A systematic review of case series and clinical trials investigating systemic oral or injectable therapies for the treatment of vitiligo.

AIMS AND OBJECTIVES: The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions. METHOD: Databases including PubMed, Scopus, and Web of Science were meticulously searched for studies spanning from 2010 to August 2023, focusing on systemic oral and injectable therapies for vitiligo, using comprehensive keywords and search syntaxes tailored to each database. Key data extracted included study design, treatment efficacy, patient outcomes, patient satisfaction, and safety profiles. RESULTS: In a total of 42 included studies, oral mini-pulse corticosteroid therapy (OMP) was the subject of six studies (14.2%). Minocycline was the focus of five studies (11.9%), while methotrexate, apremilast, and tofacitinib each were examined in four studies (9.5%). Antioxidants and Afamelanotide were the subjects of three studies each (7.1%). Cyclosporine, simvastatin, oral zinc, oral corticosteroids (excluding OMP) and injections, and baricitinib were each explored in two studies (4.8%). Azathioprine, mycophenolate mofetil, and Alefacept were the subjects of one study each (2.4%). CONCLUSION: Systemic treatments for vitiligo have been successful in controlling lesions without notable side effects. OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral/injectable corticosteroids are effective treatment methods. However, oral zinc and alefacept did not show effectiveness.

Biological therapies (immunomodulatory drugs), worsening of psoriasis and rebound effect: new evidence of similitude.

BACKGROUND: Employing the secondary action or adaptative reaction of the organism as therapeutic response, homeopathy uses the treatment by similitude (similia similibus curentur) administering to sick individuals the medicines that caused similar symptoms in healthy individuals. Such homeostatic or paradoxical reaction of the organism is scientifically explained through the rebound effect of drugs, which cause worsening of symptoms after withdrawal of several palliative treatments. Despite promoting an improvement in psoriasis at the beginning of the treatment, modern biological therapies provoke worsening of the psoriasis (rebound psoriasis) after discontinuation of drugs. METHOD: Exploratory qualitative review of the literature on the occurrence of the rebound effect with the use of immunomodulatory drugs [T-cell modulating agents and tumor necrosis factor (TNF) inhibitors drugs] in the treatment of psoriasis. RESULTS: Several researches indicate the rebound effect as the mechanism of worsening of psoriasis with the use of efalizumab causing the suspension of its marketing authorization in 2009, in view of some severe cases. Other studies also have demonstrated the occurrence of rebound psoriasis with the use of alefacept, etanercept and infliximab. CONCLUSION: As well as studied in other classes of drugs, the rebound effect of biologic agents supports the principle of similitude (primary action of the drugs followed by secondary action and opposite of the organism).

Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases.

Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.

Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.

Evolving Landscape of Biologic Therapy for Pediatric Psoriasis.

Pediatric psoriasis is a chronic inflammatory skin condition. Current treatment modalities include topical medications, phototherapy, and systemic drugs, including biological agents. In cases of moderate-to-severe psoriasis recalcitrant to other therapies, biological therapies are often an attractive option given their dosing schedules, safety profiles, and need for less frequent laboratory monitoring, when compared with traditional systemic therapies. This article reviews biological treatment options approved for pediatric psoriasis and identifies others actively under investigation.

Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells.

Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naïve CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.

Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy.

Calcineurin inhibitors (CNI) and steroids are known to promote insulin resistance, and their avoidance after islet transplantation is preferred from a metabolic standpoint. Belatacept, a B7-specific mediator of costimulation blockade (CoB), is clinically indicated as a CNI alternative in renal transplantation, and we have endeavored to develop a clinically translatable, belatacept-based regimen that could obviate the need for both CNIs and steroids. Based on the known synergy between CoB and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched islet allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on CoB-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation. All received belatacept and sirolimus; six also received alefacept. Belatacept and sirolimus significantly prolonged rejection-free graft survival (median 225 days compared to 8 days in controls receiving basiliximab and sirolimus; p = 0.022). The addition of alefacept provided no additional survival benefit, but was associated with Cytomegalovirus reactivation in four of six animals. No recipients produced donor-specific alloantibodies. The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys, but induction with alefacept provides no survival benefit and increases the risk of viral reactivation.

Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

Failure of alefacept in the treatment of vitiligo.

BACKGROUND: Vitiligo is a common acquired pigmentary disorder with a profound psychosocial impact. The exact pathogenesis of vitiligo is not fully understood; however, vitiligo appears to be an autoimmune disease involving T-cell-mediated melanocyte destruction. Recently, complete clearance of coexisting vitiligo without recurrence over 2 years was reported in 2 psoriasis patients treated with alefacept. OBJECTIVE: To evaluate the safety and efficacy of alefacept in the treatment of vitiligo. METHODS: After providing informed written consent, 4 adult patients with widespread vitiligo (covering a body surface area ≥5%) were treated with weekly intramuscular injections of 15 mg alefacept for 12 weeks. All patients were monitored clinically, by laboratory investigation, and by digital image analysis. All patients were followed up with for 24 weeks. RESULTS: All patients tolerated alefacept well, without any adverse events. None of the patients showed any repigmentation. However, 1 patient developed new depigmented patches during treatment with alefacept. LIMITATIONS: A pilot study with a small number of patients. CONCLUSION: Alefacept as a monotherapy for vitiligo treatment did not result in any patient improvement, and further evaluation in larger studies may be required.

Novel targeted therapies for eosinophilic disorders.

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.

Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes.

Variation in the preservation of ß cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3-Ig) and demonstrated C-peptide preservation in approximately 30% of new-onset T1D individuals. We analyzed islet antigen-reactive (IAR) CD4+ T cells in PBMC samples collected prior to treatment from alefacept- and placebo-treated individuals using flow cytometry and single-cell RNA sequencing. IAR CD4+ T cells at baseline had heterogeneous phenotypes. Transcript profiles formed phenotypic clusters of cells along a trajectory based on increasing maturation and activation, and T cell receptor (TCR) chains showed clonal expansion. Notably, the frequency of IAR CD4+ T cells with a memory phenotype and a unique transcript profile (cluster 3) were inversely correlated with C-peptide preservation in alefacept-treated, but not placebo-treated, individuals. Cluster 3 cells had a proinflammatory phenotype characterized by expression of the transcription factor BHLHE40 and the cytokines GM-CSF and TNF-α, and shared TCR chains with effector memory-like clusters. Our results suggest IAR CD4+ T cells as a potential baseline biomarker of response to therapies targeting the CD2 pathway and warrant investigation for other T cell-related therapies.

HLA polymorphism among Chinese patients with chronic plaque psoriasis: subgroup analysis.

BACKGROUND: HLA-Cw*06 has a strong influence on the clinical features and the susceptibility to psoriasis in different ethnicities. It is also used as a biomarker to predict the therapeutic efficacy of biologics, with inconsistent results. Additionally, most Asian patients with psoriasis do not carry HLA-Cw*06. OBJECTIVES: To determine additional HLA alleles which confer susceptibility or affect the severity of psoriasis in Chinese Han individuals. In addition, the potential of using HLA to predict treatment outcomes was also investigated. METHODS: We conducted a case-control association study in 199 Chinese patients with psoriasis and 200 unrelated healthy controls. HLA-B and HLA-C genotyping was performed and correlated with the therapeutic efficacy of the biologics, including alefacept, efalizumab, etanercept and ustekinumab. Patients with psoriasis were divided into group A (high-need patients with moderate to severe psoriasis) and B (general patients with psoriasis). RESULTS: The frequencies of HLA-B*60, HLA-B*75, HLA-Cw*06 and HLA-Cw*10 were significantly increased in patients with psoriasis compared with the healthy controls. However, the prevalence of HLA-Cw*06 was lower in group A compared with group B (6% vs. 17%, Pc=0·04). HLA-B*46 was found to be strongly associated with group A but not with group B patients with psoriasis. HLA-Cw*01/HLA-B*46 was also identified as a risk haplotype for Chinese patients with psoriasis, compatible with the results in Thais. Significant differences in response to biologics were observed between HLA-Cw*01+ and HLA-Cw*01- individuals in the alefacept treatment group, and between HLA-B*37+ and HLA-B*37-, and HLA-B*58+ and HLA-B*58- individuals in the efalizumab treatment group. CONCLUSIONS: In addition to HLA-Cw*06, the HLA-Cw*01/HLA-B*46 haplotype was also increased in Chinese patients with psoriasis. High-need patients with psoriasis had a lower frequency of HLA-Cw*06 but a higher prevalence of HLA-B*46 compared with general patients with psoriasis in our population.

Case presentation of moderate-severe psoriasis.

The use of biologic agents has greatly improved psoriasis treatment. However, some individuals fail to respond to treatment or loose initial efficacy, and it may be difficult to find the optimal treatment for these patients. We present a patient with long-standing, moderate-severe plaque psoriasis, who had received UVB therapy as well as classical systemic therapies without sufficient response previously. Alefacept only gave a moderate response with quick recurrence after the end of treatment. Adalimumab was working for some time, but finally the patient experienced a slow loss of efficacy and was especially hampered by severe involvement of his hands. This caused him great distress as his work involved a high level of customer contact. The decision was taken to change therapy to ustekinumab. After one injection of ustekinumab psoriasis was greatly improved and it was almost completely resolved after the second injection, and arthritis was no longer active. The efficacy of ustekinumab treatment could be maintained up to now; there is only minimal disease activity and the patient is extremely satisfied. In conclusion, the decision to change to another biologic with different mode of action proved to be successful, and it helped the patient to forget his disease for most of the time and to fulfil the responsibilities of his job.

Treatment of nail psoriasis with TNF-α or IL12/23 inhibitors.

Nail psoriasis appears to be an important source of psoriatic morbidity through physical impairment, pain, and cosmetic disturbances. Conventional treatment is often unsatisfactory. A systematic review of studies reporting the effect of TNF-α inhibitors and related drugs on nail psoriasis using the Nail Psoriasis Severity Index (NAPSI) as the outcome measure was therefore made. Data are available from randomized controlled trials (RCT) where NAPSI has been studied as a secondary outcome, as well as from case-series in which NAPSI has been the primary outcome studies suggest that adalimumab, briakinumab, etanercept, golimumab, infliximumab, and ustekinumab all improve NAPSI scores. No direct comparative RCTs are available in which NAPSI scores have been reported. The data further suggest that changes in NAPSI mirror changes in disease severity of other psoriatic manifestations, that is, in psoriatic arthritis and skin psoriasis. The effect only appears to be delayed due to the rate of growth of the nail plate.

A randomized controlled study of combination therapy with alefacept and narrow band UVB phototherapy (UVB) for moderate to severe psoriasis: efficacy, onset, and duration of response.

BACKGROUND: Alefacept is an effective intermittent treatment for psoriasis that can provide long-lasting remissions. Combination therapy with narrow-band ultraviolet B (nbUVB) phototherapy may enhance treatment outcomes and accelerate the onset of clinical response. OBJECTIVE: To assess the efficacy of alefacept in combination with nbUVB phototherapy compared to alefacept alone in subjects with moderate to severe psoriasis. METHODS: Ninety-eight adults with moderate to severe psoriasis were randomized to treatment with alefacept 15 mg intramuscularly (i.m.) once weekly for 12 weeks alone or in combination with three times weekly nbUVB treatments in this prospective, open-label, assessor-blinded, randomized, multicenter, parallel-group, 36-week study. RESULTS: A statistically significantly greater proportion of subjects in the alefacept plus nbUVB arm achieved the primary endpoint of PASI 75 at week 16 compared to subjects in the alefacept alone arm (44.9% vs 22.5%, P=0.032). Secondary outcomes were also in favor of the alefacept plus nbUVB group, including the proportion of subjects achieving a Physician Global Assessment (PGA) score of clear or almost clear at any time during the study (59.2% vs 34.7%, P=0.026) and reduction in percent body surface area (BSA) involved with psoriasis at week 16 (13.4% vs 8.0%, P<0.001). The onset of clinical response was significantly faster in the combination therapy group compared to monotherapy (mean time to PASI 75: 82 vs 107 days, P=0.007). Both treatments were generally well tolerated. LIMITATIONS: Open-label, assessor-blinded study without a phototherapy-only treatment arm. CONCLUSION: The addition of nbUVB to treatment with alefacept significantly enhanced and accelerated the clinical benefits of alefacept therapy and was generally safe and well-tolerated.

Oral manifestations of psoriasis. Clinical presentation and management.

Psoriasis is a chronic immune-mediated disease of unknown etiology that affects the skin and mucous membranes. According to the National Institutes of Health (NIH), approximately five million Americans, 3% of the population, have been diagnosed with psoriasis. Oral manifestations of psoriasis are less well recognized than skin lesions, and treatment for oral lesions is not standardized. This article will review the clinical presentation of skin and mucous membrane psoriasis, along with the therapeutic modalities available to oral health-care providers.

Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression.

Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8(+) effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8(+) CD2(hi) CD28(-) T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.

Immune response to pneumococcal polysaccharide vaccine in adults with chronic plaque psoriasis treated with alefacept.

BACKGROUND: Alefacept is a T cell-modulating biologic therapy for psoriasis that could affect patients' ability to mount immune responses. OBJECTIVE: This open-label, phase IV, multicenter study assessed the ability of adults with chronic plaque psoriasis receiving alefacept to generate antibodies to a pneumococcal polysaccharide vaccine (PPV). METHODS: Patients were treated with a standard 12-week course of alefacept and administered the 23-valent PPV at week 6. Antipneumococcal antibodies were measured at baseline and weeks 6, 9, 12, and 33. The primary end point was the percentage of patients with a 2-fold or greater increase from prevaccination (week 6) to 6 weeks postvaccination (week 12) in antibody titers to 2 or more of 5 designated PPV antigens. RESULTS: Of 43 patients enrolled, 42 were included in the full analysis set, with 86% of patients exhibiting a 2-fold or greater increase and 57% of patients exhibiting a 4-fold or greater increase in antibody titers to 2 or more of 5 designated antigens from prevaccination to 6 weeks postvaccination. At 6 months postvaccination, 78% of patients had a 2-fold or greater increase and 47% of patients had a 4-fold or greater increase in antibody titers to 2 or more of the 5 designated antigens. There were statistically significant increases in mean antibody titers to all 23 antigens in PPV from prevaccination to 6 weeks postvaccination. LIMITATIONS: This was an open-label study with no comparator. CONCLUSIONS: Most patients mounted immune responses to PPV; increases in antibody titers in these patients were consistent with those seen in healthy individuals.

Psoriasis in the elderly: from the Medical Board of the National Psoriasis Foundation.

BACKGROUND: The continuous increase in the US population older than 65 years and the chronic course of psoriasis make management of psoriasis in the elderly an important health care problem. OBJECTIVE: We sought to develop a treatment algorithm for patients with psoriasis who are older than 65 years. METHODS: A systematic literature search for studies on elderly patients with psoriasis was performed using MEDLINE. RESULTS: We summarize the available published data on therapeutic modalities used in the elderly. We suggest a treatment algorithm including topical medications as first-line treatment for limited disease, with phototherapy, systemic retinoids, methotrexate, and biologics as the first-line systemic treatments for patients with more extensive disease. Cyclosporine should only rarely be used as a second-line systemic treatment for extensive disease in elderly patients with psoriasis. LIMITATIONS: Limited data are available regarding treatment modalities specifically for elderly patients with psoriasis. CONCLUSION: Appropriate treatment for elderly patients with limited psoriasis includes topical corticosteroids, topical vitamin D analogues, and topical tazarotene. For appropriately monitored elderly patients who have psoriasis with extensive disease, phototherapy, acitretin, methotrexate, alefacept, etanercept, adalimumab, infliximab, and ustekinumab are first-line therapies that can generally be safely used. There remains a need for further research on the management of psoriasis in elderly patients with psoriasis.