Intra Articular (I/A) Methotrexate in Rheumatoid Arthritis

Mohammad Amjad Taqweem, Hamzullah Khan, Amera Takreem, Intekhab Alam
Medical B Unit, Department of Medicine, Post-Graduate Medical Institute, Lady Reading Hospital, Peshawar

Correspondence:
DR Hamzullah Khan
MBBS, MPH PG Student, Institute of Computer and Management Sciences, Hayatabad, Peshawar
Senior House Officer: Medical B Unit, Department of General Medicine, Postgraduate Medical Institute,Government Lady Reading Hospital Peshawar, Pakistan
Associate Editor Journal Postgraduate Medical Institute, JPMI
Government Lady Reading Hospital Peshawar, Pakistan.
Phone Number: 0092-345-9283415
Email: hamzakmc@gmail.com
Mailing Address:
Room No-10, House Job Doctor Hostel, Lady Reading Hospital (PGMI/LRH), Peshawar, Pakistan

INTRODUCTION

Based on visual observation, the ancients characterized inflammation by five cardinal signs, namely redness (rubor), swelling (tumour), heat (calor; only applicable to the body's extremities), pain (dolor) and loss of function (functio laesa). The first four of these signs were named by Celsus in ancient Rome (30-38 B.C.) and the last by Galen (A.D 130-200).

More recently, inflammation was described as "the succession of changes which occurs in a living tissue when it is injured, provided that the injury is not of such a degree as to at once destroy its structure and vitality" , or "the reaction to injury of the living microcirculation and related tissues 1. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder that causes the immune system to attack the joints, where it causes inflammation (arthritis) and destruction. It can also damage some organs, such as the lungs and skin. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility. It is diagnosed with blood tests (especially a test called rheumatoid factor) and X-rays2. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in the diseases of joints and connective tissues3.

Various treatments are available. Non-pharmacological treatment includes physical therapy and occupational therapy. Analgesia (painkillers) and anti-inflammatory drugs, as well as steroids, are used to suppress the symptoms, while disease-modifying anti-rheumatic drugs (DMARDs) are often required to reverse the disease process and prevent long-term damage. In recent times, the newer group of biologics has increased treatment options3. I/A steroid injections are commonly used for acute painful joints. A meta-analysis supports the recommendations of American and international authorities that I/A injection of corticosteroids provides short-term relief of the pain. I/A corticosteroids result in a clinically and statistically significant reduction in knee pain 1 week after injection that continues for 3 to 4 weeks4, 5. Cortisone therapy has offered relief in the past, but its long-term effects have been deemed undesirable6. However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment. Still there are some cases that are resistant to intra-articular steroids and international data has recently shown that Methotrexate has been tried intra-articularly and has shown its effectiveness as reported in various trials 7-10.

The present study was a continuation of the recently conducted trial to see the effectiveness of I/A Methotrexate.

METHODS

A total of 40 rheumatoid arthritis patients who were resistant to I/A steroids were included in the study. Twenty eight patients completed twice follow up one for re injection and other for response analysis. Eighteen (64.3%) were females and 10 (35.7%) males. The age range was from 40 to 50 years with mean age of 45.9643 +3.21 SD years. Proper informed consent was taken from all the respondents.

Inclusion criteria were all rheumatoid arthritis patients with single knee joint involvement, not responding to I/A steroids. While exclusion criteria were all patients with septic joints, sepsis around the joint, I/A steroids within last three months and bleeding disorders. After proper selection of patients, at first visit 12.5 mg intra-articular Methotrexate with lignocaine was injected with aseptic technique. Twenty eight patients completed follow up and again 12.5 mg I/A Methotrexate was given. Combination with lignocaine was aimed to increase the volume of the drug to cover more joint space. Twenty eight patients completed follow up and again 12.5 mg I/A Methotrexate alone was given. Clinical improvement was assessed with parameters of pain, swelling, flexion and ESR. Visual analogue scale was used for pain analysis. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. For example, the amount of pain that a patient feels ranges across a continuum from none to an extreme amount of pain. It asks the patient how severe is your pain right now, as shown in the Figure 1.

Figure 1

No pain agonizing pain¹¹.
Swelling and joint flexion was clinically assessed and swelling was also weighted on VAS. ESR was done in all visits and compared. Both readings were noted on a specially designed proforma prepared in accordance with the objective of the study.
Furthermore our trial was in accordance with CONSORT (consolidated standard of reporting trials) trial guidelines and its flow chart was as follows:

Flow chart of the trial based on CONSORT trial guidelines¹²:

Finally data collected was entered in SPSS¹¹ version and was analyzed in frequency, median mode statistics for age and sex parameters and cross tabulation analysis was done for pain, swelling, flexion and ESR.

RESULTS

A total of 28 patients completed two follow up visits, one for re-injection and the other for response analysis. Eighteen were females and 10 males (Table 1). The age range was from 40 to 50 years with mean age of 45.96 +3.21 SD years (Table 2). Visual analogue scale (VAS) analysis was used to see the response along with clinical examination and ESR. No response was received from 11 patients, (6 females and 5 males) with VAS 10/10 for pain and swelling, flexion up to 30 degree and ESR>60mm/hr. Partial response was recorded in 11 patients (7 females and 4 males), with VAS 5-10/10 for pain and swelling, flexion 30-90 degree and ESR 41-60mm/hr. Good response (VAS 0-4 /10 for pain and swelling) was noted in 6 patients with flexion >90 degree and ESR 20-40mm/hr. Flexion, swelling and sex cross tabulation clinically elicited response analysis of patients is shown in Table 3. Reduction in ESR improvement in pain that was orally explained by patient and recorded in terms of percentage improvement is shown in Table 4.

Table 1 Sex wise distribution of patients

Table 2 Age Statistics of patients

Table 3 Flexion, swelling and sex cross tabulation clinically elicited response analysis of patients

Table 4 ESR 'Pain' Sex -Cross Tabulation response analysis

DISCUSSION

There is no cure for rheumatoid arthritis. Treatment for rheumatoid arthritis aims to reduce inflammation in joints in order to relieve pain and prevent or slow joint damage. Clinical results from trials conducted on I/A Methotrexate support the hypothesis that Methotrexate may be used intra-articularly as an immuno-suppressor rather than at the heavily toxic doses required for a cytostatic effect. Furthermore repeated intra-articular injections of MTX results in a decrease of local as well as systemic inflammatory signs in RA 8,13. Intra articular MTX therapy results in a strong decrease of SF-granulocyte counts. This effect may be due to the impairment of IL-8 mediated chemotaxis by decreased IL-8 synthesis in synovial fluid mononuclear cells 14. Our patients received two injections in a dose of 12.5mg of MTX one month apart but still the response was satisfactory. In another study patients with definite RA and knee effusions under constant doses of DMARD therapy were treated with up to 6 intra-articular injections of 10 mg Methotrexate (MTX) every 3 to 7 days14. Iagnocco A, et al9 treated his patients with intra-articular injections of MTX 10 mg every 7 days for 8 weeks. Hence with a disciplined dosage and proper follow up a much better response can be achieved. But as it was the first ever attempt here it was not properly arranged. In the present study visual analogue scale (VAS) analysis was used to see the response along with clinical examination and ESR. Iagnocco A, et al9 also assessed the response of MTX I/A therapy through clinical evaluation measuring maximal knee flexion angle, visual analog scale (VAS) and erythrocyte sedimentation rate (ESR).

Ultrasonographic examination of the involved knee was performed to see synovial thickness in the suprapatellar bursa and the presence of joint effusion and Baker's cyst. We observed that no response was received from 11 patients (6 females and 5 males) with VAS 10/10 for pain and swelling, flexion up to 30 degree and ESR>60mm/hr. Partial response was recorded in 11 patients (7 females and 4 males), with VAS 5-10/10 for pain and swelling, flexion 30-50 degree and ESR 41-60mm/hr. Good response (VAS 0-4 /10 for pain and swelling) was noted in 6 patients with flexion >50 degree and ESR 20-40mm/hr. Iagnocco A et al9 also concluded that repeated intra-articular injections of MTX resulted in a decrease of local as well as systemic inflammatory signs. But Gao IK et al14 reported that repeated intra articular MTX therapy results in a worse 13 week outcome than I/A. steroid treatment measured in an intention-to-treat analysis. As far as we know, this is the first study reported from NWFP that explores the effects of intra-articular MTX in RA clinically.

Further studies are encouraged to prove effects of intra-articular MTX in RA by ultrasonograhy of joints. Our study has reported 28 cases with I/A MTX which are far greater than many trials that that have reported on IA Methotrexate around the world 8, 9, 10, 14 etc.

CONCLUSION

Our study response rate was 6/28 (21.42%) which is encouraging; besides our patients received only two injections I/A MTX and this was much better than as reported in a very few studies from abroad.

It is the first ever study on I/A Methotrexate from NWFP and probably from Pakistan as we have searched on pubmed, pakmedinet, and Google search. Furthermore we reported moreof cases than have so far been published in literature.

1. Punchard NA, Whelan CJ, Adcock I. The Journal of Inflammation (Editorial). Journal of Inflammation 2004, 1:1.
   
2. Majithia V, Geraci SA. "Rheumatoid arthritis: diagnosis and management". Am. J. Med. 2007;120 (11): 936-9.
   
3. Landré-Beauvais AJ. "The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800". Joint Bone Spine 2001; 68 (2): 130-43. PMID 11324929.
   
4. Balch HW, Gibson JM, El-Ghobarey AF, Bain LS, Lynvh MP. Repeated corticosteroid injections into knee joints. Rheumatol Rehabil 1977; 16(3): 137-40.
   
5. Raynauld JP, Buckland-Wright C, Wald R, Choquette D, Haraoui B, Martel-Pelletier J, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee. A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2003;48:370-7.
   
6. O'Dell J (). "Therapeutic strategies for rheumatoid arthritis". N Engl J Med 2004; 350 (25): 2591-602.
   
7. Hall GH, Jones BJ, Head AC, Jones VE. I/A methotrexate. Clinical and laboratory study in rheumatoid and psoriatic arthritis. Ann Rheum Dis. 1978; 37(4): 351-6.
   
8. Hasso N, Maddison PJ, Breslin A. I/A methotrexate in knee synovitis. Rheumatology 2004; 43: 779-782
   
9. Iagnocco A, Cerioni A, Coari G, Ossandon A, Masciangelo R, Valesini GI/A methotrexate in the treatment of rheumatoid arthritis and psoriatic arthritis: a clinical and sonographic study. Clin Rheumatol. 2006; 25(2): 159-63
   
10. Blyth T, Stirling A, Coote J, Land D, Hunter JA. injection of the rheumatoid knee: does I/A methotrexate or rifampicin add to the benefits of triamcinolone hexacetonide? Br J Rheumatol. 1998; 37(7): 770-2.
    
11. Wewers M.E. & Lowe N.K. A critical review of visual analogue scales in the measurement of clinical phenomena. Research in Nursing and Health 1990;13: 227-236.
    
12. Rennie D. How to report a clinical trial, the consort statement. Journals of American medical association, 1996; 276:649.
    
13. Franchi F, Seminara P, Codacci-Pisanelli G, Aronne T, Avella A, Bonomo LIntrarticular methotrexate in the therapy of rheumatoid arthritis. Recenti Prog Med. 1989 ;80(5):261-2.
    
14. Gao IK, Leins C, Bohlen H, Heilig B, Lemmel EM.Inhibition of interleukin-8 synthesis by intraarticular methotrexate therapy in patients with rheumatoid arthritis. Z Rheumatol. 1998 ; 57(2):95-100