcome measure. The effective sample was 40 patients in each group. Both groups were similar in terms of baseline demographic and clinical characteristics. After 8 weeks of treatment, the mean total erythema score decreased significantly in both groups (in tacrolimus treated group [TTG] from 12.53 ± 8.05 to 8.03 ± 5.69, [P < .001] and in halobetasol propionate treated group [HTG] from 11.83 ± 7.17 to 7.30 ± 4.56 [P < .001]), as well as the mean total scale/hypertrophy score (in TTG from 8.08 ± 5.30 to 4.33 ± 3.21; [P < .001] and in HTG from 7.40 ± 4.73 to 3.68 ± 2.01, [P < .001]. The magnitude of reduction was significantly better in HTG [P = .032]). The mean total activity score decreased significantly in both groups (in TTG from 22.95 ± 13.40 to 14.33 ± 8.89, [P < .001] and in HTG from 22.15 ± 11.95 to 13.7 ± 7.22, [P < .001]). The present study demonstrated that tacrolimus 0.1% ointment and halobetasol propionate 0.05% ointment had a comparable efficacy in DLE patients; however, halobetasol showed significantly better improvement regarding scaly, hypertrophic lesions.

Lupus erythematosus: Significance of dermatologic findings.

Herein, the different skin manifestations in patients with lupus erythematosus are reviewed, and their diagnostic, pathogenic and prognostic relevance are discussed, as well as their impact on therapeutic choices. The so-called specific lesions of LE result from an autoimmune pathomechanism and they allow diagnosis of LE by simple clinicopathological correlation since the findings are characteristic. They include the classic acute, subacute and chronic variants, characterised microscopically by interface dermatitis; the dermal variants of lupus, such as tumid lupus, displaying dermal perivascular lymphocytic infiltrate with mucin deposition under the microscope, and lupus profundus, in which lymphocytic lobular panniculitis progressing to hyaline fibrosis is found. Antimalarials are the treatment of choice for patients with specific LE lesions. The presence of some dermatological signs is the result of thrombotic vasculopathy. Their recognition allows the identification of lupus patients at increased cardiovascular risk and with a worse overall prognosis. Those signs include reticulated erythema on the tip of the toes, splinter hemorrhages, atrophie blanche, pseudo-Degos lesions, racemosa-type livedo, anetoderma, ulceration and necrosis. Those clinical manifestations, often subtle, must be recognised, and if present, patients should be treated with antiplatelet drugs. Finally, neutrophilic cutaneous lupus erythematosus includes a few entities that suggest that autoinflammatory mechanisms might play a key role in certain lupus manifestations. Among those entities, it is very important to diagnose neutrophilic urticarial dermatosis, which can mimic a classic lupus flare, because it is characterised by rash with joint pain, but immunosuppressants are not helpful. Dapsone is the treatment of choice.

Successful treatment of facial localized discoid lupus erythematosus with intralesional betamethasone: A report of three cases.

Discoid lupus erythematosus (DLE) is a chronic autoimmune skin disease that usually causes disfiguring scarring, dyspigmentation, and atrophy. Despite a range of available topical and systemic therapies, the treatment of DLE remains a therapeutic challenge, especially in some refractory cases. Here, we reported three male patients with long-term chronic lesions of unilateral facial localized DLE, who failed to have their disease controlled with many previous topical/systemic treatments, showed rapid and well response to intralesional injections of betamethasone (2 mg/mL, 0.2 mL/site) monotherapy once every 2 weeks for two, two, and four times of treatment, respectively. Intralesional betamethasone may provide a safe and effective alternative in the management of refractory localized DLE skin lesions.

Efficacy of Thalidomide in Discoid Lupus Erythematosus: Insights into the Molecular Mechanisms.

BACKGROUND: Thalidomide has been used successfully in a variety of chronic refractory inflammatory dermatological conditions with underlying autoimmune or infectious pathogenesis. It was first used for refractory discoid lupus erythematosus (DLE) in 1983 and has steadily grown since then. METHOD: In this review, we describe the therapeutic benefits of thalidomide for DLE treatment and its biological properties. We explain how new discoveries in DLE pathogenesis are relevant to understand thalidomide's mechanism of action and the need to find an alternative safe drug with similar therapeutic effects. SUMMARY: Thalidomide's efficacy in DLE patients is significant, with 80-90% reaching clinical remission according to different studies. However, thalidomide's use is still limited by serious adverse effects such as teratogenicity, neurotoxicity, and thrombosis. In addition, there is a frequent rate of relapse and many patients require a long-term low dose of thalidomide as maintenance. The achievement of clinical response within weeks is key to avoid irreversible DLE fibrotic sequelae, making it critical to introduce thalidomide earlier in the DLE treatment algorithm. Recently, microarray and miRNA screenings demonstrated a significant CD4+ T enrichment and T-helper 1 response predom-inance with a dysregulation of regulatory T cell (Treg) expression in DLE lesions that induced high levels of proinflammatory, chemotaxis, and apoptotic proteins that induce the chronic inflammation response. Thalidomide's anti-inflammatory, antiangiogenic, and T-cell co-stimulatory effects may be beneficial for DLE since it promotes cytokine inhibition, inhibits macrophage activation, regulates Treg responses, inhibits angiogenesis, modulates T cells, and promotes NK cell-mediated cytotoxicity.

Time to progression from discoid lupus erythematosus to systemic lupus erythematosus: a retrospective cohort study.

Determining the risk of progression to systemic lupus erythematosus (SLE) among patients diagnosed with discoid lupus erythematosus (DLE), and the time frame of this risk, are important clinical questions. Past reports have demonstrated a wide time frame of progression from DLE to SLE, with mean time to progression of approximately 8 years. Using data obtained from an academic lupus centre, we identified 32 patients who progressed from DLE to SLE. In our cohort, we found that the median time to progression from DLE to SLE was 453 days, much sooner than previously reported. We believe this information can help inform clinicians on monitoring visit intervals and how best to counsel patients on SLE progression.

Rapid response to treatment with thalidomide in an adolescent with generalized discoid lupus erythematosus.

Discoid lupus erythematosus (DLE) is the most common variant of cutaneous chronic lupus erythematosus (CLE). Sun protection, topical corticosteroids, and antimalarials constitute the first-line options for treatment. In refractory cases, alternative antimalarials, methotrexate, retinoids, and thalidomide have been utilized. We present a case of an adolescent patient with generalized DLE responding rapidly to thalidomide.

Cutaneous polyautoimmunity in two unrelated dogs: pemphigus foliaceus and generalized discoid lupus erythematosus.

BACKGROUND: Polyautoimmunity, the concurrent expression of two or more distinct autoimmune diseases (ADs) in a single individual, is a known phenomenon in humans and has been rarely reported in dogs. To the best of the authors' knowledge, comorbid pemphigus foliaceus (PF) and generalized discoid lupus erythematosus (GDLE) has not been reported in dogs. HYPOTHESIS/OBJECTIVES: To describe the clinical, histological and immunological features and treatment outcome of two unrelated dogs with comorbid PF and GDLE. ANIMALS: One 10-year-old, spayed German shepherd dog and one 8-year-old, castrated American Staffordshire terrier presented for evaluation of a symmetrical, facial- and/or pedal-dominant pustular dermatitis with concurrent, truncal scaly plaques. METHODS: For each dog, clinicopathological characterization included physical examination, lesion cytological evaluation, bacterial culture and sensitivity testing, skin histopathological investigation and direct and indirect immunofluorescence testing. Additional diagnostic imaging and haematological testing was performed to exclude extracutaneous disease. RESULTS: Both dogs exhibited lesions clinically and histologically compatible with PF and GDLE. Moreover, one dog exhibited generalized leucotrichia and chronic superficial keratitis. Remission was achieved with immunosuppressive dosages of prednisolone [high-dose pulse (Case 1) or standard immunosuppressive dosage (Case 2)] and ciclosporin (5-6 mg/kg/day). Tissue-bound antikeratinocyte immunoglobulin (Ig)G and IgM were detected in both dogs. A weak basement membrane zone deposit of C3 was seen in one dog. Circulating antikeratinocyte and anti-desmocollin-1 IgG were detected in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Cutaneous polyautoimmunity can occur in the dog. Depending on the specific disease combinations, overlapping clinical features may present diagnostic and/or therapeutic challenges. Moreover, these cases should be monitored for development of additional cutaneous or extra-cutaneous AD(s).

Computerized planimetry to assess clinical responsiveness in a phase II randomized trial of topical R333 for discoid lupus erythematosus.

BACKGROUND: R333 is a topical janus kinase and spleen tyrosine kinase inhibitor being evaluated for discoid lupus erythematosus (DLE) treatment. There is no validated measure to assess the area of active DLE lesions. OBJECTIVES: To evaluate R333 efficacy and assess a technique to measure responsiveness. METHODS: Fifty-four patients with DLE were randomized in a double-blind design to R333 or placebo. Primary end point was the proportion of patients achieving ≥ 50% decrease in erythema and scale based on lesional Cutaneous Lupus Erythematosus Disease Area and Severity IndexTM for all treated lesions at week 4. Two-dimensional (2D) area measurements for each lesion were recorded at baseline and weeks 1-6. Eighty-eight photographs (44 pre- and 44 post-treatment) were obtained from the trial and change in size of active areas was analysed by computerized planimetry and physician-assessed area change (PAAC). RESULTS: Thirty-six patients were randomized to R333 and 18 patients were randomized to placebo. Primary end point was not achieved. There was a strong association between lesion activity and physician global assessment (P < 0·001). Photos of 42 patients assessed by computerized planimetry demonstrated excellent inter- and intra-rater reliability. Area change by computerized planimetry showed a strong correlation with PAAC (Spearman r = 0·72). Area change by 2D measurements showed a weak correlation with PAAC (Spearman r = 0·29). CONCLUSIONS: Four weeks of R333 treatment did not result in significant improvement in lesion activity. Lesion activity and area change using computerized planimetry are better determinants of responsiveness than area change using 2D measurements.

Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort.

This longitudinal retrospective study aims at describing the safety profile and the reasons for discontinuation of antimalarials in patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), focusing on ocular toxicity. We analyzed the clinical data of 845 SLE and DLE patients; 59% of them were taking antimalarials: 1.4% chloroquine (CQ), 88.5% hydroxychloroquine (HCQ) and 10.1% both. The mean therapy duration was 82.5 ± 77.4 months. At least one side effect was reported by 19.4% of patients, leading to temporary or permanent withdrawal in 9.1% and 10.3% of cases, respectively; 19.3% of patients experienced side effects with HCQ and 8.6% with CQ. In 55.1% of cases, the adverse event was mild or moderate. Ophthalmological alterations were reported by 8.5% but were confirmed by the ophthalmological examination in 5.5% of cases. Retinal alterations were associated with age, disease duration and duration of the antimalarial therapy, but not to drug dose and comorbidities or lupus nephritis. This is the largest monocentric longitudinal study confirming the good safety profile of antimalarials in DLE and SLE patients. The main adverse events during the therapy were mild or moderate, but maculopathy-reported in a low percentage of patients-remains the main cause of treatment withdrawal.

Combined mepacrine-hydroxychloroquine treatment in patients with systemic lupus erythematosus and refractory cutaneous and articular activity.

Aim The aim of this study was to evaluate the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with systemic lupus erythematosus and refractory joint and/or skin disease. Methods Mepacrine was added to 46 systemic lupus erythematosus patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs ( n = 24), hydroxychloroquine + prednisone ( n = 16), hydroxychloroquine + prednisone + retinoids ( n = 2), hydroxychloroquine alone ( n = 1), hydroxychloroquine + one immunosuppressive drug ( n = 1), hydroxychloroquine + prednisone + one immunosuppressive drug + belimumab ( n = 1) or hydroxychloroquine + prednisone + belimumab ( n = 1). The outcome variable was the clinical response, either complete or partial, based on clinical judgement. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score were additionally used. Results A total of 91% patients showed complete/partial response, with similar rates among those with joint or skin disease. In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen. There also was a statistically significant decrease in the SLEDAI. The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/d ( p = 0.001). Prednisone could be discontinued in 20% of patients. No serious adverse events were seen. Smoking was the only predictor of complete response. Conclusion In the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses. The fact that smokers responded better opens the door to further studying the combination of mepacrine-hydroxychloroquine as a first-line therapy in such patients.

Rapamycin for refractory discoid lupus erythematosus.

Generalized discoid lupus erythematosus can pose a therapeutic challenge for dermatologists. Current treatment emphasizes photoprotection, topical and systemic steroids, and steroid-sparing immunosuppressive agents if necessary. Rapamycin, also known as sirolimus, selectively inhibits mammalian target of rapamycin, a regulatory kinase responsible for multiple signal transduction pathways. Mammalian target of rapamycin inhibition reduces cell division, lymphocyte proliferation, cytokine release, and downstream pathways unique from other classes of immunomodulatory drugs. Herein, we present a case of generalized discoid lupus erythematosus resistant to topical steroids, prednisone, azathioprine, mycophenolate mofetil, hydroxychloroquine, and thalidomide. The addition of rapamycin led to a positive treatment response within 6 weeks, with good tolerance of the medication and no adverse effects. The current literature supporting the use of rapamycin in the treatment of autoimmune connective tissue diseases is also briefly reviewed. For patients with severe or generalized discoid lupus erythematosus refractory to conventional treatment, rapamycin may be a useful therapeutic consideration.