Evaluating the use of the interferon‐γ response to Mycobacterium tuberculosis‐specific antigens in patients with psoriasis prior to antitumour necrosis factor‐α therapy: a prospective head‐to‐head cross‐sectional study

Background Targeted biological therapies have transformed the treatment of chronic inflammatory disease. However, reactivation of latent tuberculosis infection (LTBI) is a significant risk with the use of antitumour necrosis factor (anti‐TNF)‐α therapy and screening is mandatory prior to treatment. The tuberculin skin test (TST) may be difficult to interpret in patients with inflammatory disease or receiving immunosuppressive therapies. Objectives The aim of this study was to evaluate and compare the QuantiFERON^®‐TB Gold In‐Tube (QFR) and T‐SPOT.TB (TSTB) interferon‐γ‐release assays (IGRA) against the TST in a cohort of patients commencing anti‐TNF‐α therapies for chronic inflammatory disease. Methods A prospective cross‐sectional study was undertaken at a London tertiary referral centre. Demographic data collected included TB risk factors. TST, QFR and TSTB were performed in all patients. Results Seventy patients with chronic plaque psoriasis were included in the study. Agreement between QFR and TSTB, excluding indeterminate results, was 89% (κ = 0·567), between QFR and TST 85% (κ = 0·313) and 81% (κ = 0·244) between TSTB and TST. There was no significant association with concomitant immunosuppression and either TST or IGRA results. Seven patients received chemoprophylaxis for LTBI diagnosed after clinical risk assessment together with positive TST and/or IGRA. Three patients had positive results in all three tests. Conclusions While there was moderate overall agreement between QFR and TSTB and fair correlation between TST, QFR and TSTB, there were a number of discordant results, suggesting that a three‐pronged approach using TST, QFR and TSTB may be of additional benefit.     

TNF‐α: a treatment target or cause of sarcoidosis?

Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF‐α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF‐α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF‐α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF‐α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF‐α in granuloma formation, the therapeutic role of TNF‐α inhibition and immunologic abnormalities following treatment with these TNF‐α inhibitors including drug‐specific alterations involving interferon‐γ, lymphotoxin‐α, TNF receptor 2 (TNFR2) and T‐regulatory cells.     

Tumour necrosis factor‐α inhibition can stabilize disease in progressive vitiligo

Tumour necrosis factor (TNF)‐α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro‐ and anti‐inflammatory properties and examine the effects of blocking its actions with TNF‐α antagonist therapeutics in reports available in the literature. We found that TNF‐α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF‐α inhibition has proven useful for patients with progressive vitiligo, where TNF‐α inhibition is able to quash cytotoxic T‐cell‐mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.     

Secondary failure of TNF‐α inhibitors in clinical practice

Tumor necrosis factor alpha (TNF‐α) is a leading inflammatory cytokine that plays a pivotal role in the pathogenesis of psoriasis. In case of a severe course of psoriasis and moderate‐to‐severe disease in which traditional systemic treatments are ineffective or contraindicated, TNF‐α inhibitors (iTNF‐α) are used. This class of drugs includes monoclonal antibodies and a fusion protein (etanercept) and can induce a humoral or cell‐mediated immune response, leading to formation of anti‐drug antibodies (ADAs). The immunogenicity may affect iTNF‐α drug pharmacokinetics, which would lead to hampering the clinical response (secondary drug failure), so a need to increase the drug dose arises. Antibodies against monoclonal antibodies (adalimumab, infliximab) have been associated with diminished clinical response, while against etanercept are non‐neutralizing and appear to have no significant effect on clinical response and treatment safety. Switching of biologic agents may be one strategy in ADA‐associated secondary failure of iTNF‐α. However researches are needed to identify risk factors for ADA development and investigate management strategies for optimized treatment response. The authors reviewed the literature on the effectiveness of iTNF‐α and pointed out the prevention of secondary failure in clinical practice.     

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.     

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.     

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.     

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.     

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.     

Association of TNF‐α polymorphisms with adult dermatomyositis and systemic lupus erythematosus in Bulgarian patients

Background Single‐nucleotide polymorphisms (SNPs) of tumor necrosis factor‐alpha (TNF‐α) have been implicated in various autoimmune diseases; however, the results are quite controversial, and there is still no widely accepted opinion about their role in the pathology of the autoimmune diseases. This is a pilot study to investigate the association of six SNPs of the TNF‐α gene with the risk of adult dermatomyositis (DM) and systemic lupus erythematosus (SLE) in Bulgarian patients. Materials and methods Twenty‐seven patients with DM and 27 with SLE were included in this study. Genomic DNA was extracted from the peripheral blood, and six SNPs (?1031T/C, ?863C/A, ?857C/T, ?308G/A, ?238G/A, +489G/A) were selected for investigation by polymerase chain reaction‐restriction fragment length polymorphism analysis. Results We found association between the TNF‐α?1031CC genotype and SLE (P = 0.025) and tendency for association with DM (P = 0.0876). The association appeared even stronger in the female patients with SLE (P = 0.024) and DM (P = 0.067). The TNF‐α?857GG genotype shows weak association with SLE (P = 0.097, OR 2.06, 95% CI 0.81–5.29) when analyzed for the whole group, but it appeared significantly associated with SLE in women (P = 0.048, OR 3.23, 95% CI 0.93–11.14). The ?863C allele showed association with arthritis in patients with SLE (P = 0.008). The haplotype analysis revealed a significant association between TNF ?1031C/?863C/?857C/?308G/+489G haplotype with both DM (P = 0.022) and SLE (P = 0.007) in women. Conclusions The TNF‐α polymorphisms are associated with increased relative risk mainly for SLE, particularly in women, while their role for DM is less evident and needs further analysis in an enlarged sample cohort.     

Case Report of Lichen Planopilaris Occurring in a Pediatric Patient Receiving a Tumor Necrosis Factor α Inhibitor and a Review of the Literature

A 12‐year‐old girl with extended oligoarthritis treated with adalimumab presented with a short history of a progressive cutaneous eruption involving the legs and scalp. Physical examination and histologic results were consistent with lichen planopilaris. The adalimumab was discontinued. She received treatment with topical clobetasol propionate and the majority of the lesions resolved. Residual lesions and the extended oligoarthritis were then treated with sulfasalazine. Adalimumab is a tumor necrosis factor α (TNF‐α) inhibitor used for the treatment of a variety of immunologically mediated conditions, including lichen planus and lichen planopilaris. TNF‐α antagonists have been associated with paradoxical psoriasiform, lichenoid, eczematous, granulomatous, and acneiform eruptions. We detail this case and review the literature of lichenoid reactions secondary to TNF‐α inhibitors.     

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.     

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.     

S‐allyl cysteine inhibits TNF‐α‐induced inflammation in HaCaT keratinocytes by inhibition of NF‐ κB‐dependent gene expression via sustained ERK activation

Tumor necrosis factor‐α (TNF‐α)‐induced keratinocyte inflammation plays a key role in the pathogenesis of multiple inflammatory skin diseases. Here we investigated the anti‐inflammatory effect of S‐allyl cysteine (SAC) on TNF‐α‐induced HaCaT keratinocyte cells and the mechanism behind its anti‐inflammatory potential. SAC was found to inhibit TNF‐α‐stimulated cytokine expression. Further, SAC was found to inhibit TNF‐α‐induced activation of p38, JNK and NF‐κB pathways. Interestingly, SAC was found to differentially regulate ERK MAP kinase in cells. TNF‐α‐induced transient ERK activation and SAC treatment resulted in sustained ERK activation both in the presence and absence of TNF‐α. Additionally, SAC failed to inhibit the TNF‐α‐induced expression of the pro‐inflammatory cytokines TNF‐α and IL‐1β when cells were treated with the MEK inhibitor PD98059, suggesting that the anti‐inflammatory effect of SAC is via sustained activation of the ERK pathway. Since ERK activation has been reported to negatively regulate NF‐κB‐driven gene expression and we find that SAC activates ERK and negatively regulates NF‐κB, we investigated whether there existed any crosstalk between the ERK and the NF‐κB pathways. NF‐κB‐dependent reporter assay, visualization of the nuclear translocation of NF‐κB‐p65 subunit and determination of the cellular levels of I‐κB, the inhibitor of NF‐κB, revealed that SAC inhibited TNF‐α‐induced NF‐κB activation, and PD98059 treatment reversed this effect. These results collectively suggest that SAC inhibits TNF‐α‐induced inflammation in HaCaT cells via a combined effect entailing the inhibition of the p38 and the JNK pathways and NF‐κB pathway via the sustained activation of ERK.     

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.     

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐α

Background and objective Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro‐inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. Methods This prospective study examines the influence of MHb on serum interleukin (IL)‐6, IL‐8 and tumour necrosis tumour necrosis (TNF)‐α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. Results A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880–4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 μg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL‐6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF‐α and IL‐8 release were not found significantly increased. Three patients developed MHb concentrations >15%. Conclusions This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL‐6 but not of IL‐8 and TNF‐α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.     

Risk of tuberculosis reactivation during interleukin-17 inhibitor therapy for psoriasis: a systematic review

Immunosuppressive therapies, effective in treating inflammatory disorders such as psoriasis, increase the risk of serious infections, such as tuberculosis (TB). For example, tumour necrosis factor (TNF)-alpha inhibitors significantly increase the risk of TB reactivation in patients with latent TB infection (LTBI), which has led clinicians to routinely test for TB prior to initiation of these medications. This protocol has since extended to other, newer immunomodulatory therapies for psoriasis, such as interleukin (IL)-17 inhibitors, including secukinumab, ixekizumab and brodalumab. We conducted a systematic review to examine whether there is any evidence that IL-17 inhibitor therapy for psoriasis increases the risk of TB reactivation. Using PubMed and EMBASE, our literature search resulted in 139 total articles. After manually reviewing each article for the discussion of IL-17 inhibitors for psoriasis, with data originating from clinical trials, and assessment for incidence of TB reactivation, 23 articles met the full inclusion criteria for our review. Overall, we found no cases of TB reactivation in patients treated with IL-17 inhibitors for psoriasis. This suggests that IL-17 inhibitors may be safely used in psoriasis patients with LTBI who receive appropriate LTBI treatment. However, long-term real-world studies are warranted to further evaluate this risk.     

Cutaneous polyarteritis nodosa in pediatric patients successfully treated with TNF‐α inhibitor and methotrexate: Case series and literature review

Cutaneous polyarteritis nodosa (CPAN) is a rare necrotizing vasculitis affecting small‐ to medium‐sized arteries. Reported treatments include oral corticosteroids alone or in combination with non‐steroidal antiinflammatory drugs, intravenous immunoglobulins, cyclophosphamide, azathioprine, colchicine, or dapsone. However, some patients with CPAN do not respond to such treatments and continue to experience exacerbations over prolonged periods. This series provides support for the use of TNF‐α inhibitors in the treatment of recalcitrant CPAN in pediatric patients.