Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Microscopic Mechanism for a Higher-Spin Kitaev Model.

The spin S=1/2 Kitaev honeycomb model has attracted significant attention since emerging candidate materials have provided a playground to test non-Abelian anyons. The Kitaev model with higher spins has also been theoretically studied, as it may offer another path to a quantum spin liquid. However, a microscopic route to achieve higher spin Kitaev models in solid state materials has not been rigorously derived. Here we present a theory of the spin S=1 Kitaev interaction in two-dimensional edge-shared octahedral systems. Essential ingredients are strong spin-orbit coupling in anions and strong Hund's coupling in transition metal cations. The S=1 Kitaev and ferromagnetic Heisenberg interactions are generated from superexchange paths. Taking into account the antiferromagnetic Heisenberg term from direct-exchange paths, the Kitaev interaction dominates the physics of the S=1 system. Using an exact diagonalization technique, we show a finite regime of S=1 spin liquid in the presence of the Heisenberg interaction. Candidate materials are proposed, and generalization to higher spins is discussed.

Reactive arthritis.

Reactive arthritis (ReA) is an immune-mediated seronegative arthritis that belongs to the group of spondyloarthropathies and develops after a gastrointestinal or genitourinary system infection. The condition is considered to be characterized by a triad of symptoms (conjunctivitis, arthritis and urethritis) although a constellation of other manifestations may also be present. ReA is characterized by psoriasiform dermatological manifestations that may resemble those of pustular psoriasis and, similar to guttate psoriasis, is a post-infectious entity. Also, the articular manifestations of the disorder are similar to those of psoriatic arthritis and both conditions show a correlation with HLA-B27. These facts have led several authors to suggest that there is a connection between ReA and psoriasis, listing ReA among the disorders related to psoriasis. However, the pathogenetic mechanism behind the condition is complex and poorly understood. Bacterial antigenicity, the type of host response (i.e. Th1/Th2 imbalance) and various genetic factors (i.e. HLA-B27 etc.) play an important role in the development of the disorder. It is unknown whether all the aforementioned factors are part of a mechanism that could be similar to, or share basic aspects with known psoriasis pathogenesis mechanisms.

Drug-induced pemphigoid: a review of the literature.

Bullous pemphigoid is an acquired autoimmune disease that is characterized by subepidermal blistering and affects mainly the elderly. The pathogenesis of the condition has not yet been fully elucidated, but it is widely accepted that a strong correlation with various medications may exist. In reality, more than 50 different drugs have been associated with the appearance of bullous pemphigoid and as new therapies emerge, this number is very likely to increase. A number of pathogenetic mechanisms have been proposed in the past. It is true that a delicate immunological balance is disturbed in all patients with the disease. The variable effects that may be exhibited by the use of biological drugs could shed some light in this complex immunological behaviour. At the same time, drug-induced bullous pemphigoid is difficult to differentially diagnose from its idiopathic counterpart, as the clinical picture and histopathological findings in both conditions may only have subtle differences. Patients who present with bullous pemphigoid and receive multiple regimens should always be suspected of suffering from the drug-induced variant of the condition. This possibility must be considered, as after the withdrawal of the suspect medication most patients respond rapidly to treatment and do not experience relapses.

Correlation of antibodies against desmogleins 1 and 3 with indirect immunofluorescence and disease status in a Greek population with pemphigus vulgaris.

BACKGROUND: The use of ELISA testing of antibodies to desmogleins 1 and 3 (anti-Dsg1 and anti-Dsg3) and indirect immunofluorescence (IIF) has been strongly supported for the serologic diagnosis of pemphigus. The purpose of this study was to correlate anti-Dsg1 and anti-Dsg3 with IIF values, disease localization, treatment and clinical course in Greek patients with pemphigus vulgaris (PV). METHODS: A total of 54 patients with PV had ELISA serum testing for the presence and titers of anti-Dsg1, anti-Dsg3 and IIF. Anti-Dsg1, anti-Dsg3 and IIF were correlated with treatment and disease localization. For 40 patients, titers of anti-Dsg1 and anti-Dsg3 were assessed in relation to treatment and clinical course after 12 months. RESULTS: Anti-Dsg3 and anti-Dsg1 positivity in patients with negative IIF was 70.6% and 58.8%, respectively. Anti-Dsg1 and anti-Dsg3 were positive in 89.3% and 100% of patients with mucocutaneous disease, respectively, 88.9% and 66.7% of patients with skin limited disease, respectively and 52.9% and 76.5% of patients with mucosal limited disease, respectively. Both antibody titers showed significant correlation with IIF and treatment status. Improvement of clinical status was associated with significant decrease of both anti-Dsg1 and anti-Dsg3 after 12 months. CONCLUSIONS: Serum testing of anti-Dsg1 and anti-Dsg3 in PV patients not only provides significant correlations with IIF, treatment and disease type, but may serve as a monitoring tool for clinical course and treatment guidance.

Effectiveness of topical calcineurin inhibitors as monotherapy or in combination with hydroxychloroquine in cutaneous lupus erythematosus.

BACKGROUND: Calcineurin inhibitors show potent anti-inflammatory effects and favorable safety profile when used in the treatment of cutaneous lupus erythematosus (CLE). OBJECTIVE: The present study investigates the change in clinical parameters of erythema, desquamation and edema, when calcineurin inhibitors are used as monotherapy or in combination with hydroxychloroquine in CLE for a period of 60 days. METHODS: 18 patients were treated with topical tacrolimus and 20 patients with topical pimecrolimus, as monotherapy or in combination with hydroxychloroquine. Clinical parameters of erythema, desquamation and edema were assessed on a scale from 0 to 3 for erythema and edema and 0 to 2 for desquamation. RESULTS: Statistically significant improvement in erythema, desquamation and edema was observed in patients on monotherapy with calcineurin inhibitor and combination treatment with hydroxychloroquine, regardless of disease type. Combination treatment resulted in improvement of edema in 100% of patients, while monotherapy did so in 75% of patients. CONCLUSIONS: Topical calcineurin inhibitors enhance the therapeutic effect of systemic agents in cutaneous lupus erythematosus, and result in improvement of the clinical parameters studied.

The role of inflammatory markers in assessing disease severity and response to treatment in patients with psoriasis treated with etanercept.

BACKGROUND: Psoriasis is a chronic, systemic, inflammatory disease. Inflammatory markers are used in clinical practice to detect acute inflammation, and as markers of treatment response. Etanercept blocks tumour necrosis factor (TNF)-α, which plays a central role in the psoriatic inflammation process. AIM: To reveal any possible association between disease severity [measured by Psoriasis Area and Severity Index (PASI)] and the inflammatory burden (measured by a group of inflammatory markers), before and after etanercept treatment. METHODS: In total, 41 patients with psoriasis vulgaris, eligible for biological treatment with etanercept, were enrolled in the study. A set of inflammatory markers was measured, including levels of white blood cells and neutrophils, fibrinogen, ferritin, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), haptoglobin, ceruloplasmin and α1-antitrypsin, before and after 12 weeks of etanercept 50 mg twice weekly. RESULTS: All markers were reduced after treatment (P < 0.001). PASI correlated with fibrinogen and hs-CRP. Of the 41 patients, 19 (46.3%) achieved reduction of 75% in PASI (PASI75). An increase in hs-CRP and ESR difference (values before minus values after treatment) was related to higher likelihood of achieving PASI75. CONCLUSIONS: Inflammatory markers, particularly hs-CRP and to a lesser extent, fibrinogen and ESR, can be used to assist in assessing disease severity and response to treatment in patients with psoriasis. A combination of selected inflammatory factors (which we term the Index of Psoriasis Inflammation) in combination with PASI might reflect inflammatory status in psoriasis more accurately than each one separately.

Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a single centre.

BACKGROUND: Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long-term infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real-life clinical practice. OBJECTIVES: To report our experience with infliximab (Remicade; Schering Plough, Kenilworth, NJ, U.S.A.) for the treatment of moderate to severe plaque psoriasis (and/or arthritis) from a single clinic in Greece. PATIENTS AND METHODS: Between August 2004 and March 2008, 62 patients presenting to our clinic with moderate to severe psoriasis were treated with infliximab. Disease phenotype, clinical course, disease severity and adverse events were assessed throughout the treatment period. RESULTS: Infliximab resulted in a reduction of median Psoriasis Area and Severity Index (PASI) of 70% at week 6 and 84.4% at week 14. Nineteen patients who have completed 1 year on infliximab treatment experienced sustained efficacy with a median PASI improvement of 92.16% and a Physician's Global Assessment (PGA) of 'clear' or 'almost clear', while nine patients have reached approximately 20 months of continuous therapy. All patients with psoriatic arthritis showed marked improvement in their clinical symptoms following the first infusion. Eight patients (12.9%) experienced adverse events that required discontinuation of treatment. There were no statistically significant differences in PASI and Dermatology Life Quality Index (DLQI) scores between patients with arthritis and those with only skin lesions, or between those who received methotrexate, either from the beginning or during infliximab therapy, and those who did not receive methotrexate at all. Selected patients of interest are discussed. CONCLUSIONS: The above data confirm previous reports that treatment with infliximab is an efficacious and safe option for patients with moderate to severe plaque psoriasis (and/or arthritis). Long-term follow-up, continued pharmacovigilance, and controlled comparative studies will be required to fully evaluate its use in the treatment of psoriasis.

Serum levels of transforming growth factor-beta1 in patients with mild psoriasis vulgaris and effect of treatment with biological drugs.

BACKGROUND: Psoriasis is an immune cell-mediated disease in which cytokines play an important role. Studies have been performed to explore the relationship between the disease and cytokine blood levels with a view to finding a biomarker for monitoring disease severity/activity and treatment efficacy. AIM: To investigate the levels of transforming growth factor-beta1 (TGF-beta1) in patients with mild psoriasis vulgaris (PV) and the possible use of this cytokine in monitoring treatment with biological drugs. METHODS: Serum levels of TGF-beta1 were estimated in 33 untreated patients (PI group), in 7 of these patients (PII group) before and after 3 months of treatment with one of two biological drugs (etanercept and efalizumab) and in 19 healthy volunteers (control group). RESULTS: Significantly (P < 0.0001) higher serum levels of TGF-beta1 were found in the PI group [Psoriasis Area and Severity Index (PASI) 9-10] compared with the 19 healthy volunteers. In the PII group, after the administration of one of the biological drugs, a 50% reduction in PASI and a significant (P = 0.032) decrease in TGF-beta1 was noted. CONCLUSIONS: Raised TGF-beta1 levels in patients with mild PV decreased in tandem with a decrease in PASI after biological drug treatment. Hence, TGF-beta1 levels seem to be sensitive to changes in disease severity.

Pathogenesis of subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) is a photosensitive form of lupus-specific skin lesion that is strongly associated with the presence of anti-Ro/SSA autoantibody. The pathogenesis of SCLE includes genetic, environmental and immunologic factors. Recent studies provide strong evidence for the involvement of innate and cell-mediated immunity, underlying the important role of plasmacytoid dendritic cells, interferon-alpha and antibody-dependent cell cytotoxicity. In addition, a variety of cytokines, chemokines and adhesion molecules have been found to participate in the expansion phase of the autoimmune effector mechanisms. This article summarizes the recent immunological findings and reviews the current mechanisms which are implied in the development of the disease.

Hereditary neuropathy with liability to pressure palsies: the same molecular defect can result in diverse clinical presentation.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. Two young adult patients are reported as index cases of two families in which HNPP was diagnosed. The first patient presented with recurrent pressure palsies, whereas the second suffered from fasciculations and myokymias in his right hand, with difficulty in writing, and upper and lower limb paraesthesias of 3 years' duration. Electrodiagnostic studies revealed slowing of conduction primarily in common sites of compression in both patients. Sural nerve biopsy revealed the characteristic tomaculous swellings in both patients. DNA analysis showed that both patients have a deletion in chromosome 17p11.2 which is found in the majority of HNPP cases. In light of the common molecular defect, the different clinical symptomatology of the two patients is discussed.

Delayed hypersensitivity and differences of histologic pattern in allergic cutaneous vasculitis.

Fourteen patients with allergic cutaneous vasculitis of either the polymorphonuclear (PMN)- or the mononuclear (MN)-predominant type were studied as regards the following parameters: the disease duration, histology, monoclonal antibody typing of the mononuclear cell infiltrate from recent lesions, and the delayed hypersensitivity (DH) response, assessed both by recall antigens (tuberculin type) and the dinitrochlorobenzene skin test. From the results, it was shown that in PMN-predominant vasculitis, DH reactions were well elicited, whereas in MN-predominant vasculitis, DH skin reactions were somehow impaired. In MN-predominant cases, many OKT3+, OKT4+, OKT8+, and OKM1+ cells were usually seen to surround the skin vessels, whereas in PMN-predominant cases, rare OKT8+, OKT4+, or OKM1+ cells were seen in the dermis. The epidermal dendritic cell system, as revealed by the Na(1)34 monoclonal antibody, was unaffected in both types of allergic cutaneous vasculitis.

Cognitive function in non-demented individuals complaining of short-term memory disturbances: a study with event-related potentials (P 300) and brain CT scan.

Event-related potentials (ERPs) were elicited in 30, non-consecutive, non-demented individuals, complaining of short-term memory disturbances. Fifteen of them had a moderate diffuse cerebral atrophy on their brain CT and the other 15 had a negative brain CT. ERPs were also elicited in 15 age-matched controls with no reported memory disturbances and negative brain CTs. The statistical analysis showed that the group of individuals with cerebral atrophy had a significantly prolonged P300 (P3) latency and a decreased P3 amplitude compared to controls. It is concluded that among persons complaining of short-term memory disturbances, the individuals who show cerebral atrophy, taken as a group, have a P3 latency prolongation and/or low P3 amplitude a finding which reflects an impaired information processing.

New information on the value of plaque characterisation--relation to symptoms.

This paper reviews the literature on the significance of carotid plaque echomorphology and degree of stenosis in relation to the different types of cerebrovascular symptomatology (amaurosis fugax, hemispheric transient ischaemic attacks, stroke) and the asymptomatic status. It provides evidence that amaurosis fugax is associated with hypoechoic and severely stenosed plaques, the hemispheric transient ischaemic attacks and stroke are associated with plaques of intermediate echodensity and stenosis while the asymptomatic status is associated with hyperechoic and moderately stenosed plaque. It lends support to the notion that plaque hypoechoicity is associated with embologenicity. It supports the view that the severe carotid stenosis facilitates the opening of the cerebral collateral circulation and that amaurosis fugax is associated with an "opened" cerebral collateral supply as contrasted to the cerebrovascular symptomatology. It proposes the inclusion of the cerebral collateral circulation as a stroke risk factor along with the plaque echomorphology and the degree of stenosis in the natural history studies of asymptomatic individuals with carotid bifurcation plaques.

Successful treatment of localized pemphigus foliaceus with topical pimecrolimus.

We report the case of successful treatment of a 79-year-old male patient with recurrent pemphigus foliaceus with pimecrolimus cream 1% once daily for 40 days. The patient initially presented with localized lesions on the scalp and nose area and was treated with systemic corticosteroids. At his fourth relapse within a period of 16 months, he refused any systemic treatment. Pimecrolimus cream was suggested to him as an alternative option.