HLA‐Cw6 and psoriasis Chen, L.; Tsai, T.‐F.
British journal of dermatology (1951),
April 2018, 2018-04-00, 2018-04-01, 20180401, Letnik:
178, Številka:
4
Journal Article
Recenzirano
Summary
Psoriasis is a multifactorial disease with a strong genetic background. HLA‐Cw6 is one of the most strongly associated psoriasis susceptibility alleles. It is repeatedly observed to affect ...disease course, phenotypic features, severity, comorbidities and treatment outcomes. To the best of our knowledge, the roles of HLA‐Cw6 in psoriasis have not yet been thoroughly reviewed. The worldwide frequency of the HLA‐Cw6 allele varies greatly, with it being generally higher in white people than in Asians. The allele is associated with type I early‐onset psoriasis. Stress, obesity and streptococcal pharyngitis are commonly observed in HLA‐Cw6‐positive patients. Phenotypically, HLA‐Cw6 has been found to be associated with guttate psoriasis. In addition, patients carrying the allele are more likely to have arm, leg and trunk involvement, and the Koebner phenomenon. Patients with psoriatic arthritis with HLA‐Cw6 more often have early onset and tend to show cutaneous symptoms before musculoskeletal symptoms. HLA‐Cw6‐positive patients have been shown in several studies to be more responsive to methotrexate and ustekinumab. However, this difference in ustekinumab efficacy was only moderate in a post‐hoc analysis of a pivotal phase III study. HLA‐Cw6 positivity also tends to be less frequent in high‐need patients who fail conventional therapy. Small studies have also investigated the role of HLA‐Cw6 in remission of psoriasis during pregnancy, and with the comorbidities of photosensitivity and atherosclerosis. Given the diverse nature of psoriasis pathogenesis, as well as the difference of HLA‐Cw6 positivity in different ethnic groups, more studies are needed to confirm the role of HLA‐Cw6 in psoriasis.
What's already known about this topic?
HLA‐Cw6 positivity affects different aspects of psoriasis.
What does this study add?
This review summarizes the pertinent literature concerning the different aspects of psoriasis, including epidemiology, pathogenesis, phenotypic characteristics, disease associations and treatment implications, that have been linked with HLA‐Cw6.
Linked Comment: Borroni and Costanzo. Br J Dermatol 2018; 178:825.
Plain language summary available online
Summary
Background
Guselkumab, an anti‐interleukin‐23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials.
Objectives
To evaluate the efficacy and safety of ...guselkumab in patients with moderate‐to‐severe plaque psoriasis who had an inadequate response to ustekinumab.
Methods
In this phase III, randomized, double‐blind study, 871 patients received open‐label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab Investigator's Global Assessment (IGA) ≥ 2 were randomized (double‐blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open‐label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two‐grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed.
Results
The mean number of visits at which patients achieved IGA 0/1 and at least a two‐grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two‐grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group.
Conclusions
Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.
What's already known about this topic?
Interleukin (IL)‐23/IL‐17 is the major pathway that drives the chronic inflammation underlying the pathophysiology of psoriasis.
Ustekinumab is a monoclonal antibody targeting IL‐12 and IL‐23 and is currently approved for patients with plaque psoriasis.
Guselkumab is a novel anti‐IL‐23 monoclonal antibody and has demonstrated high efficacy in patients with plaque psoriasis in two recent phase III trials.
What does this study add?
Guselkumab demonstrated greater efficacy compared with ustekinumab among patients who failed to achieve an Investigator's Global Assessment score of 0 or 1 with ustekinumab therapy.
The types of adverse events (AEs) with guselkumab and ustekinumab were similar, with infections being the most common.
A slightly higher incidence of AEs was reported in the guselkumab group, primarily driven by AEs of back pain, psoriatic arthropathy and mild injection site reactions.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2018; 178:20.
Plain language summary available online
Summary
Background
Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open‐label extension study of tofacitinib in psoriasis are reported.
Objectives
To evaluate ...the long‐term safety and durability of efficacy of tofacitinib in adults with moderate‐to‐severe chronic plaque psoriasis.
Methods
Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of ‘clear’ or ‘almost clear’ (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75).
Results
Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient‐years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52–62% of patients and PASI 75 by 56–74% of patients at each study visit through month 54.
Conclusions
In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).
What's already known about this topic?
Tofacitinib is an oral Janus kinase inhibitor. The efficacy and safety of tofacitinib 5 mg and 10 mg twice daily has been reported in phase II and phase III trials in patients with moderate‐to‐severe plaque psoriasis.
The management of patients with plaque psoriasis requires long‐term maintenance treatment.
What does this study add?
Final safety and efficacy data from this long‐term extension study indicate that tofacitinib has a stable safety profile up to 66 months, which is consistent with that observed in previous tofacitinib studies.
Improvements in efficacy end points and patient‐reported outcomes are sustained up to 54 months.
Linked Comment: Lloyd‐Lavery. Br J Dermatol 2018; 179:815–816.
Respond to this article
Summary
Background
Ustekinumab, an interleukin (IL)‐12 and IL‐23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the ...use of ustekinumab in patients with viral hepatitis are limited.
Objective
To assess the safety profile of ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C.
Methods
This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two ustekinumab injections. Viral loads were measured at baseline and each time before the administration of ustekinumab. Relevant clinical data were recorded.
Results
Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during ustekinumab treatment. No viral reactivation was observed in the three occult HBV‐infected patients (HBsAg‐negative/hepatitis B core antibody‐positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient.
Conclusions
Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti‐viral prophylaxis, the risk/benefit of ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high‐risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation.
What's already known about this topic?
Interleukin (IL)‐12 plays a central role in mounting an immune response directed towards the elimination of pathogens.
Ustekinumab, an IL‐12/23 blocker may theoretically carry the risk of hepatitis B (HBV) and hepatitis C virus (HCV) reactivation with its use.
What does this study add?
Ustekinumab appears to be well tolerated in patients with concurrent psoriasis and HBV infection under antiviral prophylaxis.
The risk of HCV reactivation during ustekinumab treatment does exist and appropriate vigilance should be exercised, especially in specific high‐risk patient groups.
Summary
Background
Ustekinumab, an interleukin‐12/23 inhibitor, is effective in the treatment of psoriasis. A recent Italian study showed more favourable response to ustekinumab in patients with ...positive human leucocyte antigen (HLA)‐Cw6. Nonetheless, there are differences in genetic susceptibility to psoriasis between races, and no studies have specifically assessed the candidate genetic markers in predicting therapy outcome in Chinese patients with psoriasis treated with ustekinumab.
Objectives
To determine whether HLA gene polymorphisms can predict the response to ustekinumab in Chinese patients with psoriasis.
Methods
Sixty‐six patients with psoriasis treated with ustekinumab were included in the study, and the effectiveness of ustekinumab therapy was evaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI).
Results
More HLA‐Cw6‐positive patients achieved a PASI 75 response at week 4 compared with HLA‐Cw6‐negative patients (38% vs. 9%, P = 0·019). Similarly, at week 16, patients carrying the HLA‐Cw6 allele showed a higher likelihood of achieving PASI 50, 75 and 90 than Cw6‐negative patients, although this was not statistically significant. At week 28, a significantly higher percentage of HLA‐Cw6‐positive patients maintained PASI 90 response compared with Cw6‐negative patients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele polymorphisms did not show significant associations with therapeutic response to ustekinumab.
Conclusions
This pharmacogenetic study provides preliminary data indicating that positive HLA‐Cw6 is associated with a good response to ustekinumab treatment in Chinese patients with psoriasis.
What's already known about this topic?
Biological therapies have revolutionized the treatment of psoriasis. Variability in genes involved in the immunological pathways of biological therapy may account for the different treatment outcomes.
Human leucocyte antigen (HLA)‐Cw6 is the major psoriasis susceptibility gene and has a strong association with clinical psoriasis phenotypes.
Studies investigating potential predictors for response to biologics are limited, particularly in Asian populations.
What does this study add?
Our study showed that HLA‐Cw6‐positive patients have a faster response and maintain a longer treatment response to ustekinumab than HLA‐Cw6‐negative patients.
HLA‐Cw6 can be a pragmatic predictor for the response to ustekinumab not only in white patients but also in Chinese patients with psoriasis.
These results will help dermatologists in guiding therapeutic decisions.
Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium ...tuberculosis.
Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab‐treated patients with psoriasis.
Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON®‐TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis.
Results At baseline, 101/2898 (3·5%) non‐Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab‐treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab‐treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH‐related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline.
Conclusions Across five trials of ustekinumab‐treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.
See also the Commentary by Shear
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