Pyoderma Gangrenosum and Interleukin Inhibitors: A Semi-Systematic Review

<b><i>Background:</i></b> Pyoderma gangrenosum (PG) is a rare ulcerating skin disease associated with multiple comorbidities and increased mortality. In recent decades, newer biologics such as interleukin inhibitors have been used to treat PG; however, the literature is scarce, consisting predominantly of case reports and caseseries. The aim of our review was to evaluate the effectiveness and safety of interleukin inhibitors for the treatment of PG in adults. <b><i>Summary:</i></b> A literature search was conducted using search terms related to PG and interleukin inhibitors in databases such as PubMed, Embase, Scopus, Web of Science, and Cochrane Library. The study eligibility criteria included patients diagnosed with PG, over the age of 18, and treated with an interleukin inhibitor. Our study included 60 papers describing 81 patients fulfilling the eligibility criteria. The treatment with interleukin inhibitors resulted in 70% (95% CI 59–80%) response and 57% (95% CI 45–68%) complete response rates, and few (4%) mild adverse events, hence supporting the off-label use for the treatment of recalcitrant PG in adults. The response and complete response rates were 59% (17/29) and 38% (11/29) for anakinra, 64% (7/11) and 55% (6/11) for canakinumab, and 79% (27/34) and 71% (24/34) for ustekinumab, respectively. Limitations include publication bias that might have overestimated the efficacy as successful cases responding to treatment are more likely to be reported than nonresponding cases. Additionally, the heterogeneity of the treatment groups does not allow conclusions of superiority or inferiority of the different interleukin inhibitors to be drawn. Further studies are needed to investigate the efficacy of the different interleukin inhibitors and to investigate the importance of underlying disease for treatment response.

Increased Fungal Infections while using Emerging Therapies (Biologics and Small-molecule Inhibitors) for Treating Skin Diseases: A Review

Biologics, such as tumor necrosis factor-α and interleukin inhibitors, are commonly used for treating immunological skin diseases, including psoriasis, psoriatic arthritis, and atopic dermatitis. The cluster of differentiation inhibitors and immune checkpoint inhibitors has also been used for treating bullous disorders and melanoma, respectively. Other small-molecule inhibitors, such as JAK inhibitors, have been introduced for treating atopic dermatitis and alopecia areata. Hence, given the importance of cytokines and small molecules in antifungal immunity, using these new treatments are proposed to increase the risk of fungal infections. Thus, this review presents an overview of the reported incidences and possible mechanisms of fungal infections related to the use of biologics, including small-molecule inhibitors used for dermatological treatments.

The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection

BackgroundImmunosuppression may worsen SARS-CoV-2 infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark.MethodsWe identified all SARS-CoV-2 test-positive patients from February to October 2020 and linked health care data from nationwide registers, including prescriptions for the exposure, immunosuppressant drugs. We estimated relative risks of hospital admission, intensive care unit (ICU) admission, and death (each studied independently up to 30 days from testing) with a log linear binomial regression adjusted for confounders using a propensity score-based matching weights model.ResultsA composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1·56 [95% confidence interval 1.10–2.22]). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (aRR 2.38 [95% CI 1.72–3.30]), which were also associated with an increased risk of hospital admission (aRR 1.34 [95% CI 1.10–1.62]), but not ICU admission (aRR 1.76 [95% CI [0.93–3.35]); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors, or interleukin inhibitors, was not associated with an increased risk of hospitalisation, ICU admission, or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine, or chloroquine.ConclusionsExposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of COVID-19 in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids.

Number needed to treat for interleukin inhibitors approved for the treatment of moderate-to-severe plaque psoriasis in Italy

Background: Interleukin (IL) inhibitors achieve greater levels of efficacy than older systemic therapies. We calculated the number needed to treat (NNT) of ixekizumab compared with other IL inhibitors approved in Italy for the treatment of moderate-to-severe plaque psoriasis. Methods: The clinical efficacy was evaluated in terms of NNT, based on the results of a recent network meta-analysis (NMA) by the Cochrane Database of Systematic Reviews. The NMA investigated many systemic and biological treatments, but this analysis compared only the efficacy of the following IL inhibitors – brodalumab, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab and ustekinumab – for patients with moderate-to-severe plaque psoriasis. Drugs were compared and ranked according to effectiveness considering the PASI (Psoriasis Area and Severity Index) 90 score. Results: One-hundred and forty trials (51,749 patients) were included in the NMA. Considering the proportion of patients who achieve PASI90, ixekizumab showed the lowest NNT among all comparators (ixekizumab 2.01 [2.46-3.00]; risankizumab 2.05 [2.50-3-05]; guselkumab 2.16 [2.68-3.36]; secukinumab 2.40 [2.90-3.51]; brodalumab 2.61 [3.18-3.88]; ustekinumab 3.44 [4.12-4.95]; tildrakizumab 3.10 [4.15-5.59]. Conclusion: The findings show that ixekizumab is the most effective option (NNT) for the treatment of moderate-to-severe plaque psoriasis.

New-onset refractory status epilepticus (NORSE)

New-onset refractory status epilepticus and its subcategory febrile infection-related epilepsy syndrome are rare devastating clinical presentations in those without pre-existing relevant history, often in schoolchildren or young adults, without a clear cause on initial investigations. A cause is later identified in up to half of adults, but in many fewer children. Patients often require protracted intensive care and are at significant risk of dying. Functional disability is common and subsequent chronic epilepsy is the norm, but some people do have good outcomes, even after prolonged status epilepticus. Patients need prompt investigations and treatment. Anaesthetic and antiseizure medications are supplemented by other treatment modalities, including the ketogenic diet. Despite limited evidence, it is appropriate to try to modify the presumed underlying pathogenesis with immune modulation early, with a more recent focus on using interleukin inhibitors. Optimising management will require concerted multicentre international efforts.

Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19

BackgroundThere is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19.MethodsElectronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality.Results71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I2=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I2=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I2=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI −0.07 to 0.80, I2=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent.ConclusionTocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings.PROSPERO registration numberCRD42020176375.

Update on the therapeutic management of patients with either psoriatic arthritis or ulcerative colitis: focus on the JAK inhibitor tofacitinib

Psoriatic arthritis (PsA) and ulcerative colitis (UC) are immune-mediated diseases that cause significant burden worldwide. Recent advances in their management have improved patient outcomes. However, significant unmet needs still remain as not all patients respond to current treatments, and patients may lose responsiveness over time. An improved understanding of the pathophysiology of these diseases has brought about the development of novel disease-modifying agents, including interleukin inhibitors and, more recently, Janus kinase (JAK) inhibitors. With the approval of tofacitinib for the treatment of adults with active PsA and in adult patients with moderately-to-severely active UC, JAK inhibitors have recently entered the treatment armamentarium for PsA and UC. A number of other JAK inhibitors are also undergoing clinical development and are currently in phase III trials. This review provides an overview of the current therapeutic options for PsA and UC, with a focus on the JAK inhibitors.

Safety and efficacy of interleukin inhibitors in elderly patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis

Elderly patients with rheumatoid arthritis, psoriasis and psoriatic arthritis encompass those with elderly-onset disease, over 60 years of age, but also those with earlier disease onset who entered old age. Considering the age-related changes of the immune system, possible frailty, susceptibility to infection and concomitant comorbidity that implies multiple medicines, the treatment of these diseases in elderly patients can be challenging. Interleukin inhibitors have been shown to be an efficient and safe treatment for these diseases. However, elderly patients with these diseases were often included in the pivotal clinical trials for interleukin inhibitors in numbers insufficient to determine whether they responded differently from younger subjects. The aim of this paper was to review the findings on the efficacy and safety of interleukin inhibitor treatment in elderly patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis. The findings suggest that, for all the interleukin inhibitors reviewed herein, used in elderly patients with rheumatoid arthritis, or with psoriasis and psoriatic arthritis, the efficacy was comparable to younger patients. Furthermore, the incidence of reported adverse events was similar in these two age groups. Severe adverse events, which were related to sarilumab treatment for rheumatoid arthritis and secukinumab treatment for psoriasis, were higher in elderly patients. The reviewed findings suggest that the interleukin inhibitors approved and currently in use in clinical practice for the treatment of rheumatoid arthritis, psoriasis, and psoriatic arthritis can be considered a safe and efficient option for these diseases in elderly patients.