METHOTREXATE

• FOLIC ACID ANALOGUE
• ANTI-INFLAMMATORY
• ANTI-METABOLITE
• IMMUNO-MODULATOR
• ?a ADENOSINELEVELS
  - INHIBITS NEUTRO-ADHERENCE
• INHIBITS PROLIFERATION OF
  SYNOVIAL CELLS
• INHIBITS CMI

INHIBITS ENZYMES

• DIHYDROFOLATE REDUCTASE
• 5. AMINOIMIDAZOLE – 4 – CARBOXANIDE RIBO NUCLEOTIDE TRANSFORMYLASE
• THYMIDYLATE SYNTHETASE
• ADENOSINE DEAMINASE

KINETICS

• 50-70% Abs – ORAL Admn
• PLASMA HALF LIFE – 2 Hrs
• TRIPHASIC PHARMACOKINETICS
  - BLOOD LEVELS ASSAY
  - LATENT PERIOD OF WEEKS
  - PROBABLY TRUE ANTI-INFLAM
• 80% eliminated by kidneys within 8-48 Hrs.
• 11-57% Protein bound at low doses.
• Oral MTX abs. – saturable process, SC is not.

METHOTREXATE IN CHILDREN

• WHERE & WHEN TO USE
• HOW TO USE
• SAFETY ISSUES
• MONITORING
• HOW LONG TO USE
• WHEN TO DISCONTINUE

WHERE & WHEN

• JIA – POLYARTICULAR
  - EXTENDED PAUCI
  - SOJIA
  - ERA
  - JPsA
  
• JDMS “ Steroid non responsive
• SLE
• SARCOIDOSIS
• SCLERODERMA

HOW TO USE

• DOSE – 10-15 mg/kg/wk
  Or 0.3 – 0.6 mg/kg/wk (20-25 mg/m2/wk, 1.1 mg/kg/wk)
• ROUTE Oral – empty stomach
  - With clear liquids
  - Or 1 Hr before BF Parenteral – SC, IM, IV
• Availability – Tablets 2.5, 5, 7.3, 10 mg Inj 15 mg/ml

PARENTERAL MTX

• Patients with poor clinical response to oral MTX
• Need a dose in excess of 15 mg/m2/wk
• Develop significant GI Toxicity with oral MTX
• Is SC better than Oral ?
• Folic acid-to give or not ?
• Avoid in renal insufficiency.

SIDE EFFECTS

• GIT – Nausea, vomiting, ulceration, diarrhea
• Haematological – Bone marrow suppression cytopenia
• Hepatic – Raised enzymes (9%), Fibrosis?
• Alopecia, Dermatitis
• Renal
• Risk of infection
• Oncogenicity, Gonadal dysfunction, Nodulosis
• Teratogenicity

MONITORING
BASELINE –
Wt, Ht Surface Area
  - CBC, UA, LFT, KFT, S.protein
  - ESR, CRP
      Clinical – global assessment
        - No of Active joints / joints with limited ROM
         - Duration of morning stiffness
After Starting MTX – Initially Lab – every 2 wks x 3 mths.
then every 1-3 mths
Clinical 1-3 mth.

MONITORING

• DISCONTINUE / REDUCE> 3 TIMES UPPER N LIMIT
• FULL BLOOD COUNT       Platelets <150 x 109/L
        WBC <3.5 x 109xL
        Neutrophils <1.5x109L

* Rash/Severe oral ulcers/new or increasing dyspnoea or cough

DURATION / DISCONTINUATION

MTX-GIVE FOR 3-6 MONTHS
RESPONSE-CONTINUE
IF NO RESPONSE-I DOSE/

CHANGE ROUTE 3-6 MONTHS
IF STILL NO RESPONSE-CHANGE
No VALIDATED GUIDELINES FOR DURATION
- Clinical remission for 1 year
- Disease Flare in more than 50%

R M L H Experience

MTX TOTAL NO OF PATIENTS
ANALYSED 24+2
POLY JIA = 10,
SOJIA = 12
EXTENDED PAUCI = 2

-	POLY (n = 10)	SOJIA (n = 12)
AGE (yr)	5-12	3.5-10
DIS. DURATION (yr)	1-6 (3.25 ± 1.75	2-4.5 (3.3 ± 1.3)
DUR. MTX (WK)	60-208 (104 ± 64)	16-162 (86 ± 70)
ROUTE	ORAL / SC-2	ORAL
RESPONSE	-	-
COMPLETE	5	2
PARTIAL	3	6
NONE	2	3
SIDE EFFECTS	Nausea –2, Vom 2	Pn., boils
OTHER DRUGS	NSAID, SSZ	NSAID, STRD.

RCIAPCON 2005 - Conference Abstracts.Pediatric Oncall [serial online] 2006 [cited 15 June 2006(Supplement 6)];3. Available from:
http://www.pediatriconcall.com/fordoctor/Conference_abstracts/
METHOTREXATE_IN_CHILDREN.asp