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.     

Asymmetric dimethylarginine but not osteoprotegerin correlates with disease severity in patients with moderate‐to‐severe psoriasis undergoing anti‐tumor necrosis factor‐α therapy

Patients with psoriasis, in particular those with severe disease, have an increased risk of cardiovascular (CV) events compared with the general population. The aim of the present study is to determine whether correlation between asymmetric dimethylarginine (ADMA) and osteoprotegerin (OPG), two biomarkers associated with CV disease, and disease severity may exist in patients with moderate‐to‐severe psoriasis. We also aimed to establish if baseline serum levels of these two biomarkers could correlate with the degree of change in the clinical parameters of disease severity following the use of anti‐tumor necrosis factor (TNF)‐α therapy in these patients. This was a prospective study on a series of consecutive non‐diabetic patients with moderate‐to‐severe psoriasis who completed 6 months of therapy with anti‐TNF‐α‐adalimumab. Patients with kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Metabolic and clinical evaluation was performed immediately prior to the onset of treatment and at month 6. Twenty‐nine patients were assessed. Unlike OPG, a significant positive correlation between ADMA and resistin serum levels was found at the onset of adalimumab and also after 6 months of biologic therapy. We also observed a positive correlation between the percent of body surface area affected (BSA) and ADMA levels obtained before the onset of adalimumab and a negative correlation between baseline ADMA levels and a 6‐month BSA change compared with baseline results. In patients with moderate‐to‐severe psoriasis, ADMA levels correlate with clinical markers of disease severity.     

Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti‐aminoacyl‐tRNA synthetase antibody

Homocysteine is a sulfhydryl‐containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud’s phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic’s hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen‐6 (KL‐6), surfactant protein‐D and creatine kinase levels, and anti‐aminoacyl‐tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic’s hand, ILD and anti‐ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL‐6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti‐ARS Ab, and further examination is required.     

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.     

Responses to ustekinumab in the anti‐TNF agent‐naïve vs. anti‐TNF agent‐exposed patients with psoriasis vulgaris

Background Approximately 20–30% of patients with psoriasis treated with anti‐tumour necrosis factor α (TNFα) agents will discontinue treatment within 2 years due to loss of efficacy or side‐effects. Switching to another anti‐TNFα agent produces clinical responses inferior to previously untreated patients. Ustekinumab binds to the p40 subunit of interleukin (IL)‐12 and IL‐23 and provides a mechanism of action independent of TNFα. Objective To investigate the efficacy of ustekinumab in a clinical practice setting and to compare treatment responses to ustekinumab in patients previously treated with TNFα inhibitors and anti‐TNFα‐naïve patients. Methods Patients receiving either ustekinumab (n = 71) or the subcutaneous TNFα inhibitors adalimumab or etanercept (n = 108) were identified through the registry of psoriasis patients in our Institutions. Efficacy effect outcome was a 75% improvement in the psoriasis area severity index (PASI75). Kaplan–Meier statistics evaluated the adherence to the treatments expressed as drug survival rate. Results PASI75 was achieved in 80% of the ustekinumab‐treated patients after a median time of 112 days. There was no difference in efficacy in anti‐TNFα‐naïve patients compared with anti‐TNFα unresponsive patients. Patients treated with ustekinumab showed a superior adherence to treatment in comparison with adalimumab and etanercept. Limitations Patients were non‐randomly assigned to treatment, which potentially may lead to biases. Observation time was short (1 year). Conclusion In clinical practice, the short‐term efficacy and patient adherence to ustekinumab are excellent and comparable to the data obtained in clinical trials. Lack of response to previous anti‐TNF treatment does not impair clinical response to ustekinumab.     

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.     

Development of MGUS in psoriatic patients: a possible undiagnosed event during anti‐TNF‐α‐treatment

Background Monoclonal gammopathies are haematological conditions characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin that accumulates in the blood. They have already been reported during treatment with a range of drugs but never before during treatment with the anti‐TNF‐α treatments: adalimumab, etanercept and infliximab currently used in the therapy of moderate‐severe psoriasis and psoriatic arthritis. Objective This is a case series describing the development of MGUS in psoriatic patients treated with anti‐TNF‐α. Methods Three hundred patients receiving an anti‐TNF‐α treatment for chronic plaque psoriasis or psoriatic arthritis in a clinical setting in Italy, These patients were screened through serum protein electrophoresis to investigate the possible development of MGUS. Results Eight patients were found to have developed monoclonal gammopathy of undetermined significance. The median treatment duration for the eight patients was 1 year with excessive IgG present in five patients, IgM accumulation in one patient and a double monoclonal component in two patients. Conclusion Our data suggest that there may be an association between anti‐TNF‐α therapy and development of MGUS.     

A case of tumour necrosis factor‐α inhibitor‐ and rituximab‐induced plantar pustular psoriasis that completely resolved with tocilizumab

Rituximab, a chimeric B‐cell‐depleting monoclonal antibody, is a well‐established therapy for rheumatoid arthritis. It is emerging that classical psoriatic lesions and plantar pustular psoriasis (PPP) are cutaneous side‐effects of this drug. Antitumour necrosis factor (anti‐TNF) therapies have multiple documented side‐effects including PPP and psoriasis. We report a patient who has rheumatoid arthritis, who failed on anti‐TNF therapies and then was commenced on rituximab. Subsequently she developed localized PPP. Due to deterioration of her joint disease she was switched to the interleukin‐6 blocker tocilizumab, and the PPP resolved.     

Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti‐tumour necrosis factor agents: subanalysis of BELIEVE

Background Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti‐TNFs) is likely to improve psoriasis in patients with prior anti‐TNF treatment. Objective The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti‐TNF treatment. Methods The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16‐week, double‐blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1–15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti‐TNFs. Results Of 730 patients enrolled, 282 (38.6%) had prior anti‐TNFs and 448 (61.4%) were anti‐TNF‐naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti‐TNFs achieved PASI 75 at week 16, compared with 71.7% of anti‐TNF‐naïve patients (P = 0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti‐TNF agent had been used, the number of prior anti‐TNFs tried, or reasons for discontinuation of prior anti‐TNF therapy. Adverse event incidences were similar between patients with and without prior anti‐TNF therapy. Conclusion Adalimumab was effective and well‐tolerated in patients with psoriasis previously treated with anti‐TNF therapy.     

Study of pro‐ and anti‐inflammatory cytokine profile in the patients with parthenium dermatitis

Background: Parthenium dermatitis is a common airborne allergic contact dermatitis induced by exposures to the weed Parthenium hysterophorus. The disease manifests as itchy erythematous papules, papulovesicular and plaque lesions on exposed areas of the body. Objectives: The aim of this study was to show the alterations in pro/anti‐inflammatory cytokines in parthenium dermatitis. Methods: The study included 50 patients with parthenium dermatitis confirmed by patch testing using aqueous extracts of P. hysterophorus and 50 age‐matched healthy controls. The levels of pro‐inflammatory [tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐17] and anti‐inflammatory (IL‐4 and IL‐10) cytokines were estimated by commercially available high sensitivity enzyme‐linked immunosorbent assay (ELISA) kits. Results: All the dermatitis patients showed significantly (P < 0.001) elevated levels of TNF‐α, IL‐6, IL‐8, and IL‐17 levels as compared to healthy controls. In contrast, the anti‐inflammatory cytokine IL‐4 showed an insignificant decrease (P < 0.217) and a decrease in level of IL‐10 was statistically significant (0.001) compared with controls. Conclusions: The present study suggests the involvement of pro‐inflammatory cytokines in the pathogenesis of parthenium dermatitis. A decrease in levels of anti‐inflammatory cytokines was demonstrated, which could not downregulate pro‐inflammatory cytokines in parthenium dermatitis.     

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.     

Adalimumab‐induced scalp psoriasis with severe alopecia

In recent years, with the increase usage of tumor necrosis factor (TNF) inhibitors, more side effects have revealed. The incidence of paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis, or their combinations) ranges from 1 to 5%; however alopecia due to anti‐TNF‐α‐induced scalp psoriasis, rarely reported in the literature. We report a 37‐year‐old woman who developed palmoplantar pustulosis and scalp psoriasis with severe alopecia after 2 months of treatment with adalimumab for chronic plaque psoriasis. Biopsies from the palmar and scalp lesions showed psoriasiform changes. Adalimumab treatment was discontinued, and methotrexate was started (15 mg/weekly, subcutaneously) with topical adjuvant agents. A dramatic improvement was seen in both the skin and scalp with complete hair regrowth in 1 month. We conclude that, in anti‐TNF‐α‐induced scalp psoriasis, suspension of anti‐TNF‐α agent and systemic and topical treatments should be considered to avoid scarring alopecia.     

Cutaneous events during treatment of chronic inflammatory joint disorders with anti‐tumour necrosis factor alpha: a cross‐sectional study

Background Anti‐tumour necrosis factors (anti‐TNF) are more and more used, but the rate of skin adverse events is not known. Objective The aim was to assess the number of skin infections and other dermatoses in patients treated with anti‐TNFα. Patients and methods One hundred eighty‐seven patients suffering from rheumatoid arthritis or ankylosing spondylitis underwent a dermatological exam. Patients with anti‐TNF were compared with those without this treatment in a prospective transversal study. Results Among them, 59 patients were treated with anti‐TNFα and steroids were prescribed in 100 cases. There was no difference in the prevalence of skin infections or eczema or tumours. Skin drug reactions were observed in six patients. Infections by dermatophytes appear very frequent, approaching 70% in both groups. Conclusions This study shows that skin infections (or other skin diseases) are not more frequent in these patients. No differences were observed in infections (bacterial fungal, parasital or viral), tumours, psoriasis or the manifestations of atopic dermatitis. Nonetheless, a long‐term survey might be interesting, especially about skin tumours.     

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.     

Severe infliximab‐induced psoriasis treated with adalimumab switching

Background Antitumor necrosis factor (anti‐TNF) agents are a well‐established treatment for various medical conditions, including psoriasis and psoriatic arthritis. However, anti‐TNF agents may themselves induce psoriasis in some patients. Methods The authors report two cases of patients with severe and refractory infliximab‐induced psoriasis. Results The patients had good clinical responses after switching to another TNF blocker. Conclusion For severe cases, infliximab withdrawal combined with conventional immunosuppressive psoriasis drugs or with adalimumab may be a therapeutic option.     

Presence of anti‐phosphatidylserine–prothrombin complex antibodies and anti‐moesin antibodies in patients with polyarteritis nodosa

We measured both serum anti‐phosphatidylserine–prothrombin complex (anti‐PSPT) antibodies and anti‐moesin antibodies, as well as various cytokines (interleukin [IL]‐2, IL‐4, IL‐5, IL‐10, IL‐13, IL‐17, granulocyte macrophage colony‐stimulating factor, γ‐interferon, tumor necrosis factor‐α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV‐CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV‐CY or steroid pulse therapy. We found a significant positive correlation between serum anti‐moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti‐PSPT antibody and IL‐2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti‐moesin antibody levels were higher following IV‐CY or steroid pulse therapy compared with the pretreatment levels. In the treatment‐resistant PAN patients (n = 8), anti‐PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti‐moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti‐PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti‐moesin antibodies could play some role of the exacerbation in patients with PAN.     

Adalimumab‐Induced Cutaneous Lupus Erythematosus in a 16‐Year‐Old Girl with Juvenile Idiopathic Arthritis

Tumor necrosis factor α (TNF‐α) antagonists are used in the treatment of numerous autoimmune conditions. Adalimumab is the first monoclonal antibody to TNF‐α and is used to treat juvenile idiopathic arthritis. A growing body of literature associates anti‐TNF‐α therapies with several adverse dermatologic manifestations, including drug‐induced lupus erythematosus (LE). We describe a case of cutaneous LE in a 16‐year‐old girl treated with adalimumab for juvenile idiopathic arthritis. The temporal association between her presenting symptoms and adalimumab initiation and gradual improvement after stopping biologic therapy suggest adalimumab‐induced cutaneous LE. With increasing use of anti‐TNF therapies in children, the potential for drug‐induced LE should not be overlooked.     

Incidence of tuberculosis infection in psoriatic patients on anti‐TNF therapy: report of a case series with 144 patients

Background Worldwide clinical trials and post‐marketing surveillance data have demonstrated an increased incidence of tuberculosis (TB) disease associated with antitumour necrosis factor (anti‐TNF) agents. The majority of these cases are presumed to result from a reactivation of latent disease, while the rate of new infections is unknown. A study was performed to evaluate the incidence of latent tuberculosis infection (LTBI) in psoriatic patients screened for biological therapy in a high‐incidence area, such as Madrid, Spain. Patients and methods One hundred and forty‐four patients with moderate‐to‐severe psoriasis treated with anti‐TNF agents were recruited. All of them were screened for active TB or LTBI before therapy. The screening included a detailed medical study, physical examination, chest X‐ray, tuberculin skin test (TST) with purified protein derivative and re‐TST. Results A total of 42 (29%) patients were diagnosed with LTBI based on a positive TST or re‐TST, and/or signs of past TB in the chest X‐ray. All of them received chemoprophylaxis with isoniazide. One patient developed a primary active lymphnode TB. Conclusion This is the first study to underscore the incidence of LTBI in patients with psoriasis treated with anti‐TNF therapy in the Spanish population. We support that the use of TST is still reliable and an effective diagnostic method for the detection of LTBI in anti‐TNF therapy.