Impact of anti‐tumor necrosis factor‐α agents on serum levels of KL‐6 and surfactant protein‐D in patients with psoriasis

We longitudinally examined the influence of anti‐tumor necrosis factor (TNF)‐α treatment on serum levels of KL‐6 and surfactant protein‐D (SP‐D). The study group comprised 22 patients with psoriasis treated with infliximab or adalimumab and with no history of interstitial lung disease (ILD). KL‐6 and SP‐D levels were measured in serum samples. Twelve of the 22 patients (55%) showed at least a 20% increase in KL‐6 levels compared with baseline. Of these 12 patients, none exhibited any signs of ILD on chest computed tomography and nine who showed an increase in KL‐6 levels (75%) showed at least a 20% increase in SP‐D levels. Some patients showed simultaneous increases in KL‐6 and SP‐D levels after treatment with anti‐TNF‐α agents. Although these patients may have undetectable or subtle alveolar damage, careful observation is needed.     

Anti‐tumor necrosis factor‐alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6‐month prospective study

The aim of the present study was to determine if the use of the anti‐tumor necrosis factor (TNF)‐α monoclonal antibody adalimumab could improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. This was a prospective study on a series of consecutive patients with moderate to severe psoriasis who completed 6 months of therapy with adalimumab. Patients with history of cardiovascular events, diabetes mellitus, kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Assessment of endothelial function by brachial artery reactivity measuring flow‐mediated endothelial dependent vasodilatation (FMD%), and carotid arterial stiffness by pulse wave velocity (PWV) was performed at the onset of treatment (time 0) and at month 6. Twenty‐nine patients were studied. Anti‐TNF‐α adalimumab therapy yielded a significant improvement of endothelial function. The mean ± standard deviation (SD) FMD% values increased from 6.19 ± 2.44% at the onset of adalimumab to 7.46 ± 2.43% after 6 months of treatment with this biologic agent (P = 0.008). Likewise, following the use of adalimumab, PWV levels decreased from 6.28 ± 1.04 m/s at the onset of adalimumab to 5.69 ± 1.31 m/s at 6 months (P = 0.03). In conclusion, patients with moderate to severe psoriasis exhibit improvement of endothelial function and arterial stiffness following anti‐TNF‐α therapy. These findings are of potential relevance due to increased risk of cardiovascular disease in patients with severe psoriasis.     

Combination therapy of cyclosporine and anti‐tumor necrosis factor α in psoriasis: a case series of 10 patients

Combination therapy has become important in treating psoriasis, using synergism between different mechanisms to maximize efficacy and minimize toxicity. Little has been published on the combination of cyclosporine and anti‐tumor necrosis factor (TNF) α agents. In this study, a retrospective chart review was made of the effects of this combination therapy in 10 patients with recalcitrant psoriasis. Treatment included a conditioning phase with cyclosporine, 3.14 ± 0.37 mg/kg for 4.6 ± 2 weeks, and a combination phase during which etanercept/adalimumab were initiated and cyclosporine was tapered over 10.2 ± 3.7 weeks. Treatment success, evaluated after each phase, was classified as complete recovery (CR, more than 75% improvement), partial response (PR, 25–75% improvement), and no response (NR, less than 25% improvement). All patients reached CR at the end of the combination therapy. Two were still on combination therapy after 12 and 20 weeks. Adverse event occurred in three cases, all in the conditioning phase. We conclude that combination therapy with cyclosporine and anti‐TNF α appears to offer an effective and safe approach to treatment of psoriasis.     

Antinuclear antibodies associate with loss of response to antitumour necrosis factor‐α therapy in psoriasis: a retrospective,observational study

Background An increasing number of patients with severe psoriasis are failing to respond to antitumour necrosis factor (TNF)‐α therapy (etanercept, infliximab and adalimumab). Objectives We observed that many of these patients developed antinuclear antibodies (ANA) and antidouble‐stranded DNA (anti‐dsDNA) antibodies while on treatment prompting us to investigate whether their development is associated with anti‐TNF treatment failure. Methods All patients with psoriasis who had received anti‐TNF therapies were identified and their blood results and treatment histories were obtained from electronic patient records and case notes. Results A total of 97 patients had been treated with anti‐TNF agents (60 were on their first agent, 22 had been on and stopped one agent, nine had been on and stopped two agents and six had been on and stopped all three agents). ANA developed in 17% of patients on their first treatment, 54% of patients who had failed one treatment, 78% of patients who had failed two treatments and 83% of patients who had failed all three treatments. Anti‐dsDNA antibodies developed in 2%, 27%, 33% and 83% of patients from the same respective groups. Significantly, the antibodies developed before treatment had failed with all three agents and their development was not related to the total time that patients had been on anti‐TNF therapy. Conclusions This study suggests that the development of ANA and anti‐dsDNA antibodies on anti‐TNF treatment may act as a marker of forthcoming treatment failure. Large‐scale prospective studies are required to assess the importance of this observation.     

Pregnancy outcomes in women with moderate‐to‐severe psoriasis

Background The association between psoriasis and pregnancy outcomes has not been adequately examined, although psoriasis onset is common in the reproductive period. Objective To evaluate the association between moderate‐to‐severe psoriasis and pregnancy complications. Methods A retrospective, matched cohort study of 68 deliveries in 35 women with moderate‐to‐severe psoriasis compared to 237 deliveries in 236 women without psoriasis randomly selected after matching for age, parity and gestational age. Results The psoriasis patients had higher mean of past spontaneous (0.42 ± 0.58 vs. 0.26 ± 0.63, P = 0.002) and induced (0.32 ± 0.60 vs. 0.06 ± 0.25, P = 0.001) abortions than controls. They had a higher percentage of pregnancy‐induced hypertensive diseases (7.4% vs. 2.1%, P < 0.05) and premature rupture of membranes (16% vs. 5.5%, P < 0.008). Newborns to women with psoriasis had higher birth weight (3375 ± 543 g vs. 3247 ± 460 g, P = 0.03), increased percentage of large‐for‐gestational age (24% vs. 12%, P = 0.02), and macrosomia (13% vs. 4.2%P = 0.02). In multivariate analysis, moderate‐to‐severe psoriasis was an independent risk factor for previous spontaneous abortions, induced abortions, premature rupture of membranes (PROM), and newborn macrosomia. Conclusion Moderate‐to‐severe psoriasis is associated with spontaneous and induced abortions, pregnancy‐induced hypertensive diseases, premature rupture of membranes, large‐for‐gestational age newborns, and macrosomia.     

Increased circulating anti‐α6‐integrin autoantibodies in psoriasis and psoriatic arthritis but not in rheumatoid arthritis

In psoriatic skin, laminin integrity is altered, which could lead to insufficient laminin integrin interactions, leaving the α6‐integrin exposed and possibly accessible for autoantibody production. Therefore we investigated the presence of anti‐α6‐integrin autoantibodies in the serum of patients with psoriasis vulgaris (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in comparison with healthy donors. The level of circulating anti‐α6‐integrin antibodies was determined by enzyme‐linked immunoassay using α6‐integrin fragments. Antibodies against at least one recombinant fragment were found in approximately 30% of Ps and PsA patients. In contrast, in RA patients, the frequency of antibodies was similar to healthy controls. Our study shows the presence of anti‐α6‐integrin antibodies in Ps and PsA but not in RA, which could indicate ongoing abnormal processes in the skin. Anti‐α6‐integrin autoantibodies may contribute to the formation of micro‐wounds in the skin and to the characteristic wound‐healing phenotype in psoriasis.     

Efficacy comparison of ustekinumab between anti‐tumor necrosis factor‐α drug‐naïve and anti‐tumor necrosis factor‐α drug‐resistant Japanese psoriasis cases

Ustekinumab is highly efficacious for psoriasis; however, it has not been fully clarified whether previous failure in anti‐tumor necrosis factor‐α (TNF‐α) therapy affects the treatment response with ustekinumab. Therefore, we evaluated the efficacy of ustekinumab in anti‐TNF‐α‐naïve and anti‐TNF‐α‐resistant cases and compared the clinical efficacies of adalimumab and ustekinumab in biologic naïve cases. Thirty‐five patients with plaque psoriasis who showed resistance to conventional therapies were enrolled; 26 patients, who had never been treated with biologics, were allocated to ustekinumab or adalimumab; nine patients who failed to achieve psoriasis area and severity index (PASI) 50 at week 16 with one or two TNF‐α antagonists were switched to ustekinumab. The end of the study was defined as 52 weeks after starting the first biologic for anti‐TNF‐α‐naïve patients and after switching to ustekinumab for anti‐TNF‐α‐resistant patients. The primary outcome measurement was the percentage of patients achieving PASI75 at week 16. In patients treated with ustekinumab, 87.5% of anti‐TNF‐α‐naïve and 77.8% of anti‐TNF‐α‐resistant cases achieved a PASI75 response at week 16, and no statistically significant difference was found between the treatment response rates (P = 0.60). When comparing the treatment efficacy of ustekinumab and adalimumab among anti‐TNF‐α‐naïve patients, there was also no statistically significant difference in PASI75 achievement rates (87.5 vs. 83.3%, P = 0.79). Our study suggests that ustekinumab can be considered as a first‐line biologic for psoriasis and a rescue therapy for anti‐TNF‐α‐resistant cases.     

Elevation of serum KL‐6 in patients with psoriasis treated with anti‐tumour necrosis factor‐α therapy

We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)‐6 increased during therapy with anti‐tumour necrosis factor (TNF)‐α. A diagnosis of early‐phase or subclinical interstitial pneumonia was made in two patients, and their KL‐6 level decreased after anti‐TNF‐α discontinuation. The rise in KL‐6 in the other patient was attributed to methotrexate. We propose that serum KL‐6 should be monitored routinely in patients treated with anti‐TNF agents.     

Effects of anti‐TNF‐α agents on circulating endothelial‐derived and platelet‐derived microparticles in psoriasis

Psoriasis involves TNF‐α secretion leading to release of microparticles into the bloodstream. We investigated the effect of TNF blockers on microparticles levels before and after treatment in patients (twenty treated by anti‐TNF‐α agents and 6 by methotrexate) with severe psoriasis. Plasmatic microparticles were labelled using fluorescent monoclonal antibodies and were analysed using cytometry. Three months later, 70% of patients treated with anti‐TNF‐α agents achieved a reduction in PASI score of at least 75%. The clinical improvement in patients treated with anti‐TNF‐α agents was associated with a significant reduction of the mean number of platelet microparticles (2837/μl vs 1849/μl, P = 0.02) and of endothelial microparticles (64/μl vs 22/μl, P = 0.001). Microparticles are significantly decreased in psoriatic patients successfully treated by anti‐TNF‐α. Microparticles levels as circulating endothelial cells represent signs of endothelial dysfunction and are elevated in psoriasis. Then, TNF blockade may be effective to reduce cardiovascular risk through the reduction of circulating microparticles.     

Clinical predictors of nonresponse to anti‐TNF‐α agents in psoriatic patients: A retrospective study

Although the heterogeneity of the therapeutic response to TNF‐α blockers seems to be mainly due to genetic factors, several studies showed that a range of factors may influence it. The aim of our study was to investigate the impact of patients' demographic and clinical characteristics on primary response to an anti‐TNF‐α therapy in psoriatic patients. We retrospectively examined the relationship between various clinical and demographic features and response to treatment with etanercept, adalimumab, and infliximab, evaluated as PASI75 and average PASI improvement at weeks 12, 16, and 14, respectively. We analyzed data obtained from 199 patients. A better response to the treatment was significantly associated with male gender (OR = 2.59), coexistence of psoriatic arthritis (OR = 1.97), and PASI ≤15 at baseline (OR = 0.91). The present study supports that some clinical factors may be potential predictors of response to anti‐TNF‐α agents in psoriatic patients.     

Effects of tumor necrosis factor‐α, interleukin‐23 and interleukin‐17A inhibitors on bodyweight and body mass index in patients with psoriasis

Treatment with tumor necrosis factor‐α inhibitors has been reported to cause weight gain in patients with psoriasis; however, limited information is available in terms of the effects of interleukin (IL)‐23 and IL‐17A inhibitors on bodyweight (BW) in patients with psoriasis. This study aimed to investigate the effects of infliximab, ustekinumab and secukinumab on BW and body mass index (BMI) in patients with psoriasis. We retrospectively examined changes in BW and BMI among patients treated with these biologics at our hospital. At baseline, no significant differences in BW and BMI were observed among the patients treated with infliximab (n = 18), ustekinumab (n = 30) or secukinumab (n = 20). After 7 months of the therapy, significant increases in mean BW (from 71.4 to 74.3 kg) and mean BMI (from 24.7 to 25.7) were observed in the patients treated with infliximab, whereas no significant changes were observed in those treated with ustekinumab (BW, from 70.3 to 70.1 kg; BMI, from 25.4 to 25.3) or secukinumab (BW, from 69.0 to 68.9 kg; BMI, from 25.2 to 25.2). There were no differences in the proportion of the patients who showed 75% or more improvement in the Psoriasis Area and Severity Index among the three groups. These results suggest that infliximab increases BW in the patients with psoriasis, whereas ustekinumab and secukinumab do not affect the BW in these patients.     

Perioperative management of tumor necrosis factor‐alpha blocker‐treated psoriatic patients: Case reports and review

Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque‐type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)‐α blocker therapy. Three GPP cases experienced uneventful post‐surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF‐α blockers in all cases were determined following the Japanese guideline.     

Alopecia areata as another immune‐mediated disease developed in patients treated with tumour necrosis factor‐α blocker agents

Background Tumour necrosis factor antagonists (anti‐TNF‐α) have demonstrated the efficacy in different chronic immune inflammatory disorders. Within the spectrum of adverse events, autoimmune diseases have been observed, including cases of alopecia areata (AA). Objectives The objective of the study is to characterize AA developed during anti‐TNF‐α therapy. Methods We present five new cases and review all the cases reported in the literature (eleven). Results One third of the cases had a positive (personal or family) history of AA. Most of them presented with rapid extensive AA, usually involving the ophiasis area. Prognosis was usually poor, with slight response to treatments. In the cases where anti‐TNF‐α therapy was maintained, the course did not seem to change. Conclusions Although rare, AA developed during anti‐TNF‐α therapy might be more frequent than suggested by reports of isolated cases. Personal and family history of autoimmune disease might alert clinicians to their possible development or relapse once the anti‐TNF‐α therapy is started.     

Secukinumab efficacy and safety in Japanese patients with moderate‐to‐severe plaque psoriasis: Subanalysis from ERASURE,a randomized,placebo‐controlled,phase 3 study

Secukinumab, a fully human anti‐IL‐17A monoclonal antibody, neutralizes IL‐17A, a key cytokine in the pathogenesis of psoriasis. Efficacy and safety of secukinumab was evaluated in Japanese patients with moderate‐to‐severe plaque psoriasis as part of a large Phase 3 global study (ERASURE). In this 52‐week, double‐blind study (ClinicalTrials.gov Identifier: NCT01365455, JapicCTI‐111529), 87 patients from Japan (11.8% of 738 patients randomized in the overall study population) were equally randomized to receive secukinumab 300 mg or 150 mg, or placebo once weekly at baseline and at Weeks 1, 2, 3 and 4, then every 4 weeks. Co‐primary endpoints (Week 12) were ≥75% improvement in psoriasis area‐and‐severity index (PASI 75) from baseline and a score of 0 (clear) or 1 (almost clear) on a 5‐point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo. PASI 75 and IGA mod 2011 0/1 responses at Week 12 were superior with secukinumab 300 mg (82.8% and 55.2%, respectively) or 150 mg (86.2% and 55.2%, respectively) versus placebo (6.9% and 3.4%, respectively; P < 0.0001 for all). Greater than 90% improvement in PASI (PASI 90) was also superior with secukinumab 300 mg (62.1%) or 150 mg (55.2%) versus placebo (0.0%) at Week 12 (P < 0.0001 for both). Clinical responses were sustained up to Week 52 in the majority of patients. During a 12‐week induction period, adverse event incidences were 48.3% with secukinumab 300 mg, 55.2% with 150 mg, and 41.4% with placebo. Secukinumab showed robust and sustainable efficacy in symptom reduction for moderate‐to‐severe plaque psoriasis in the Japanese patients.     

Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)‐α level and the efficacy of TNF‐inhibitor therapy in psoriasis

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)‐α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF‐α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab‐treated patients and 29.6% of adalimumab‐treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody‐positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF‐inhibitor concentration and elevated plasma TNF‐α level.