Covers immunosuppression across all clinical indications: autoimmune disease, solid organ transplant, IBD, rheumatology, dermatology & haematology. For transplant-specific surgical nursing, see the Transplant Guide.
Immune System Overview
Innate Immunity (Non-specific, Immediate)
First line: physical barriers, neutrophils, macrophages, NK cells
Caution: More agents = multiplicatively higher infection risk. Each addition must be carefully justified.
General Principles for Nurses
Core principle: Infection is the primary clinical concern in immunosuppressed patients. Immunosuppressed patients may NOT mount a normal febrile or inflammatory response — atypical presentations are the rule, not the exception.
Recognition of Atypical Presentations
Fever may be absent or low-grade even in severe sepsis
WBC may not rise significantly
C-reactive protein may be blunted by steroids
Pneumonia may present as mild dyspnoea without prominent cough
Meningitis without neck stiffness or photophobia
Any unexplained deterioration = infection until proven otherwise
Nursing Assessment Priorities
Full drug reconciliation — what agents, what doses, for how long
Identify the cumulative immunosuppression burden
Vaccination history review
Screen for latent infections before starting (TB, HBV, CMV serology)
Monitor drug levels for CNIs (tacrolimus, cyclosporin)
Regular FBC, renal function, LFTs as per protocol
Patient education: avoid live vaccines, report any fever/infection promptly
Mechanism of Action
Corticosteroids enter cells and bind glucocorticoid receptors → translocate to nucleus → suppress NF-κB transcription factor → reduce production of IL-1, IL-2, IL-6, TNF-α, and multiple other pro-inflammatory cytokines. Also stabilise mast cells, reduce capillary permeability, and cause lymphocyte redistribution (not destruction).
Onset: Anti-inflammatory effects begin within hours. Full immunosuppressive effect takes days–weeks. Rapid onset makes them useful for acute crises.
Opportunistic infection risk increases rapidly with dose and duration
Side Effects — Long-Term (>3 months)
Bone & Musculoskeletal
Osteoporosis: bone density decreases rapidly in first 6 months
Bisphosphonate prophylaxis (alendronate 70mg weekly or risedronate 35mg weekly) for anyone on prednisolone ≥7.5mg/day for >3 months
Calcium 1000–1500mg/day + vitamin D 800 IU/day supplementation
Avascular necrosis (especially femoral head) — report new hip/groin pain
Proximal myopathy — assess muscle strength at each review
Adrenal Suppression
Suppression of HPA axis occurs with >3 weeks of any supraphysiological dose
Sick-day rules: double/triple steroid dose during illness, surgery, or stress
Medic alert bracelet recommended
Ophthalmological & GI
Posterior subcapsular cataract — annual ophthalmology review for patients on long-term steroids
Raised intraocular pressure / glaucoma risk
Peptic ulcer disease — PPI co-prescription (omeprazole 20mg OD) mandatory when on NSAIDs concomitantly; recommended for all high-dose prolonged courses
Cushingoid Features
Moon face, buffalo hump, central obesity, striae
Hirsutism, acne
These are cosmetically distressing — psychological support important
Infection — PCP Prophylaxis
PCP prophylaxis (co-trimoxazole) required when prednisolone ≥20mg/day for >1 month, or on combination immunosuppression. See Infection & Prophylaxis tab.
Nursing Monitoring Summary — Corticosteroids
Parameter
Frequency
Action Threshold
Blood glucose (BGL)
4-hourly during IV pulse; daily on high oral dose
>10 mmol/L → insulin protocol; notify prescriber
Blood pressure
Daily during acute therapy; each visit outpatient
>140/90 sustained → antihypertensive review
Electrolytes (K+)
Daily during IV pulse; weekly high-dose oral
K+ <3.5 → oral/IV replacement
Weight/fluid balance
Daily inpatient
>2kg gain in 24h → fluid restriction/diuretic review
Bone density (DEXA)
At baseline; annually if on long-term steroids
T-score <-2.5 → treat as osteoporosis
Mood/behaviour
Daily inpatient; each visit outpatient
Psychosis, severe agitation → psychiatric review
Tacrolimus (FK506)
Mechanism
Binds FKBP12 → inhibits calcineurin → prevents NFAT dephosphorylation → blocks IL-2 gene transcription → T-cell activation and proliferation inhibited. 10–100x more potent than cyclosporin.
Drug Level Monitoring
Phase
Trough Target
Early post-transplant (0–3 months)
8–12 ng/mL
Late post-transplant (>6 months)
5–8 ng/mL
Autoimmune / non-transplant
5–10 ng/mL (indication-dependent)
Sampling: Trough (12-hour post-dose for BD formulation; 24-hour for OD extended-release). Draw BEFORE morning dose. Consistent timing is critical.
Toxicity Profile
Nephrotoxicity — most important; acute (vasoconstriction) and chronic (interstitial fibrosis); monitor Cr/eGFR at every visit
Neurotoxicity — tremor, paraesthesia, headache, posterior reversible encephalopathy syndrome (PRES) at high levels
Azithromycin, clarithromycin, voriconazole, fluconazole, diltiazem, grapefruit juice
INCREASE ↑ (risk toxicity)
Dose reduction + increased level monitoring
CYP3A4 Inducers
Rifampicin, St John's Wort, carbamazepine, phenytoin
DECREASE ↓ (risk rejection)
Dose increase + increased level monitoring
Food interaction
Grapefruit / pomelo juice
INCREASE ↑
Counsel patient — absolutely avoid
Nephrotoxins
NSAIDs, aminoglycosides, amphotericin B
No level change but additive renal toxicity
Avoid concomitant use where possible
Do NOT switch between tacrolimus formulations (immediate-release vs extended-release) without pharmacist/physician review. Bioavailability differs; level can change significantly.
Cyclosporin (Ciclosporin)
Mechanism & Monitoring
Binds cyclophilin → inhibits calcineurin → same pathway as tacrolimus but less potent. Two monitoring approaches used in different centres:
Know which monitoring strategy your centre uses. Confirm with pharmacy/prescriber on admission.
Distinguishing Toxicities from Tacrolimus
Gingival hyperplasia — overgrowth of gum tissue; common in >30% patients; associated with poor dental hygiene; refer to dentist at 3 months
Hirsutism — increased body hair; cosmetically distressing, especially for female patients
Nephrotoxicity — same mechanism as tacrolimus; acute and chronic forms
Less diabetogenic than tacrolimus
More hypertensive than tacrolimus
Same CYP3A4 interactions as tacrolimus
mTOR Inhibitors — Sirolimus & Everolimus
Mechanism
Binds FKBP12 (same binding protein as tacrolimus) → inhibits mTOR complex 1 → blocks progression from G1 to S phase of cell cycle → prevents T & B cell proliferation in response to IL-2 (acts downstream of calcineurin). Does NOT block IL-2 production itself.
Long half-life (sirolimus ~62 hours) — takes 5–7 days to reach steady state after dose change
Toxicity Profile
Impaired wound healing — major surgical concern; typically avoid or minimise dose in first 3–6 months post-transplant surgery; always document on surgical handover
Pneumonitis — dyspnoea, dry cough, hypoxia; diagnose with HRCT (ground-glass); dose reduction or cessation required
Hyperlipidaemia — monitor fasting lipid profile; statin therapy often required
Mouth ulcers — aphthous-type; use topical steroid mouth rinse
Less nephrotoxic than calcineurin inhibitors
TMA Risk: Combining mTOR inhibitors with calcineurin inhibitors (especially tacrolimus) in the early post-transplant period increases risk of thrombotic microangiopathy (TMA). Most centres avoid this combination until >3 months post-transplant.
CNI vs mTOR — Side Effect Comparison
Side Effect
Tacrolimus
Cyclosporin
Sirolimus/Everolimus
Nephrotoxicity
High
High
Low
Diabetes (PTDM)
High (15–20%)
Moderate
Moderate
Hypertension
Moderate
High
Moderate
Neurotoxicity/Tremor
Significant
Mild
Rare
Gingival hyperplasia
No
Yes (30%+)
No
Hirsutism
No
Yes
No
Alopecia
Yes
No
No
Wound healing impairment
Minimal
Minimal
Significant
Hyperlipidaemia
Mild
Moderate
High
Pneumonitis
Rare
Rare
Yes (5–10%)
Mycophenolate Mofetil (MMF / CellCept)
Mechanism & Dosing
Prodrug → mycophenolic acid (MPA) → inhibits IMPDH (inosine monophosphate dehydrogenase) → blocks de novo purine synthesis. Lymphocytes rely almost exclusively on this pathway (unlike other cells that use salvage pathway) → relatively selective immunosuppression.
Standard dose: 1–1.5g twice daily (BD)
Mycophenolate sodium (Myfortic): 720mg BD (enteric-coated — may have fewer GI effects)
Take with food to reduce GI side effects
MPA level monitoring available but not routine in all centres
Side Effects & Nursing Considerations
GI side effects (most common): nausea, vomiting, diarrhoea, abdominal cramps — take with food, consider enteric-coated formulation
Leucopaenia / myelosuppression: monitor FBC — reduce or hold if WBC <3.0 or neutrophils <1.5
Teratogenicity: Category D — absolutely contraindicated in pregnancy; requires two forms of reliable contraception; counsel at every visit; check urine/serum HCG before starting; continue contraception for 6 weeks after stopping
CMV susceptibility: increased risk — CMV monitoring and prophylaxis protocol (see Tab 5)
Invasive fungal & opportunistic infections
Teratogenicity counselling is a nursing responsibility before MMF dispensing. Document the counselling in notes.
Azathioprine
Mechanism & TPMT Genotyping
Prodrug → 6-mercaptopurine → inhibits purine synthesis and DNA incorporation → lymphocyte suppression. Metabolised by thiopurine methyltransferase (TPMT).
TPMT testing MANDATORY before starting azathioprine. TPMT slow metabolisers (1 in 300 people) cannot metabolise the drug → toxic metabolite accumulation → severe, life-threatening myelosuppression. Intermediate metabolisers: start at 50% dose.
Standard dose: 1–2.5 mg/kg/day (once daily)
Check FBC at 2 weeks, 4 weeks, then monthly × 3 months, then 3-monthly
Also check LFTs at baseline and at monitoring intervals
Side Effects
Nausea, vomiting (take with food)
Hepatotoxicity — elevated LFTs; can cause cholestasis or veno-occlusive disease at high doses
Increased skin cancer risk with long-term use — sun protection education
Critical Drug Interaction
Allopurinol + Azathioprine = LIFE-THREATENING. Allopurinol inhibits xanthine oxidase → azathioprine cannot be metabolised → toxic accumulation. If allopurinol is essential, reduce azathioprine dose by 75% and monitor FBC very closely. Consider switching to MMF instead.
Methotrexate (MTX)
Mechanism & Dosing
Inhibits dihydrofolate reductase (DHFR) → blocks folate metabolism → impairs purine and pyrimidine synthesis → anti-proliferative and anti-inflammatory. Also has adenosine-mediated anti-inflammatory effects at low doses.
WEEKLY DOSING ONLY for immunosuppressive use. Multiple patient deaths have resulted from nurses or patients administering methotrexate daily (instead of weekly). The dose is written as mg per WEEK. Confirm dosing frequency at every administration.
Rheumatoid arthritis: 7.5–25mg once weekly
IBD (Crohn's): 25mg SC/IM once weekly (induction)
Psoriasis: 5–25mg once weekly
Routes: oral, SC injection, IM injection, IV (oncology doses different)
Folic Acid Supplementation
Folic acid 5mg should be taken the day AFTER methotrexate (not the same day — may reduce efficacy). Reduces nausea, mucositis, and hepatotoxicity. Some centres use 1mg daily on non-MTX days. Always check local protocol.
Side Effects
Hepatotoxicity: cumulative dose-dependent; liver biopsy or FibroScan considered at cumulative dose ≥1.5g; avoid alcohol; check LFTs monthly
Pulmonary toxicity (MTX pneumonitis): hypersensitivity pneumonitis; onset anytime; present with cough, dyspnoea, fever; must withhold MTX and seek urgent respiratory review
Myelosuppression: FBC monitoring monthly
Mucositis/stomatitis
Teratogenicity: Category X — contraindicated in pregnancy; stop 3 months before conception; adequate contraception mandatory
Infliximab: IV infusion every 8 weeks (after loading doses); infusion reactions common (see below)
Adalimumab: SC injection every 2 weeks; patient self-injects at home
Biosimilars widely available — counsel patients that biosimilars are equivalent
TB screening MANDATORY before starting anti-TNF: IGRA (QuantiFERON) + CXR. If latent TB detected: treat with isoniazid 6–9 months (or rifampicin 4 months) BEFORE starting anti-TNF. TNF is critical for granuloma maintenance — reactivation risk is high.
Infusion reactions (infliximab): flushing, chest tightness, hypotension — have resuscitation equipment available; observe patient for 30 min post-infusion
Anti-drug antibody formation → loss of efficacy → drug level monitoring available
Rituximab (Anti-CD20)
Chimeric monoclonal antibody targeting CD20 on B cells → B-cell depletion
Used in: RA (second-line), ANCA vasculitis, SLE, haematological malignancies, transplant desensitisation
IV infusion: typically 1g × 2 doses (2 weeks apart) — given every 6–12 months
Pre-medicate with methylprednisolone, antihistamine, paracetamol to reduce infusion reactions
Progressive Multifocal Leucoencephalopathy (PML): JC virus reactivation → demyelination → high mortality. Rare but devastating. New neurological symptoms in any patient on rituximab require urgent neurological assessment and MRI brain.
HBV reactivation: Screen all patients for HBsAg and anti-HBc before rituximab. If HBsAg positive or isolated anti-HBc positive: start antiviral prophylaxis (entecavir 0.5mg OD or tenofovir) and continue for 12+ months after last rituximab dose. Monitor HBV DNA.
Belimumab (Anti-BLyS) — SLE
Targets B lymphocyte stimulator (BLyS/BAFF) → reduces B-cell survival and differentiation
Specifically approved for SLE (not SLE nephritis in all regions) and lupus nephritis (belimumab IV)
IV infusion monthly or SC weekly self-injection
Screen for TB and HBV before starting (same as other biologics)
Depression and suicidality reported — neuropsychiatric screening at each visit
Infusion reactions less common than rituximab but monitor
PCP prophylaxis indicated when ANY of the following:
Prednisolone ≥20mg/day for >1 month
Solid organ transplant (all patients)
Haematological malignancy treatment
Combination of 2+ immunosuppressants
CD4 count <200 cells/µL (HIV)
Prophylaxis Regimens
Agent
Dose
Indication
Co-trimoxazole (first-line)
480mg OD or 960mg three times weekly
All patients without sulpha allergy
Dapsone
100mg OD
Sulpha allergy; check G6PD first (haemolysis risk)
Atovaquone
750mg BD with food
Sulpha allergy + G6PD deficiency
Inhaled pentamidine
300mg monthly nebulised
Unable to tolerate oral agents; less effective
Antifungal Prophylaxis
Patient Group
Recommended Agent
Dose
Duration
Solid organ transplant (low-moderate risk)
Fluconazole
100–200mg OD
First 1–3 months post-transplant
High-dose steroids (>3 months)
Fluconazole or nystatin oral rinse (for candidiasis prevention only)
50–100mg OD
Duration of high-dose steroids
Haematological malignancy / HSCT
Posaconazole (preferred) or Voriconazole
Posaconazole 300mg OD; Voriconazole 200mg BD
During neutropaenia / intensive chemotherapy
Lung transplant
Voriconazole or inhaled amphotericin
Voriconazole 200mg BD
First 3–6 months
Azole–tacrolimus interaction: Voriconazole and fluconazole are potent CYP3A4 inhibitors — tacrolimus/cyclosporin levels will rise significantly. Dose reduction of CNI required (often 50–75%) when starting azoles. Check levels within 48–72 hours of starting antifungal.
Aciclovir 400mg BD (especially if prior HSV history)
VZV post-exposure prophylaxis in seronegative
Varicella-zoster immunoglobulin (VZIG) within 96h; then aciclovir prophylaxis
CMV Prophylaxis & Pre-emptive Therapy
CMV is a major opportunistic pathogen post-transplant. Risk stratified by donor/recipient serostatus:
D+/R- (highest risk): 3–6 months IV ganciclovir or oral valganciclovir prophylaxis
D+/R+ or D-/R+: 3 months prophylaxis or pre-emptive monitoring strategy
D-/R- (lowest risk): minimal prophylaxis; surveillance only
Monitoring: CMV pp65 antigen test or CMV PCR (DNA viral load). CMV PCR preferred — more sensitive. Frequency: weekly for 12 weeks post-transplant, then monthly to 6 months, then as clinically indicated.
Floaters, visual field loss, painless visual deterioration
Ophthalmology review; retinal examination
Vaccination in Immunosuppressed Patients
CONTRAINDICATED — LIVE VACCINES: Never administer live vaccines to immunosuppressed patients or household contacts (some vaccines). Live vaccine contraindication applies to moderate-to-severely immunosuppressed patients.
Vaccine
Type
Immunosuppressed?
Timing & Notes
MMR (measles/mumps/rubella)
Live attenuated
CONTRAINDICATED
Give before immunosuppression if possible; ≥3 months after stopping
Varicella (chickenpox)
Live attenuated
CONTRAINDICATED
Serology at baseline; if non-immune: vaccinate before IS starts
Yellow fever
Live attenuated
CONTRAINDICATED
Travel advice essential; avoid endemic regions or seek medical exemption certificate
BCG (tuberculosis)
Live attenuated
CONTRAINDICATED
Do not give on immunosuppression
Oral polio (OPV)
Live attenuated
CONTRAINDICATED
Use inactivated polio (IPV) instead
Influenza (flu) — injectable
Inactivated
SAFE — RECOMMENDED
Annual; may have reduced immunogenicity; give regardless
Pneumococcal (PCV13 + PPV23)
Inactivated
SAFE — RECOMMENDED
PCV13 first, then PPV23 8 weeks later; repeat PPV23 every 5 years
Meningococcal (MenACWY)
Inactivated
SAFE — RECOMMENDED
Especially if on anti-complement therapy (eculizumab) or asplenic
Hepatitis B
Recombinant
SAFE — RECOMMENDED
3-dose series; check anti-HBs titre 4–8 weeks after last dose; may need booster or accelerated schedule
Hepatitis A
Inactivated
SAFE
Recommended for travel and certain high-risk groups
COVID-19 (mRNA/non-replicating viral vector)
Non-live
SAFE — RECOMMENDED
Primary series + boosters; may have reduced response; timing around rituximab important
Herpes zoster (Shingrix — recombinant)
Recombinant subunit
SAFE — RECOMMENDED
2-dose series; recommended in immunosuppressed ≥18 years
Optimal timing principle: Vaccinate BEFORE starting immunosuppression whenever possible. If not possible, inactivated vaccines can be given during immunosuppression (response may be suboptimal). For patients being considered for rituximab: ideally vaccinate at least 4 weeks before rituximab; or wait 6 months after rituximab for B-cell recovery before vaccinating.
GCC-Specific Considerations
TB in the GCC — High Priority
TB prevalence is significantly elevated in the GCC due to large South Asian and Southeast Asian expat worker populations from high-burden countries (India, Pakistan, Bangladesh, Philippines). TB reactivation on immunosuppression is a major clinical risk.
Mandatory TB screening before biologics and CNIs:
IGRA (QuantiFERON-TB Gold or T-SPOT.TB) — preferred over tuberculin skin test (TST/Mantoux) in immunosuppressed patients as TST has higher false-negative rate
CXR in all patients
CT thorax if CXR abnormal or high suspicion
Latent TB treatment before immunosuppression:
Isoniazid 300mg OD × 6–9 months (most common)
Rifampicin 600mg OD × 4 months (shorter, less hepatotoxic)
Isoniazid + rifampicin × 3 months (3HR)
Ideally complete at least 1 month of treatment before starting anti-TNF
Monitor LFTs during isoniazid therapy (hepatotoxicity risk)
HBV Reactivation — GCC Context
HBsAg prevalence in the GCC ranges from 1–3% in nationals and higher in certain expat populations. HBV reactivation on rituximab (and other B-cell depleting or high-dose immunosuppression) is potentially fatal if not anticipated.
HBV screening before rituximab (and high-dose immunosuppression):
HBsAg, Anti-HBc (total), Anti-HBs
If HBsAg positive: start entecavir 0.5mg OD or tenofovir (TDF/TAF) before rituximab; continue for 12 months after last rituximab dose
If Anti-HBc positive only (resolved HBV): prophylax with entecavir or monitor HBV DNA monthly — most guidelines favour prophylaxis for rituximab
Living related donors in GCC: extended family considerations for CMV counselling
Drug Access & Biological Considerations in GCC
Biologic Drug Access
Biologics are expensive in the GCC — typically require prior approval from hospital pharmacy committees or health insurance
Biosimilars increasingly available and approved in GCC countries (Saudi FDA, Dubai Health Authority, MOH UAE) — bioequivalent to originator; nurses should counsel patients that biosimilars are equivalent
Cold chain storage critical — biologics (infliximab, adalimumab) require refrigeration; document temperature log on receipt
Importation delays can disrupt treatment continuity — flag shortages early
Halal and Religious Considerations
Mycophenolate capsule gelatin: Original MMF (CellCept) capsules contain porcine gelatin. Some Muslim patients may have concerns. Alternatives:
— Mycophenolate mofetil tablets (non-gelatin) are available and bioequivalent
— Mycophenolate sodium (Myfortic) enteric-coated tablets — no porcine gelatin
Nurses should be aware and facilitate access to halal-compatible formulations. Islamic jurisprudence in most GCC countries permits use of the original capsule if no alternative is available (medical necessity), but patient preference should be respected.
Ramadan and Immunosuppression
Ramadan fasting is observed by Muslim patients across the GCC. Many patients wish to fast. While medically challenging, it can often be accommodated with careful planning.
Tacrolimus During Ramadan
Extended-release (once-daily) tacrolimus: take at iftar (sunset meal) — maintains once-daily dosing interval
Twice-daily tacrolimus: divide dose at iftar and suhoor (pre-dawn meal) — maintains 12-hour interval; typically clinically stable
Check trough levels 1–2 weeks into Ramadan — dietary changes and altered gastric motility can affect absorption
Advise patient to take same time relative to meals as pre-Ramadan
Cyclosporin During Ramadan
Similar approach — twice-daily dosing at iftar and suhoor
Grapefruit and pomelo commonly consumed at iftar — reinforce avoidance (CYP3A4 inhibitor)
Dehydration risk from fasting + CNI nephrotoxicity — monitor renal function
Advise adequate fluid intake at iftar and suhoor
General Ramadan Principles
Corticosteroids: if once-daily, take at iftar; if BD, split at iftar and suhoor
IV medications (infliximab infusion) — permissible during fasting in most Islamic scholarship (IV nutrition/medication does not break fast)
Engage with hospital imam/chaplain for complex cases
Immunosuppression Infection Risk Calculator
Select all current immunosuppressants to calculate composite infection risk and recommended prophylaxis.
Corticosteroid dose
Calcineurin inhibitor
Antimetabolite
Biologic agent
Duration of immunosuppression
CD4 count known?
TB Screening Requirement Checker
Select the planned immunosuppressive therapy to determine TB screening and latent TB treatment requirements.
Planned immunosuppression type
Patient origin / high TB burden background?
Prior TB history?
Practice MCQs — Immunosuppression Nursing (10 Questions)
0/0
Score — attempt questions below
1. A patient on prednisolone 40mg/day for 6 weeks is admitted with confusion, hypotension and hypoglycaemia after abruptly stopping their steroids at home. What is the most likely diagnosis?
2. A transplant patient starts voriconazole for a pulmonary Aspergillus infection. Their tacrolimus trough was 7 ng/mL yesterday. What do you anticipate?
3. A patient with rheumatoid arthritis is being started on azathioprine. Before the first dose, which genetic test is essential?
4. A nurse administers methotrexate 15mg daily for 3 consecutive days, believing it to be a once-daily medication. The patient develops severe myelosuppression. What error occurred?
5. A patient on high-dose MMF and tacrolimus post-kidney transplant presents with a 3-day history of low-grade fever, dry cough, and progressive dyspnoea. What opportunistic infection should be a top priority to exclude?
6. A GCC nurse is caring for a Pakistani expat worker about to start adalimumab for Crohn's disease. What investigation is mandatory before starting the biologic?
7. A patient on long-term corticosteroids asks about receiving the live herpes zoster (Zostavax) vaccine for shingles prevention. What is the correct advice?
8. A Muslim patient on twice-daily tacrolimus wishes to fast during Ramadan. What is the most appropriate counselling regarding tacrolimus timing?
9. A patient on rituximab therapy develops new-onset confusion, ataxia, and progressive weakness over 3 weeks. MRI brain shows non-enhancing white matter lesions. What serious complication must be considered?
10. Which of the following correctly describes the rationale for combination immunosuppression (e.g., tacrolimus + MMF + prednisolone) rather than using a single agent at high dose?