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The Breakthrough in the Treatment of NSAID-refractory Ankylosing Spondylitis by the John Darmawan Protocol (JDP).

Remission under intravenous and oral therapy is achieved after 2-4 months since initiation of the JDP

Remission sustained by oral drugs is achieved after 5.5-7.5 months since initiation of the JDP

Remission without drug is obtained after 3.5-4.5 years since initiation of the JDP

Ankylosing Spondylitis (AS) is a long-term chronic and progressive disease with mainly involvement of the axial joint. NSAID-refractory AS is defined when failure of at least two non-steroidal anti-inflammatory drugs (NSAIDs) during a single three month treatment period.

The JDP is a Step-down Bridge Protocol of Intravenous and Oral Combination of 6 Immunosuppressants. The JDP is applied when: a diagnosis of NSAID-refractory AS is established; Bath AS Disease Activity Index (BASDAI) of at least 4 over a period of at least 4 weeks; ESR > 40 mm per hour Westergren; CRP > 3 mg%.

The principle of the JDP is to induce Remission in the shortest possible period of time, before Bath AS Radiological Index (BASRI) 2 Or more. By intensive daily administration of intravenous combination of 4 Immunosuppressants Remission is achieved. The 4 intravenous Immunosuppressants comprise Cyclophosphamide, 5-Flurouracil, Methylprednisolone, and Methotrexate.

Remission under intravenous and oral therapy is acquired after 2-4 months since initiation of the JDP. The Remission achieved is sustained by oral combination of 2-3 Immunosuppressants, while the intravenous therapy is tapered off after 5.5-7.5 months since initiation of treatment. This is called Remission with oral Drugs. The oral therapy is initiated together with the intravenous therapy for initial loading. The oral therapy will attain a serum level effective in maintaining ESR of less 20 mm per hour when the intravenous therapy is tapered off.

The oral therapy consists of Mycophenolate Mofetil and Methotrexate/Cyclosporine and must be continued for at least 2 years. After 2 years in Remission, the oral drugs are tapered off over a period of 1 year. If no flare occurs after oral drugs are tapered off then Remission without Drug is achieved in NSAID-refractory AS after 3.5-4.5 years since initiation of the JDP.

Flare is defined when the arthritis re-appears in 1 Or more joints, the ESR becomes abnormal (more than 25 mm per hour), and BASDAI becomes more than 1. Early (within 1 week) Flare of NSAID-refractory AS must be immediately suppressed by reinstitution of the JDP to maintain short, medium, and long-term Remission.

To induce Remission under intravenous and oral therapy, the JDP must be administered daily 5 X weekly until ESR drops to less than 40 mm per hour. This is to avoid weekly cumulative dose induced adverse effects.

After ESR dropped to less than 40, 30, and 25 mm/hour (men < 30, < 20, and < 15 mm), the IV sessions are tapered to 3X, 2X, and 1X weekly respectively. When ESR is < 20 (women) or < 10 mm (men) disease is controlled. When disease is controlled, the IV session is tapered to once fortnightly (in conjunction with switching IV to once weekly oral equivalent dosage of Methotrexate), 4-weekly, 8-weekly and then terminated to Remission with oral Drugs.

The variable schedules in achieving various types of Remisions

1. Induction of Remission over 1-2 months after initiation by the JDP
2. Reduction of weekly IV sessions over 1-2 months
3. Remission achieved after 2-4 months
4. Tapering off intravenous sessions after 3.5 - 5.5 months since initiation of the JDP
5. Remission with oral Drugs after 5.5-7.5 months since initiation of the JDp
6. Consolidation of Remission with oral Drugs over 2 years
7. One year taperinf off oral drugs
8. Remission without Drug achieved after 3.5 - 4.5 years including Radiological
   Remission since initiation of the JDP.

Remission without drug is not a cure for NSAID-refractory AS. Flare can be induced by mental and physical stress, and a viral infection.

The adverse effects of the 6 Immunosuppressants are listed in a leaflet in the drug package. Neupogen, Recormon, and combination of Epineprine+Methylprednisolone can overcome blood toxicities in a relative short period of time. Gastrointestinal toxicities such as anorexia, nausea, vomiting, diarrhea, including allergy can be treated and prevented by Kytril, spasmolytics, and anti-allergics.

The dreaded blood toxicities of low white blood cell, red cell, and thrombocytes count are avoided by daily intravenous low dosages of the immunosuppressants and low total frequency of administration, limited weekly and total cumulative dosages, and limited period of exposure.

Total Immunosuppressant-naivety is defined when the patient has never been treated with Cyclophosphamide, 5-Flurorouracil, Methylprednisolone, Methotrexate, and Mycophenolate Mofetil, and Cyclosporine. Partial Immunosuppressant-naivety is defined when the patient has been treated with several of the 6 Immunosuppressants. Total Immunosuppressant non-naivety is defined when the patient has been treated previously with all the 6 Immunosuppressants for example when a flare occurs. These naivety and non-naivety have implication for the outcome of NSAID-refractory AS by the JDP.

Cyclophosphamide, 5-Fluorouracil, and Methylprednisolone are not given by oral route because of:

Intravenous	versus	Oral administration
Faster efficacy Maximum efficacy Effect lasts longer Minimum adverse effects		Slower efficacy Minimum efficacy Effect last shorter Maximum adverse effects

Hematological adverse effects are very rarely encountered, but mild gastrointestinal ones oocur in 25% of the patients treated with the JDP. These can be easily overcome Or prevented.
 

 

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