Naushad Abid  ( Department of Medicine, Aga Khan University Hospital, Karachi )

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown etiology characterized by chronic inflammation in the synovial membranes of the affected joints resulting in joint deformities. It affects approximately 1% of US population. In a study on Pakistani patients, only 6 cases out of 4232 adults were identified with definite RA fulfilling the ACR (American College of Rheumatology) criteria.. The prevalence was 0.9 and 1.98 per thousand in the poor and affluent districts of Karachi respectively. These figures were substantially less than the prevalence rates obtained from the west indicating difficulty in applying ACR criteria to our patients.1

The disease has considerable economic impact not only because of health care cost but also because of considerable loss of person's productivity. In a study, it was shown that the most severe disease expression of RA has the greatest cost.2 The economic impact might be much higher in developing countries like Pakistan but we do not have enough data to validate.

The management of Rheumatoid arthritis has changed dramatically over the last few decades because of better understanding of pathogenesis, new disease modifying antirheumatic drugs and more recently the introduction of new biologic agents.
New Concepts into RA Pathogenesis

New Concepts into RA Pathogenesis

The pathologic hall mark of this inflammatory joint disease is synovial proliferation leading to joint destruction and deformities. The inciting antigen is not yet defined but it is believed that specific CD4+ T-cells are involved in the induction of immune response. There is subsequent recruitment of monocytes, macrophage, and fibroblasts in the synovium followed by the release of cytokines such as tumor necrosis factors alpha and interleukin. These cytokines trigger the productions of matrix metalloproteinases and osteoclasts, resulting in joint damage.3

Although RA is predominantly T cell mediated disease, B cells are also involved in the pathogenesis, as evident from beneficial effects of B cell depletion therapy in controlling RA activity.4 Tumor necrosis factor (TNF) alpha is a central cytokine involved in RA pathogenesis, participating in the early stages of the inflammatory cascades and also stimulating release of other inflammatory cytokines. It affects all aspects of RA and plays key role in joint destruction. TNF alpha also stimulates the synthesis of other proinflammatory cytokines and induces endothelial cells to express adhesion molecules that attracts leukocytes into affected joints.5

Role of Primary Care Physician - Early referral is the Key

Most patients in our set up are managed by primary care physicians who may not be experienced in the management or may be reluctant to use disease modifying antirheumatic drugs(DMARDs) because of the adverse effects. Several randomized control trials demonstrate that an early and aggressive approach to treatment is essential to control the disease activity and to prevent subsequent deformities. In a survey done in Europe it was found that most of the European Rheumatologists consider disease duration of three months or less as early RA, however most of these rheumatologists agree that majority of their patients are referred after six months.6 It has been confirmed by prospective studies that more the time lapsed between the onset of RA and initiation of proper management greater are the chances of erosive disease. Emery et al indicated that 60% of patients have erosive disease by one year.7 In a prospective study, patients whose treatment was started within 15 days of referral were compared with the patients whose treatment was delayed upto four months. It was concluded that in the early treatment group radiographic damage stopped progressing and in comparison the delayed group had significant joint damage, as assessed by various scoring system.8 Thus it is agreed that giving early treatment, as early as three months, with traditional DMARDs improves long term out come and functional ability and that's why early referral to a proper rheumatologist is essential. Patients should be referred to rheumatologist upon mere clinical suspicion of RA.7

Role of DMARDs - Monotherapy vs Combination

DMARDs in RA can be used in as a monotherapy or more recently as a combination therapy. Traditionally DMARDs that are in use are Methotrexate (MTX), sulfasalazine, hydroxyl chloroquine and more recently, Leflunomide . MTX has been found to be effective not only in western patients but in our patients as well.9 In a prospective study after two years follow up in Pakistani patients, it was found that MTX, despite its side effects in some patients is still an effective well tolerated and inexpensive disease modifying drug.10 Traditional practice was to start with one DMARD and if that was not effective then that DMARD was discontinued and another drug was started. However in last few years, concepts have changed and rheumatologists are more inclined towards the use of combination of DMARDs. Most studies suggested that combination therapy is more effective and less toxic than monotherapy.11,12 Corticosteroids have a controversial role in RA treatment. They have dramatic short term anti-inflammatory properties but may have adverse consequences when used for prolonged periods. Then can be used in early RA in combination with DMARDs but should not be used as the only treatment for RA.13

Biologial Agents in RA

Although DMARDS have proved to be effective, they have certain limitations. They have delayed onset of action, require close monitoring because of multiple toxicities and high recurrence rate after drug with drawl. In a study, 50% of patients taking MTX discontinued it, because of ineffectiveness or toxicity.14

Because of associated limitations with DMARDs and better understanding of pathogenesis and cytokine mechanism in RA pathogenesis, biological agents have emerged. These biological agents have changed the therapeutic standards of RA because of their action on underlying disease activity.

Tumor necrosis factor alpha is a key cytokine that has been found in high concentration in the synovium of RA patients and is targeted by anti TNF blocking drugs. Currently three TNF blocking drugs, etanercept, infliximab, and adalimumab, are available for clinical use. Etanercept, a soluble TNF -receptor fusion protein, is composed of two dimers. This fusion protein binds to TNF alpha preventing them from interacting with its respective receptors. In a randomized trial, 10 mg and 25 mg of Etanercept administered subcutaneously and placebo were compared. Both doses of etanercept appeared to be effective and the response rate was more in patients who were given 25 mg dose.15 As MTX has been considered standard in RA management, so all new DMARDs have to be compared with it. A randomized study on 632 patients with early RA compared 10 or 25 mg of etanercept twice weekly with methotrexate. Patients who received the higher dose of etanercept had a more rapid response within the first two week but after 12 months responses rate were similar.16 Patients with an inadequate response to MTX receive benefit when Etanercept is added rather than placebo.17 Infliximab is a chimeric IgG1 anti TNF antibody containing the antigen binding region of the mouse antibody. It binds to TNF alpha impairing its binding to receptors. Studies have proved that monotherapy with infliximab (at a dose of 3 or 10 mg/ kg) was superior to placebo, but the development of anti ifliiximab antibodies led to its use in combination with MTX rather than as a monotherapy.18 All regimens of infliximab plus MTX were more effective than MTX plus placebo in preventing disease progression.19 Adalimumab is recombinant human IgG1 antibody that binds to human TNF with high affinity. In a double blind randomized trial, response rates for 40 mg of adalimumab administered weekly was similar to the rate for same dose administered every other week and significantly higher when compared with placebo.20 Adalimumab has additive effects when used with MTX.21

Various studies have revealed that anti TNF antagonist are not free from side effects. Anti TNF antagonist have been associated with a wide variety of infections including tuberculosis, aspergillosis, etc. The rate of TB among patients with RA who had been treated with infliximab was 24.4 cases per 100,000.22 Lymphoma has also been reported in association with these agents23 but any direct relationship remains unclear.24 An illness similar to multiple sclerosis has also been reported.25 Anakinra, interleukin1 receptor antagonist, is also in clinical use. Interleukin1 is a cytokine produced by monocytes, macrophage, and has inflammatory effects.26 The actions of interleukin are antagonized by anakirina as evident from animal studies.27,28 Anakinra alone as well as in combination with MTX has been found more effective than placebo and it slows the radiologic progression too.29

Treatment for RA continues to advance rapidly. Recently B cell depletion therapy with rituximab (monoclonal antibodies directed against CD20) has shown to be effective in patients with RA not responding well to MTX alone.30

Rheumatoid Arthritis from Pakistan's Perspective

The prevalence of RA in Pakistan is not known because of improper database system in most of the hospitals. Absence of proper health care set up and referral system, most of the patients remain with primary care physicians who may be inexperienced to deal with this condition. It is necessary that primary care physicians should attend continuing medical education (CME) sessions and guidelines should be formed for early referral to a trained Rheumatologist. We have very few trained rheumatologists in our country, therefore postgraduate training in rheumatology will increase well trained rheumatologists in sufficient number to meet the demand. This might play a significant role in improving functional ability and quality of life for RA patients. The new biologic agents are in use in the west since more than ten years and none of them is yet available in our country. Few of our patients have been able to arrange it from abroad at a very high cost. This is high time that our Pharmaceutical industry should come forward and make every possible effort to make these agents available in Pakistan at affordable prices.

1. Hameed K, Gibson G, Kadir M. The prevalence of rheumatoid arthritis in affluent and poor urban communities of Pakistan. Br J Rheumatol 1995; 34:252-6.

2. Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction in long term disability in patients with rheumatoid arthritis by disease modifying antirheumatic drug based treatment strategies. Arthritis Rheum 1996; 39:616-22.

3. Okada Y. Proteinases and matrix degradation. In: Rudy S, Harris ED, Sledge CB , EDS. Kelleys text book of rheumatology. 6th ed. Philadelphia: W. B. Saunders, 2001, pp. 55-72.

4. Bukahri M, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register study, a large inception cohort. Arthritis Rheum 2002;46:906-12.

5. Choy EHS, Panayi GS. Cytokine pathway and joint inflammation in rheumatoid arthritis. N Eng J Med 2001;344:164-9.

6. Aletaha D, Ebert G, Nell VPK, Machold KP, Smolen JS. Practical Progress in realisation of early diagnosis and treatment of patients with suspected rheumatoid arthritis: results from two matched questionnaires within three years. Ann Rheum Dis 2002;61:630-4.

7. Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS, et al. Early referral recommendations for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002;61:290-7.

8. Lard LR, Visser H, Speyer I, Vander Horst Bruinsma IE, Zwinderman AH, Breedveld F, et al. Early versus delayed treatment in patients with recent onset rheumatoid arthritis: comparision of two cohorts who received different treatment strategies. Am J Med 2001;111:446-51.

9. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173-7.

10. Ali AA, Iqbal MP, Hussain MA, Mehboodali N, Beg JA, Rahbar MH, et al. Methotrexate in rheumatoid arthritis: a 2 year experience at a university hospital in Pakistan . J Pak Med Assoc 1998;48:3-6.

11. Boers M, Verhoeven AC, Markusse HM, Vander Laar MA, Westhovens R, van Derderen JC, et al. Randomised comparision of combined step down prednisolone, methotrexate and sulfasalazine with sulfasalazine alone in early rheumatoid arthritis . Lancet 1997;350:309-18.

12. O'Dell JR , Haire CE , Erikson N, Drymalski W, Palmer W, Eckhoff PJ, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxy chloroquine or a combination of all three medications . N Eng Med 1996;334:1287-91.

13. Wilder RL. Corticosteroids .In: Klippel JH, Crofford LI, Stone JH Primer on rheumatic diseases. 12th ed. Atlanta: the Arthritis foundation, 2001, pp. 593-8.

14. Alateha D, Smolen JS. Effectiveness profiles and dose dependent retentition of traditional disease modifying antirheumatic drugs for rheumatoid arthritis: an observational study. J Rheumatol 2002;29:631-8.

15. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM.Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p-75)-Fc fusion protein. N Eng J Med 1997;337:141-7.

16. Bathon JM, Martin RW, Fleischmann RM, Terser JR, Schiff MH, Keystone EC. A comparision of etanercept and methotrexate in patients with early rheumatoid arthritis. N Eng J Med. 2001;344:6.

17. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receotor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Eng J Med 1999;340:253-9.

18. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlani JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti - tumor necrosis factor alpha monoclonal antibody combined with low dose methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.

19. Lipsky PE, van der Heijde DMFM, St Clair EW, Furst DE, Brudveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Eng J Med 2000;343:1594-602.

20. Van de Putte LBA, Atkins C, Malaise M. Adalimumab (D2E7) monotherapy in the treatment of patients with severely active rheumatoid arthritis . Arthritis Rheum 2002;46 (Suppl): S205. abstract.

21. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH. Adalimumab, a fully human anti tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking methotrexate: the ARAMDA trial. Arthritis Rheum 2003;48:35-45.

22. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Eng J Med 2001;344:1099-100.

23. Keane J, Gershan S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha neutralizing agent. N Eng J Med 2001;345:1098-104.

24. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MH. Tumor necrosis factor antagonist therapy and lymphoma development: twenty six cases reported to the food and Drug Administration. Arthritis Rheum 2002;46:3151-8.

25. Ekstrom K, Hjalgrim H, Brandt L, Baecklund E, Klareskog L, Ekbom A, et al. Risk of malignant Lymphomas in patients with rheumatoid arthritis and in their first degree relatives. Arthritis Rheum 2003;48:963-70.

26. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, et al. Demyelination occurring during anti tumor necrosis factor alpha therapy for inflammatory arthritides . Arthritis Rheum 2001;44:2862-9.

27. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095-147.

28. Horal R, Saijo S, Taniko H, et al .Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interlrukin -1 receptor antagonist-deficient mice. J Exp Med 2000;191:313-20.

29. Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan T, Emery P, et al.Treatment of rheumatoid arthritis with recombinant human interleukin -1 receptor antagonist . Arthritis Rheum 1998; 41:2196-204.

30. Edwards JCW, Szczepanski L, Szechinski J, Filipowicz-Sasnowska A, Emery P, Close DR, et al. Efficacy of B-cell-Targeted therapy with rituximab in Patients with Rheumatoid arthritis. New Eng J Med 2004;350:2572-81.