Psoriasis is still an incurable disease, and most patients do not achieve long-term clinical remission, so maintenance therapy is needed to achieve long-term remission. However, foreign studies have shown that about 20% of patients with moderate-to-severe psoriasis receiving conventional therapy and phototherapy do not adhere to their treatment for 1 year, 10%-15% of patients with psoriasis treated with biologic agents discontinue treatment in the first year, and most patients with moderate-to-severe psoriasis relapse within 2-6 months after discontinuing treatment, which affects the efficacy and increases the financial burden, thus emphasizing the need for maintenance therapy for moderate-to-severe psoriasis.
The definition of maintenance therapy for psoriasis has not been clearly defined, and Mrowietz et al. mentioned that the treatment of moderate-to-severe plaque psoriasis is divided into two phases, namely the induction phase and the maintenance phase. The induction phase is defined as 16 weeks, which can be extended to 24 weeks as appropriate, and the maintenance phase is the time period after the induction phase. The concept of maintenance treatment proposed in this paper refers to the treatment after the lesions have largely subsided.
I. Reasons
The causes of maintenance therapy in patients with moderate-to-severe psoriasis are mainly related to their relapse. It is currently believed that psoriasis is a chronic inflammatory disease mediated by T-cell immunity, and its pathogenesis is related to the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and other inflammatory factors induced by pathogenic microorganisms or mechanical stimuli that cause damage to dendritic cells and macrophages after activation of specific T cells (e.g. Th1 cells, Th17 cells). The vicious cycle caused by damage to keratinocytes is related, but the mechanism of relapse after interruption of treatment in psoriasis patients has not been clearly established.
Johnson-Huang et al. found an increase in CD3+ T cells, neutrophils, CDllc+ and CD83+ myeloid dendritic cells, but not CDlc+ non-volatile cells, in a group of moderate-to-severe psoriasis patients who relapsed after interruption of efalizumab treatment, and a large number of CDllc+CDlc- inflammatory myeloid dendritic cells were found in the relapsed lesions.
Efalizumab blocked the entry of circulating inflammatory myeloid dendritic cell precursors and T cells into the skin, thereby blocking the waterfall of inflammatory factors caused by both, and once treatment was interrupted these immune cells re-migrated into the skin, eventually leading to a relapse of psoriasis, and the efalizumab-improved psoriasis gene was found to increase again in the relapsed lesions.
In contrast, Suarez-Farinas et al. studied another group of patients with psoriasis treated with etanercept and found that clinical and pathological healed lesions were not completely cleared of inflammation, although most inflammatory factors returned to normal levels, including IL-12p35, MXI, IL-22, IL-17, and IFN-y, with less than 75% improvement in five inflammatory genes.
The LYVE-1, WNT5A, RAB31, and AQP9 genes clustered in the psoriatic lesions did not return to normal baseline levels, and the microstructural changes in the skin and lymphatic vessels did not return to normal. All these studies suggest that the current treatment has not completely reversed the pathological mechanism of psoriasis, and therefore maintenance treatment is needed for long-term control of the disease.
II. Methods
At present, the common treatment methods for the maintenance of patients with moderate to severe psoriasis include traditional drugs such as methotrexate, cyclosporine, Avi A, and phototherapy, but the current view is that the safety of long-term use of traditional treatment needs to be investigated, and biological agents have become a new choice for maintenance treatment recently because of their targeted effects and less toxicity. Topical treatment is also an important element of maintenance therapy.
Methotrexate: It is a folic acid antagonist that inhibits DNA synthetase, affects epithelial cell replication, and also inhibits T-cell activity. Low doses of methotrexate (0.1 – 0.3 mg/kg per week) inhibit lymphocyte proliferation without affecting keratinocytes in in vitro tests. Methotrexate is effective in moderate to severe psoriasis, but there is little clinical evidence for methotrexate maintenance therapy.
The Department of Dermatology at the University Hospital Nijmegen in the Netherlands conducted an early series of clinical studies on the maintenance treatment of psoriasis with methotrexate. Since 1971, low-dose methotrexate maintenance therapy, usually methotrexate (5 mg per dose, 3 times a week at 12-h intervals), has been administered to inpatients with psoriasis who have failed to respond to Ingram therapy (tar baths, ultraviolet radiation, dithranol) and who relapse rapidly after interruption of this therapy.
At the same time, Ingram therapy was continued until the lesions were completely cleared, and the patients were discharged from Ingram therapy at week 5 of admission and treated with maintenance methotrexate, which was tapered to 2.5 mg per dose at 12-h intervals three times a week after an average of 10 months, and in some cases to 1.25 mg per dose at 12-h intervals three times a week.
In a retrospective study of these patients in 1980, the mean treatment period for methotrexate was 29 months and the mean cumulative dose was 1.18 9. The relapse period for patients not on maintenance therapy ranged from 1 month (start of relapse) to 5 months (complete relapse), whereas the relapse period for patients on methotrexate maintenance therapy ranged from 1 year (start of relapse) to 3 years (complete relapse), and there was no rebound after interruption of methotrexate maintenance therapy.
One of the adverse effects of long-term methotrexate use is liver damage. In 1984, the hospital studied the results of liver biopsies of 44 patients with psoriasis treated with methotrexate maintenance therapy and noted that liver damage was not clearly related to the cumulative amount of methotrexate or the duration of maintenance therapy, but was closely related to the age of the patients.
In 1993, a retrospective study of 113 patients with severe psoriasis treated with methotrexate maintenance therapy over the past 22 years showed that low-dose methotrexate (≤15 mg/week) maintenance therapy for severe psoriasis is a relatively safe treatment, provided that patients are carefully selected and monitored for adverse drug reactions and drug-drug interactions during treatment. A liver biopsy is recommended at 3 months of treatment before the availability of non-invasive assays, and again at subsequent doses of 1.5 g cumulative.
Some scholars currently recommend procollagen type III amino terminal peptide (PIIINP) for primary screening of liver fibrosis.
2. Cyclosporine: Cyclosporine is usually recommended for short-term intermittent induction therapy for psoriasis, but there are many reports in the literature on the use of cyclosporine for maintenance therapy. It is generally agreed that the dose of cyclosporine for maintenance treatment of psoriasis should not exceed 5 mg.kg-1.d-1, with most studies having a dose of < 3.5 mg.kg-1.d-1, and it is recommended that the duration of maintenance therapy should preferably be limited to less than 2 years.
Ozawa et al. compared two uses of cyclosporine for long-term treatment of psoriasis, i.e., continuous therapy, with a starting dose of 3 mg.kg-1.d-1 or 5 mg.kg-1.d-1, reduced by 0.5-1.0 mg.kg-1.d-1 weekly after remission, and maintained at the lowest possible dose of 0.5-3 mg.kg-1.d-1 depending on the condition, and intermittent therapy, with a starting dose of 3-5 mg.kg-1.d-1, reduced by 0.5-1.0 mg.kg-1.d-1 every other week after remission. kg-1.d-1, followed by interruption of treatment.
The interrupted treatment phase was followed by topical application of a strong or medium-acting glucocorticoid, and both treatments were repeated after relapse, concluding that continuous treatment was more effective than intermittent treatment, despite >70% improvement in Psoriasis Area and Severity Index (PASI) scores for both treatments.
A 2-year cohort study by Ho et al. showed that intermittent therapy was effective and safer than continuous therapy, and Ohtsuki et al. showed that although intermittent therapy was slightly less effective than continuous therapy, it was more practical given the potential for malignancy with continuous therapy. The most common adverse effects of cyclosporine maintenance therapy for psoriasis are nephrotoxicity and hypertension, but if the cyclosporine dose is ≤5 mg.kg-1.d-1, the rise in serum creatinine is <30% of baseline, renal damage can be recovered after interruption of therapy and no rebound phenomenon occurs after interruption of therapy, and annual monitoring of glomerular filtration rate (CFR) is recommended for patients on long-term cyclosporine therapy.
A randomized, double-blind, parallel study by Dogra et al. showed that Avi A 35 mg/d was more effective than 25 mg/d and 50 mg/d and had a better safety profile than 50 mg/d. After the lesions of psoriasis have largely resolved, Avi A is gradually reduced to the lowest effective dose for maintenance therapy (from 50 mg/d to 25 mg/d and then to 25 mg every other day or 10 mg/d). or 10 mg/d).
It is generally accepted that the efficacy of Ave A monotherapy in patients with psoriasis vulgaris is inferior to that of combination therapy, and therefore Ave A is often combined with broad-spectrum medium-wave ultraviolet (WB-UVB), narrow-spectrum medium-wave ultraviolet (NB-UVB), and PUVA at lower doses than monotherapy, usually intolerable at >25 mg/d, usually 10-25 mg/d.
The adverse effects of Ave A are dose-related, and low doses of Ave A (≤25 mg/d) are ideal for long-term maintenance treatment of psoriasis. A 5-year study of nearly 1,000 patients treated with Ave A showed that Ave A did not increase the risk of cardiovascular disease, tumors, diabetes, or inflammatory bowel disease, and that Ave A is a non-immunosuppressive agent that does not increase the risk of infection or tumor development, making it ideal for the treatment of patients with chronic infections and immune insufficiency. It is ideal for the treatment of patients with co-chronic infections and immune insufficiency. If liver damage, hyperlipidemia or diffuse bone hypertrophy occur during Avi A treatment, treatment should be interrupted.
4. Phototherapy: Phototherapy is the first-line treatment of choice for most patients with psoriasis, but given its potential to increase the risk of skin tumors, especially PUVA, the maintenance treatment of psoriasis with phototherapy is controversial and the clinical evidence for its maintenance is limited. A prospective controlled study by Radakovic et al. showed that the mean time to relapse was (4.5±3.4) and (4.6±3.4) months in patients with plaque psoriasis treated with PUVA interruption and maintenance therapy, respectively, and that short-term maintenance therapy with PUVA was not effective in preventing psoriasis relapse and should be avoided.
NB-UVB is safer than PUVA, more effective than WB-UVB, and is the first-line treatment for generalized plaque psoriasis. The standard regimen for NB-UVB is three times weekly, with dose adjustment according to the patient’s skin type and minimal erythema (MED), for at least 3 months.
Boztepe et al. divided patients who achieved 75% remission on PASI scores after standard NB-UVB treatment into two groups, one with discontinuation of treatment and the other with maintenance NB-UVB twice weekly for the first 4 weeks and once weekly for the second 4 weeks, suggesting that longer remissions may be achieved with maintenance NB-UVB for plaque psoriasis.
ReUVB, i.e. Ave A combined with UVB therapy, can bring patients into remission faster and achieve higher clearance rates than the two alone, and can reduce the cumulative dose of phototherapy, and maintenance therapy with Ave A alone after the lesions have largely resolved is an effective and safe treatment for psoriasis.
Biologics: Etanercept, efalizumab (banned in the United States in 2009), infliximab, adalimumab have earlier been shown to be safe and effective for maintenance therapy, and in recent years ustekinumab has also been shown to be suitable for maintenance therapy.
In a 5-year PHONENIXI study, patients with psoriasis treated with ustekinumab were divided into 2 groups according to the degree of improvement in PASI scores: an initial response group (PASI improvement ≥75%) and a partial response group (PASI improvement <75%), with patients in the initial response group receiving ustekinumab 45 mg or 90 mg maintenance therapy every 12 weeks at week 40 and the partial response group receiving ustekinumab 45 mg or 90 mg maintenance therapy every 8 weeks at week 28 or week 40, depending on the degree of improvement in PASI scores.
The results showed that 68.7% of patients completed up to 244 weeks of treatment, with 79.1% and 80.8% of patients in the initial response group receiving PASI 75 in the 45 mg and 90 mg groups, respectively, and 57.6% and 55.1% of patients in the partial response group receiving PASI 75 in the 45 mg and 90 mg groups, respectively, and 63.4% and 55.1% of patients in the 45 mg group receiving PASI 75, PASI 90, and PASI 100 in the initial response and partial response groups, respectively. The above results support the effectiveness and relative safety of ustekinumab for long-term maintenance treatment of psoriasis.
It is worth noting that some patients initially treated with TNF-α inhibitors etanercept, adalimumab, and infliximab were effective, but the efficacy may disappear after a period of maintenance treatment. The percentages of patients still using infliximab, adalimumab, and etanercept after 4 years were 70%, 40%, and 40%, respectively.
Clinicians should also be aware that the efficacy of fixed-dose biologics may be relatively lower in obese patients. Brezinski et al. suggest that increasing the dose improves the efficacy of biologics in poorly treated patients with moderate-to-severe psoriasis and suggest that maintenance therapy with TNF-α inhibitors and ustekinumab is more effective than intermittent therapy. The patient’s disease severity, complications and quality of life should be taken into account before using doses beyond the standard.
Topical therapy: Commonly used drugs for the topical treatment of psoriasis include: glucocorticoids, vitamin D3 and its derivatives, calcium phosphatase inhibitors, vitamin A acid, tar, dithranol, keratin strippers such as salicylic acid and urea, and emollients. Studies have shown that after interruption of topical treatment with these agents, the lesions recur within a short period of time in 20-80% of patients and after 6 months in 88% of patients.
Therefore, topical treatment is also an important part of maintenance therapy for patients with moderate to severe psoriasis. Potent glucocorticoids are not recommended for maintenance therapy because of their clinical adverse effects, but potent glucocorticoids and vitamin D3 derivatives, either in combination or applied alone once daily, are the most effective topical agents, with no significant difference in efficacy between the two regimens.
There is no consistent evidence that one of the above topical medications is significantly superior to the other. In addition to the efficacy and safety of the medications, the clinical application should take into account the needs of the patient, the type, location and extent of the lesions and other practical issues such as cosmetology and duration of use to select the appropriate topical medication.
The current status of maintenance therapy in patients with moderate-to-severe psoriasis is poor, with patients interrupting conventional therapy and phototherapy for a median of 6-12 months and interrupting biologic therapy for a slightly longer period of 12-20.5 months, suggesting that patients interrupt conventional therapy mainly because of adverse drug reactions, interrupting phototherapy mainly because of inconvenient access to medical care, and interrupting biologic therapy mainly because of loss of efficacy or unsatisfactory efficacy, suggesting that psoriasis This suggests that maintenance therapy research needs to be continued.