Phototherapy and the Classic Systemics: Methotrexate, Ciclosporin, Acitretin
Before biologics rewrote the ceiling of what psoriasis treatment could achieve, dermatologists had a ladder — and they still climb it every day, because it is cheaper, faster in a crisis, and sometimes simply the right tool. Light first, then three old drugs, each with a personality: methotrexate the workhorse that also treats the joints, ciclosporin the fire-extinguisher you cannot leave running, and acitretin the retinoid that spares the immune system but scars the future with years of teratogenicity. Knowing when to reach for each — and what blood test protects the patient from it — is the heart of practical psoriasis therapy.
A 38-year-old man has had plaque psoriasis since his twenties, but this winter it has covered his trunk, elbows and shins, and lately his fingers ache and swell in the mornings. Topical steroids and vitamin D creams are no longer enough — too much skin, too much misery. His dermatologist explains the ladder ahead. They start with narrowband UVB three times a week, and for a while the plaques thin. But the joint pain worsens, and the light alone cannot reach it. So they move to methotrexate — one dose a week, with folic acid on the other days, and a blood test to guard his liver and marrow. Within two months his skin is clearer than it has been in years and his fingers move freely. In a single patient you see the logic of the whole chapter: escalate from light to systemic drugs, and let the comorbidity — here, psoriatic arthritis — choose which drug.
When topical treatment runs out of room
The trigger to escalate is not just severity — it is surface area, site, and impact on life. Mild psoriasis lives on creams: topical corticosteroids, vitamin D analogues, and their combinations. But once plaques cover too much body-surface area, or land in disabling sites (palms, soles, scalp, genitals), or the joints become involved, no reasonable amount of cream can keep up — and slathering potent steroids over large areas brings its own harm. This is the threshold of moderate-to-severe disease, and it opens the door to phototherapy and systemic drugs. The decision is as much about quality of life as about the percentage of skin: psoriasis is a systemic inflammatory disease, and treating it well means treating the whole patient, not just the visible plaque.
Light as a drug: narrowband UVB
The first rung above creams is often not a pill at all but light. Narrowband UVB — a tightly filtered band around 311 nanometres — is delivered in a booth two or three times a week. It is genuinely first-line phototherapy: effective, well tolerated, and safe enough to use in pregnancy and children. Its mechanism is local and immunological, not a mystery sun-tan effect. UVB penetrates the epidermis and upper dermis, where it damages DNA in the overactive keratinocytes and, crucially, drives apoptosis of the pathogenic T cells that fuel the psoriatic plaque. It shifts the local immune balance away from the inflammatory drive and slows the runaway keratinocyte turnover. Because the drug never enters the bloodstream, it has no systemic toxicity — the price is only inconvenience (repeated hospital visits) and a small long-term rise in skin-cancer risk with heavy cumulative exposure.
PUVA: adding a photosensitiser — and a long shadow
PUVA is more powerful than narrowband UVB, but you pay for the power over decades. PUVA stands for Psoralen plus UVA. Psoralen is a photosensitising drug, taken by mouth (or applied in a bath), that intercalates into DNA and becomes chemically reactive only when struck by UVA light. The patient then stands in a UVA booth, and where the light lands the activated psoralen cross-links DNA, halting the excessive proliferation of keratinocytes and suppressing the local immune response. Because UVA reaches deeper than UVB, and because psoralen amplifies its effect, PUVA can clear stubborn, thick plaques that narrowband UVB cannot. But that same DNA-damaging power carries a well-documented, dose-dependent long-term risk of skin cancer — squamous cell carcinoma above all, and melanoma with very heavy exposure. This is why narrowband UVB is preferred first, and PUVA is reserved for resistant disease and used with a lifetime-dose conscience. The carcinogenicity theme links directly to the Skin cancer chapter of the Oncology section.
Think of the psoriatic plaque as a fire fed by two things: keratinocytes multiplying too fast (the fuel) and inflammatory T cells fanning the flames (the wind). Narrowband UVB is a firebreak sprayed on the surface — it kills the T cells and slows the fuel where the light reaches. PUVA is the same idea with an accelerant that lets you douse deeper fires — but the accelerant is itself flammable over the long run. Methotrexate and ciclosporin, coming next, work from the inside: they don't spray the surface, they cut the wind at its source.
Methotrexate: the antifolate workhorse
When light is not enough — or the joints are involved — methotrexate is the classic first oral systemic. Chemically it is an antifolate: it inhibits dihydrofolate reductase, choking the folate-dependent synthesis of DNA. At the high doses of cancer chemotherapy that is a cytotoxic effect, but at the low, once-weekly doses used in psoriasis its benefit is better understood as anti-inflammatory — it dampens the activated lymphocytes driving the plaque (partly through adenosine release). The dosing rhythm is the single most important safety fact: methotrexate is taken once a week, never daily. Daily dosing by mistake is a classic, sometimes fatal, prescribing error. Folic acid is given on the other days to soften the mucosal and marrow side effects without abolishing the benefit.
Methotrexate is safe only because it is watched. Its two organ threats define the monitoring. The bone marrow can be suppressed — a full blood count is checked regularly to catch falling white cells and platelets before infection or bleeding. The liver is the other worry: chronic use can cause hepatotoxicity and, over years, fibrosis, so liver function tests are followed and cumulative dose is respected (procollagen markers or elastography may be used to watch for fibrosis). Two rarer but serious harms complete the picture: an idiosyncratic pneumonitis (a new dry cough and breathlessness must be taken seriously) and profound myelosuppression if dosing goes wrong or renal function falls. Methotrexate is also strongly teratogenic and an abortifacient — it must be stopped well before conception in both women and men, a point that ties into every pre-treatment counselling conversation.
The interactions that catch people out share one theme: anything that also lowers folate or reduces methotrexate clearance. Trimethoprim (and co-trimoxazole) is the classic trap — it is itself an antifolate, and combined with methotrexate can precipitate severe, even fatal, marrow suppression. NSAIDs and some other renally-cleared drugs raise methotrexate levels by reducing its excretion. And alcohol compounds the liver risk, so heavy drinking is a strong caution. If you remember one sentence about methotrexate safety: once a week, with folic acid, never with trimethoprim, and watch the liver and the count.
- Narrowband UVB is first-line phototherapy — drives T-cell apoptosis in skin, no systemic toxicity, safe in pregnancy.
- PUVA (psoralen + UVA) is more potent for thick plaques but carries a dose-dependent long-term skin-cancer risk.
- Methotrexate is an antifolate; low weekly dosing works mainly as an anti-inflammatory, not as chemotherapy.
- Methotrexate is taken ONCE WEEKLY with folic acid — daily dosing is a classic, potentially fatal error.
- Monitor FBC and LFTs: watch for myelosuppression, hepatotoxicity/fibrosis; beware pneumonitis and teratogenicity.
- Key interactions: trimethoprim/co-trimoxazole and NSAIDs raise toxicity; alcohol compounds liver risk.
Ciclosporin: the fast rescue you cannot leave running
When a patient is in crisis — an explosive flare, erythroderma, or severe disease that must be brought under control in days rather than weeks — ciclosporin is the fast option. It is a calcineurin inhibitor: by blocking calcineurin inside the T cell it prevents the transcription of interleukin-2, starving the T-cell response that drives the plaque. Because it strikes so directly at the activated T cell, it works quickly — often the fastest of the classic systemics. That speed is its role: ciclosporin is a rescue and bridging drug, used in short courses to gain rapid control, then handed off to a safer long-term agent. It is not a drug you keep a patient on for years, and the reason is its toxicity.
The clock on ciclosporin is set by the kidney and the blood pressure. Its two dose-limiting harms are nephrotoxicity and hypertension. Ciclosporin constricts the renal vasculature and, over time, causes structural kidney damage — so renal function and blood pressure are checked before and throughout treatment, and the total duration is deliberately capped (typically a year at most in continuous use). It also has a large and dangerous interaction profile, because it is metabolised by the CYP3A4 enzyme system: inhibitors of CYP3A4 (such as many azole antifungals, macrolide antibiotics, and even grapefruit juice) push ciclosporin levels up toward toxicity, while inducers drop them and lose control of the disease. Other cumulative effects — gum overgrowth, hirsutism, tremor and raised lipids — round out its personality. The immunosuppressant principles here, shared with transplant medicine, are developed in full in the Inflammation & Joints section.
Acitretin: the retinoid that spares immunity
Acitretin is the odd one out — an oral retinoid (a vitamin A derivative) that normalises the disordered differentiation and proliferation of keratinocytes rather than suppressing the immune system. That single property makes it valuable in exactly the situations where immunosuppression is unwelcome: it is the systemic of choice in HIV-associated psoriasis, and it shines in the pustular and erythrodermic variants, where calming the keratinocyte chaos matters more than blunting T cells. It can be combined with phototherapy (so-called re-PUVA or re-UVB) to boost clearance. But its non-immunosuppressive nature does not make it gentle, and one feature dominates its prescribing.
Acitretin's defining danger is that it stays teratogenic for years after the last dose. Like all systemic retinoids, acitretin is a powerful teratogen — it causes severe birth defects. What sets it apart from isotretinoin is its persistence: acitretin can be converted back to etretinate, a long-lived retinoid stored in fat, so it must be avoided in women of childbearing potential and pregnancy must be prevented for a very long time after stopping — up to around three years. For this reason many prescribers simply do not use acitretin in women who might conceive, choosing another agent instead. Its everyday side effects are mucocutaneous and metabolic: dry, cracked lips (cheilitis) almost universally, dryness of skin and eyes, hair thinning, raised blood lipids (triglycerides and cholesterol), and deranged liver function tests. So the monitoring mantra is lips, lipids and LFTs — check a fasting lipid profile and liver tests, and warn every patient about the dryness that is coming.
The classic systemics are not interchangeable — the patient's comorbidity usually names the drug. Psoriasis with psoriatic arthritis → methotrexate, because it treats skin and joints together. An acute, out-of-control flare or erythroderma needing rapid control → ciclosporin as a short rescue. Psoriasis in a patient with HIV, or a pustular/erythrodermic pattern, where immunosuppression is unwise → acitretin, the non-immunosuppressive retinoid. A young woman planning pregnancy → avoid methotrexate and acitretin entirely (both teratogenic, acitretin for years); narrowband UVB is the safest choice. And when all of these fail or are contraindicated, the ladder continues into the biologics — targeted anti-TNF, IL-17 and IL-23 agents — and the oral PDE4 inhibitor apremilast, both taken up in the next chapter.
- Ciclosporin is a calcineurin inhibitor blocking IL-2 transcription — fastest classic systemic, used for short-term rescue.
- Ciclosporin's dose-limiting harms are nephrotoxicity and hypertension; it has many CYP3A4 interactions.
- Acitretin is an oral retinoid, non-immunosuppressive — good in HIV, pustular and erythrodermic psoriasis.
- Acitretin is teratogenic for up to ~3 years after stopping — avoid in women of childbearing potential.
- Acitretin monitoring: lips (cheilitis), lipids (triglycerides/cholesterol) and LFTs.
- Comorbidity chooses the drug: arthritis → methotrexate; flare → ciclosporin; HIV/pustular → acitretin; pregnancy → UVB.
- Prescribing methotrexate daily instead of once weekly — a classic, potentially fatal error; and forgetting the folic acid.
- Co-prescribing trimethoprim/co-trimoxazole (or high-dose NSAIDs) with methotrexate and triggering severe marrow suppression.
- Giving acitretin to a woman who could become pregnant, forgetting it stays teratogenic for years — or keeping a patient on ciclosporin long-term and ignoring the creeping kidney damage.
A 34-year-old woman with moderate-to-severe plaque psoriasis and painful, swollen finger joints is being started on a systemic agent. She has no immediate plans for pregnancy but might in a few years, and has normal kidneys and liver. Which is the most appropriate first-line systemic?
- Escalate from topicals when disease is extensive, disabling in site, or joints are involved: phototherapy first, then systemics.
- Narrowband UVB (first-line phototherapy; T-cell apoptosis, no systemic toxicity) vs PUVA (psoralen + UVA; stronger but long-term skin-cancer risk).
- Methotrexate: weekly antifolate + folic acid, treats joints too, monitor FBC/LFTs (hepatotoxicity, myelosuppression, pneumonitis), teratogenic, avoid trimethoprim/NSAIDs/alcohol.
- Ciclosporin = fast short-term rescue (calcineurin inhibitor; nephrotoxicity, hypertension, CYP3A4 interactions). Acitretin = non-immunosuppressive retinoid (HIV/pustular/erythrodermic), teratogenic for ~3 years, watch lips/lipids/LFTs. Comorbidity picks the drug; biologics and apremilast come next.
- Rook's Textbook of Dermatology — Psoriasis: phototherapy and systemic therapy.
- Wolverton SE. Comprehensive Dermatologic Drug Therapy — Methotrexate, Ciclosporin, Systemic Retinoids, Phototherapy.
- British National Formulary (BNF) — Methotrexate, Ciclosporin, Acitretin monographs.
- Katzung & Trevor's Basic & Clinical Pharmacology — Immunosuppressants and antifolates.
- NICE Guideline CG153 / BAD Guidelines — Assessment and management of psoriasis; biologics and systemic therapy.
- Menter A, et al. Joint AAD–NPF guidelines of care for the management of psoriasis with systemic non-biologic therapies. J Am Acad Dermatol.
