Systematic Review and Recommendations to Combine Newer Therapies With Conventional Therapy in Psoriatic Disease

Background: Psoriasis continues to have unmet needs in its management despite introduction of newer molecules. Monotherapy with these newer agents may not achieve therapeutic goals in all cases, hence necessitating their combinations with other molecules. Improved understanding of newer as well as conventional treatment modalities and experiences in their combinations hence necessitates therapeutic guidelines for their use in psoriasis. Objective: To review the combinations of treatments reported in literature and recommendations for their use based on best current evidence in literature. Methods: A literature review of MEDLINE database for studies evaluating combinations of newer therapies with conventional therapies in psoriasis was done. Newer therapies were identified as biologic disease modifying anti rheumatic drugs and other molecules such as apremilast while conventional therapies included methotrexate, cyclosporine, or retinoids, phototherapy and others. The therapeutic guidelines are proposed with the aim to provide evidenced based approach to combine newer and conventional agents in day-to-day psoriasis management. Findings: Combination of acitretin and narrow band ultraviolet B (NB-UVB)/Psoralen with ultraviolet A (PUVA) achieves faster clearance and allows reduction of dose of the latter. A variable outcome is reported of methotrexate with TNF-α inhibitors vs. TNF-α inhibitors alone, although addition of methotrexate appears to reduce immunogenicity of TNF-α inhibitors thereby preventing formation of anti-drug antibodies especially in case of infliximab. While combination of acitretin and PUVA is beneficial, combining TNF-α inhibitors and phototherapy too produces better and faster results but long term risks of Non Melanoma Skin Cancers (NMSCs) may preclude their use together. Combination of cyclosporine and phototherapy is not recommended due to greater chances of NMSCs. Adding phototherapy to Fumaric Acid Esters (FAEs) improves efficacy. Apremilast can be safely combined with available biologic agents in patients with plaque psoriasis or psoriatic arthritis not responding adequately to biologics alone. Hydroxyurea and acitretin may be used together increasing their efficacy and reducing doses of both and hence their adverse effects. Conclusion: Selected clinical scenarios shall benefit from combinations therapies, improving efficacy of both conventional and newer agents and at the same time helping reduce toxicity of higher dosages when used individually.

Background: Psoriasis continues to have unmet needs in its management despite introduction of newer molecules. Monotherapy with these newer agents may not achieve therapeutic goals in all cases, hence necessitating their combinations with other molecules. Improved understanding of newer as well as conventional treatment modalities and experiences in their combinations hence necessitates therapeutic guidelines for their use in psoriasis.
Objective: To review the combinations of treatments reported in literature and recommendations for their use based on best current evidence in literature.
Methods: A literature review of MEDLINE database for studies evaluating combinations of newer therapies with conventional therapies in psoriasis was done. Newer therapies were identified as biologic disease modifying anti rheumatic drugs and other molecules such as apremilast while conventional therapies included methotrexate, cyclosporine, or retinoids, phototherapy and others. The therapeutic guidelines are proposed with the aim to provide evidenced based approach to combine newer and conventional agents in day-to-day psoriasis management.
Findings: Combination of acitretin and narrow band ultraviolet B (NB-UVB)/Psoralen with ultraviolet A (PUVA) achieves faster clearance and allows reduction of dose of the latter. A variable outcome is reported of methotrexate with TNF-α inhibitors vs. TNF-α inhibitors alone, although addition of methotrexate appears to reduce immunogenicity of TNF-α inhibitors thereby preventing formation of anti-drug antibodies especially in case of infliximab. While combination of acitretin and PUVA is beneficial, combining TNF-α inhibitors and phototherapy too produces better and faster results but long term risks of Non Melanoma Skin Cancers (NMSCs) may preclude their use together. Combination of cyclosporine and phototherapy is not recommended due to greater chances of NMSCs. Adding phototherapy to Fumaric Acid Esters (FAEs) improves efficacy. Apremilast can be safely combined with available biologic agents in patients with plaque psoriasis or psoriatic arthritis not responding adequately to biologics alone. Hydroxyurea and acitretin may be used together increasing their efficacy and reducing doses of both and hence their adverse effects.

INTRODUCTION
Psoriasis is a chronic relapsing-remitting inflammatory papulosquamous disease, which affects ∼0. .43% of adults worldwide (1). This immune-mediated disease causes chronic inflammation in milieu which not only affects skin, but also joints, blood vessels, heart, liver, and kidneys (2) as well as metabolic syndrome (3,4). PsA (Psoriatic Arthritis) may be present in >40% of psoriasis patients leading to joint damage and deformities thereby severely affecting QoL (Quality of Life) and physical functioning (5)(6)(7). Early diagnosis and treatment intervention are crucial for optimal patient care (8,9). The chronic relapsing course of disease with these co-morbidities are associated with increased physical and psychological burden, which leads to impaired Quality of Life (QoL) and depression (10). Mild psoriasis responds to topical therapy while moderate to severe psoriasis may need augmentation with phototherapy or systemic agents. Severe psoriasis may sometimes be refractory to one systemic agents requiring combination with another to maintain remission (11,12). Combining therapeutic agents holds potential in synergistic action for a better control over disease activity. Moreover, a combination may be needed to reduce adverse effects by allowing reduction of dose despite severe disease. However, combining therapies pose challenges in tolerability, acute and long-term adverse effects in the absence of clear overall guidelines. Conventionally, immunosuppressive and non-biologic disease modifying immune-modulatory drugs such as methotrexate, cyclosporine, retinoids, phototherapy, and others have been used. Management of psoriasis has been revolutionized by biologics which have improved management of psoriasis but aren't panaceas either. Combining newer and conventional therapies provide a tantalizing option for managing psoriasis, to achieve prolonged remission and better Quality of Life (QoL). Although there are numerous Randomized Control Trials (RCTs), case series, case reports, and expert opinions proving efficacy of different combinations in various clinical scenarios, literature is lacking in clear cut guidelines on how and when to combine the newer and conventional therapeutic options. This review aims at analyzing data available from studies with highest quality of evidence i.e., RCTs and generate recommendations for combining newer and conventional therapies in psoriatic disease.

Search Strategy
A literature search was performed for studies conducted in psoriasis therapeutics published before 01 Jan 2021. MEDLINE (OVID, from 1948), EMBASE (OVID, from 1980), Cochrane Central Register of Controlled Trials (CENTRAL), ahead of print subset fraction from Pubmed-not yet published in (OVID MEDLINE), and ongoing trial registries (http://clinicaltrials. gov/) were searched with no language restrictions. The search was carried out through use of keywords targeting all drugs used in conventional as well as newer therapies. In MEDLINE and EMBASE, a methodologic filter for search was used to identify RCTs and clinical controlled trials in Medical Subject Headings and titles and abstracts (adapted from the Cochrane Central Register of Controlled Trials). For potential drug combinations where RCTs were not found, the search was extended to include lower tiers of hierarchy of evidence up to case series. A systematic method in search was used for each database to broaden the search through inclusion of pertinent search terms as relevant citations were recognized (i.e., by scrutinizing references and citing articles).

Inclusion Criteria
Randomized Controlled Trials (N > 10) which reported on the efficacy and safety of combined use of conventional and newer drugs in psoriatic disease were included. Potential combinations in which RCTs have not been carried out, studies with lower levels of evidence were also included.

Exclusion Criteria
In-vitro, preclinical and animal studies, case reports and expert opinions were excluded from the review as well as all studies not meeting the inclusion criteria. Studies with rotational or sequential therapies using these drugs as well as those combining alternative medicines (i.e., Chinese herbal) were excluded. Biosimilars were excluded from the study to maintain uniformity on drug efficacy data.

Selection of Studies
Using the above keywords, the titles and abstracts from electronic literature search were screened, and full text of articles that met the pre-defined inclusion criteria were obtained. Successively, articles were scanned for inclusion or exclusion. The selection of studies were implemented by 2 reviewers independent of each other (S.A. and P.D.). The quality of each included articles was assessed in agreement with the Cochrane handbook of systematic reviews of interventions 5.1.0 (updated March 2011). Any disagreements between the two reviewers were resolved by commonly drawn consensus by discussion or intervention by a third reviewer (G.A.).

Data Extraction
Information on the year of publication, study design, study reference, number of patients (N), baseline disease severity, treatment schedule, duration of combination therapy, and period of follow-up were extracted. Critical as well as important outcomes were carefully chosen to determine the quality of evidence. Critical outcomes were defined as the proportion of patients who attained a PASI (Psoriasis Area and Severity Index) of 90, PASI of 75, and a PGA (Physician Global Assessment) of clear or almost clear; discontinuation of a particular drug because of AEs (Adverse Effects); proportion of patients who encountered SAEs (Serious Adverse Events); and mean change in DLQI (Dermatology Life Quality Index). Important outcomes were defined as lack of efficacy leading to withdrawals (number), proportion of patients with AEs (not leading to drug withdrawal), mean time to clearance, mean change in PASI (0-72, 0-18, and 0-16) and mean time to relapse.

RESULTS
Our literature search yielded 25 RCTs ( Table 1) combining different drugs which met the criteria to be included for analysis in the present study. Potential drug combinations for which RCTs have not been done, studies with lesser levels of evidence up to case series were searched for to look for evidence and gaps in research ( Table 2).

Discussion and Recommendations
Literature search yielded 25 RCTs combining different agents to treat psoriasis and/or psoriatic arthropathy. Most of the studies involved combinations with Narrow Band Ultraviolet B (NB-UVB) /Psoralen with Ultraviolet A (PUVA) or methotrexate.

NB-UVB/PUVA and Acitretin
There are 02 RCTs involving acitretin and UVB/PUVA by Tanew et al. (15) and Lowe et al. (16). The former found that the cumulative PUVA dose required for complete clearance in PUVA-acitretin group was 58.7 ± 17.9 J/cm 2 whereas in PUVAplacebo group was 101.5 ± 15.8 J/cm 2 . In RCT by Lowe et al. (16), 14 participants in the UVB-acitretin group took a total of 873 min of UVB exposure for complete clearance as compared to a significantly higher time-1,236 min in the UVB-placebo group (n = 15). At the end of 12 weeks, the mean PASI ± SD in acitretin + UVB group reduced significantly from 8.83 ± 1.8 to 2.27 ± 1.04 (p < 0.01), whereas it reduced from 9.75 ± 2.34 to 6.36 ± 3.07 in placebo + UVB group. Both the RCTs concluded that adding UVB/PUVA to acitretin achieves greater as well as faster clearance than either placebo-UVB/PUVA or acitretin alone. Clinical adverse effects of added acitretin in both the studies were generally well-tolerated and similar to previous studies in treatment of psoriasis with acitretin (46)(47)(48).

Recommendation
We recommend combining these two modalities when patients do not respond to either one of the two. In addition to increased efficacy, the combination allows reduction of cumulative dose of UVB/PUVA. Also important is the prevention of non-melanoma skin cancers by acitretin which may be caused by long term UVB/PUVA (49,50).

NB-UVB With TNFα Inhibitors
who performed an intra-individual RCT in receiving etanercept and a randomized half of the body with NB-UVB for found that The PSI (Psoriasis Severity Index) scores of nonirradiated control lesions were 6.4 ± 2.3 and 5.8 ± 2.5 (p = not significant) before and after the treatment respectively, whereas the PSI of irradiated psoriatic plaques were 6.3 ± 2.3 and 0.5 ± 0.8 (p < 0.05). In the combination group, the mean PASI ± SD value reduced from 16.2 ± 9.2 to 2.4 ± 2.8 in 12 weeks. The patients received 14.6 ± 3.3 exposures resulting in a cumulative dose of 8.4 ± 4.2 J cm −2 . While the combined treatment was always well-tolerated, it was aimed at short duration of NB-UVB therapy for faster clearance to avoid long term adverse effects. It also may help reduce total doses as well as cost of

Recommendation
As the implication of malignancy in treatment with TNF-α blockers alone or in combination with NB-UVB complex with levels of TNF-α having varied effects on tumoral growth, (51) we recommend to restrict this highly effective combination for short duration up to 24 weeks, to obtain a quicker response and to avoid long-term complications (52)(53)(54). European Academy of Dermatology and Venereology (EADV) guidelines on management of psoriasis mention that TNFα blockers and NB-UVB may or may not be combined and it is not as strict a contraindication as cyclosporine with NB-UVB (55).

NB-UVB and IL12/23 Inhibitor
There is only a single intra-individual RCT combining injection ustekinumab at 45/90 mg 4 weeks apart and thrice weekly 311nm UVB by Wolf et al. (21) in 10 patients. At baseline, the mean PASI was similar in both irradiated and unirradiated body halves (13.6 vs. 13.3). At 6 weeks, PASI was significantly lower on irradiated body halves (2.5 vs. 6.1), (95% confidence interval 1.3-5). PASI 75 was achieved significantly more often on UVirradiated body halves than on un-irradiated ones [7/9 patients (78%) vs. 1/9 (11%)]. They concluded that treatment with NB-UVB accelerates the clearance of psoriatic lesions at week 6 as well as at week 12 in ustekinumab-treated patients without increase in incidence of severe adverse effects.

Recommendation
We recommend combining NB-UVB with methotrexate for faster clearance of lesions. However, either may be discontinued after achieving PASI 75 and the other continued for maintenance therapy the duration of which shall be dictated by the disease burden.

TNFα Inhibitors and Methotrexate
The following RCTs combining TNFα blockers with methotrexate met the inclusion criteria-Zachariae et al.  < 0.001). An ACR 20/50/70 response was achieved by, respectively, 85, 81, and 58% in the combination arm vs. 58, 33, and 13% in the methotrexate arm (p = 0.039, p = 0.001, and p = 0.001, respectively). The most frequent adverse effect was nausea and occurred in similar incidences in both treatment arms and considered to be treatment related but was not severe enough to discontinue treatment. Likewise, a double-blind RCT by Vieira-Sousa et al. (31) comparing similar doses of golimumab plus methotrexate vs. placebo plus methotrexate in dactylitis in psoriatic arthropathy concluded that the combination of golimumab and methotrexate was superior to methotrexate alone in reducing Dactylitis Severity Score (DSS) and Leeds Dactylitis Index (LDI) with comparable incidence of adverse effects between treatment arms. All patients had active dactylitis at baseline, with a median baseline DSS of 6 in both arms. The patients treated with golimumab/methotrexate exhibited significantly greater improvements by DSS at week 24 (median change of 5) relative to the placebo/methotrexate group (median change of 2) (p = 0.026), and as early as 12 weeks (p = 0.004). The proportion of DSS50 (Dactylitis Severity Score 50) and DSS70 (Dactylitis Severity Score 70) responders at week 24 were also significantly higher for patients treated with golimumab/methotrexate (DSS50: p = 0.005, DSS70: p = 0.010) Endpoints to measure cutaneous efficacy like PASI, BSA and skin-related quality of life (Dermatology Life Quality Index) improved in both groups at week 24 but difference in both treatment groups was not significant. 102 adverse events were reported during study period, with similar incidence between the treatment arms and mostly of mild to moderate severity. According to systematic review by Hsu et al. (56), there are 06 studies measuring anti-drug antibodies in etanercept and its possible effect on drug efficacy-they found the prevalence of anti-etanercept antibodies (AEA) ranging from 0 (57) to 18.3% (58) in psoriasis, and none of which had significant effect on treatment efficacy (56). Similarly, 10 studies proved prevalence of anti-infliximab antibodies (AIA) ranging from 5.4 (59) to 43.6% (60) with most of these studies showing significant decreased mean PASI scores and greater loss of clinical response when compared to AIA-negative patients (56). A study by Adisen et al. (61) with five patients of psoriasis who developed AIA, determined that AIA positivity disappeared after 8 weeks of combined methotrexate pulse therapy, ranging from 5 to 15 mg/week. Six studies assessed for Anti-Ustekinumab Antibody (AUA) formation in patients with moderate-to severe psoriasis showed ranges from 3.8 (62) to 5.4% (63) in psoriasis (56). But their clinical significance on treatment response is yet to be evaluated (56).

Recommendation
We recommend combining TNFα blockers with methotrexate in moderate to severe psoriatic disease especially while using infliximab. Poor response to etanercept alone at lower doses as elaborated below necessitates an additional drug, methotrexate being a good option.

Recommendation
We recommend TNFα blockers with cyclosporine in moderate to severe psoriasis with arthropathy for rapid remission, however side effects limit the duration of treatment with cyclosporine and sequential therapy with methotrexate is recommended.

Recommendation
We recommend apremilast 30 mg twice daily and NB-UVB as a combination modality not responding or minimally responding to either of the two. The combination of apremilast and a biologic may be a safe, useful treatment option for managing patients with psoriasis showing biologic fatigue, but not as a routine. However, large scale studies with higher level of evidence like RCTs are needed in future.

Miscellaneous Combination Therapies
RCTs combining less used unconventional drugs in psoriasis included in this review dealt with fumaric acid esters (FAEs) calcitriol, sulfasalazine, pentoxifylline, and pioglitazone with conventional modes of therapy. An exploratory RCT by Bezooijen et al. (34) combining etanercept 50 mg twice weekly for 12 weeks followed by once weekly for another 12 weeks with oral fumarates 215 mg four times daily for the whole period vs. etanercept alone found out that the reduction in PASI score per week for the combination therapy was 5.97% (95% confidence interval, CI: 5.08-6.85) and in the monotherapy group 4.76% (95% CI: 3.57-5.93; p = 0.11). They concluded that combination therapy caused quicker improvement in PASI 75 in first 24 weeks although difference in the PASI score between the two groups was statistically insignificant but with satisfactory tolerability. In an another RCT by Tzaneva et al. (35), an increasing dose of FAEs was combined with NB-UVB. At 26 weeks of treatment, the median baseline PASI of 15.4 [interquartile range (IQR) 11.7-21.0] was reduced to 2.8 (IQR 1. 6-4.8) in the combination group and from 14.0 (IQR 12.5-15.1) to 9.0 (IQR 6.5-12.1) in the FAE group, respectively. The mean absolute and relative reduction in PASI was significantly greater in the combination group (10 and 69%) compared with patients receiving only FAE (5 and 36%) (p = 0.016). Side-effects related to FAE were mainly mild gastrointestinal complaints reported by 12/16 patients (75%) in the monotherapy group and 3/14 patients (21%) in the combination group. These were abdominal pain, nausea, flatulence, diarrhea that occurred at the beginning of treatment, were dose-dependent and improved after a temporary dose reduction. They found an accelerated as well as augmented response improving the quality of life in the patients with combination therapy as compared with fumaric acid esters monotherapy with no increase in adverse effects in the combination group.
A single blinded, placebo-controlled trial combining calcitriol 0.5-2.0 µg per day plus NB-UVB against NB-UVB alone by Prystowsky et al. (36) concluded that there was no added benefit to treatment when oral calcitriol was administered with phototherapy. Our search yielded only a single RCT combining acitretin and calcitriol-Ezquerra et al. (37) who compared the combination with acitretin alone. Initial PASI of 26.90 reduced to 13.3 in acitretin alone group; whereas it reduced from 28.35 to 10.3 in acitretin+calcitriol combination group which was statistically significant (p < 0.05). A double-blind RCT by Mittal et al. (38) compared combination of acitretin plus pioglitazone hydrochloride with acitretin alone. The percentage of reduction in the PASI score from baseline to 12 weeks of treatment was 64.2% (95% CI, 49.2-79.3%) in the combination group compared with 51.7% (95% CI, 38.7-64.7%) in the acitretin plus placebo group (p = 0.04). The adverse effects in both the groups were mild to moderate and were comparable. el-Mofty et al. (39) conducted a quadri-armed RCT comparing the combination of sulfasalazine and pentoxifylline to methotrexate alone (active control group), sulfasalazine alone and pentoxifylline alone and concluded that combination of sulfasalazine and pentoxifylline though effective than when used alone, is not as effective as methotrexate, may be promising and tried because they present as safer and well-tolerated alternatives to methotrexate. There are no RCTs on hydroxyurea in psoriasis. Hydroxyurea becomes one of the drugs of choice in settings of psoriasis in HIV, where not only it helps in controlling psoriasis, but also in controlling viral loads especially when combined with didanosine (NRTI) (68,69). In a retrospective study, Narang et al. (45) combined lower doses of hydroxyurea 1 g daily with acitretin 25 mg daily for the management of refractory cases and found them to be superior to either to hydroxyurea and acitretin alone as found in previous studies. Combining acitretin with hydroxyurea may theoretically reduce the risk of non-melanoma skin cancers and actinic keratosis, which are rare but serious adverse effect of hydroxyurea (49,70). Methotrexate too have been combined with hydroxyurea in lower doses (5-10 mg/week and 500 mg per day, respectively) to good effect with no increase in adverse effects of either of the two (71). Though theoretically both the drugs may cause GI intolerance and myelosuppression, they were not found in the study.

Recommendation
We recommend combining hydroxyurea and acitretin in recalcitrant cases of psoriasis not responding to conventional stand-alone drugs. This combination also may be used in HIV where both the drugs do not cause immune suppression with added benefit of anti-viral action of hydroxyurea.
Combining methotrexate with hydroxurea in lower doses may help reducing dose-dependent or cumulative toxic effects of either of the two.
Our search for combinations comprising relatively newer drugs like guselkumab, tildrakizumab, certolizumab pegol, and tofacitinib yielded no results and provide gap in research with a massive potential.

CONCLUSION
Combining newer therapies with conventional ones is a promising prospect to manage difficult to treat psoriasis. Combining drugs when suited to patients needs can enhance efficacy, achieve remission, while reducing adverse effects. With available evidence, there are limited options with highest level of evidence and hence recommendation. Due to a smaller number of studies in combination of drugs, research providing more high-quality evidence is required.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
SA: conception and design, acquisition of data, literature search, analysis and interpretation of data, drafting the manuscript, and revising it. PD and GA: acquisition of data, literature search, analysis and interpretation of data, drafting the manuscript, and revising it. All authors contributed to the article and approved the submitted version.