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INTERDISCIPLINARY PLATFORM |
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| Year : 2006 | Volume
: 51
| Issue : 1 | Page : 13-17 |
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| Management strategies of rheumatological diseases |
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Alakendu Ghosh1, Biswadip Ghosh2, Dipankar Sircar2
1 Rheumatology Unit, IPGMER & SSKM Hospital Kolkata, India
2 Department of Medicine, IPGMER & SSKM Hospital Kolkata, India
Correspondence Address:
Biswadip Ghosh
118, N. S. Road, Suripara, Chinsuah, Hooghly, West Bengal - 712 101
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0019-5154.25180
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Keywords: Rheumatology, Management, Diseases
How to cite this article:
Ghosh A, Ghosh B, Sircar D. Management strategies of rheumatological diseases. Indian J Dermatol 2006;51:13-7 |
Management of rheumatologic diseases has come a long way beyond prescribing NSAIDs and steroids. We have started using biological agents in diseases like ankylosing spondylitis and rheumatoid arthritis where it was thought that besides pain-killers and physiotherapy, there was only another things left and that was prayer to God.
Broadly, management can be divided in two headings: (a) Pharmacological (b) Non Pharmacological
| (a) Pharmacological | |  |
The mainstay of the pharmacological treatment is disease modifying artirheumatic drugs (DMARDs). Analgesics are added for the time taken by DMARDs to act and at the time of flare-ups.
NSAIDS: Since pain is the most prominent complaint, nonsteroidal anti-inflammatory drugs (NSAIDs) are discussed first. Paracetamol in the dose of 500-650 mg 6 hrly is very effective. NSAIDs like diclofenac sodium, ibuprofen and naproxen are used. Indomethacin in acute gout and aspirin in rheumatic fever are frequently the drugs of choice.
Though there are concerns regarding cardiovascular safety profile of Coxibs, they are considered in high risk patients for their G.I. friendliness. These groups of patients are
(i) Older than 60 years, (ii) History of NSAIDs induced g.i. toxicity, (iii) History of g.i. bleeding, cardiovascular disease, (iv) Taking high dose of NSAIDs, concomitant oral gulcocorticoids or combinations of NSAIDs.[1]
DMARDs: It is generally agreed upon that as soon as diagnosis is established in Rheumatoid Arthritis, patient is to be put on combination "Disease modifying antirheumatic drugs".
Methotrexate (MTX) : This is a folate antagonist, usually the first and probably the safest DMARD. Usual dose is 7.5-25 mg/wk. Folic acid is used to decrease adverse effect; loss of efficacy do not occur if given on separate days. Main use is in rheumatoid arthritis, psoriatic arthritis, juvenile chronic arthritis and spondyloarthropathy with peripheral arthritis. Monitoring is done by SGPT and hemogram. Hepatic dysfunction is very rare in our experience. Pneumonitis[2] is an uncommon complication (2-6%), which is treated by corticosteroids and cessation of MTX.
Sulphasalazine: This inhibits the production of prostanoids. Usual dose is 1-3 g/day. Used in rheumatoid arthritis, juvenile chronic arthritis, spondyloarthropathy with peripheral arthritis. It is less effective that MTX but more effective than artimalarials.[3] Adverse effects include rash, G.I. intolerance, aplastic anemia, agranulocytosis, hepatic damage. Monitoring is by clinical examination and by blood count and SGPT estimation at 3-6 months interval.
Hydroxychloroquine: This interferes with cellular function in lysosome, endosome, Golgi complex and inhibits cytokine production. Some studies show that chloroquine may be more effective than hydroxychloroquine but later is preferred due to its better tolerance and lesser side effects. Chloroquine should be considered as an option in poor people. In DLE, effect is often seen in first week. It is used in SLE, rheumatoid arthritis (RA) and childhood dermatomyositis. Baseline ophthalmologic examination and a follow-up examination every 12 months are recommended during the period of treatment. G.I. complaints are frequently present. Dose: 400 mg/d.
Leflunomide: First tailor made DMARD that inhibits action of an enzyme for de nova synthesis of pyrimidine in T lymphocytes. It is both disease modifier and anti-inflammatory. Used in R.A. Dose is 100 mg/d x 3d then 20 mg/d. Side effects are pancytopenia, hepatitis, G.I. intolerance and morbilliform skin cruption. Toxicity may require treatment with cholestyra-mine or activated charcoal. It is teratogenic. Women should discontinue for at least 2 years before having children.[4]
MTX remains the most commonly used DMARD[5] but leflunomide is a useful alternative in the face of intolerance to methotrexate. Leflunomide is containdicated in patients with any type of liver impairment and regular monitoring is required. It minor adverse effects such as diarrhea or abdominal cramps occur, a dose of 10 mg can be effective and may be better tolerated. The combination of leflunomide and methotrexate appears to be more effective than methotrexate and placebo, resulting in American college of rheumatology (ACR) 20 response rates of 46.2 and 19.5 percent, respectively.[5] The primary drawback of this combination is its potential for hepatotoxic effects;[6] thus, patients who are treated with both agents should be monitored closely.[7]
Others: Tetracyclines are being evaluated as DMARDs. Tetracyclines, in particular minocycline, were associated with a clinically significant improvement in disease activity in RA with no absolute increased risk of side effects.[7] Encouraging results are found also in osteoarthritis.[8] Gold and penicillamine are not used nowadays.
Immunosuppressives
Glucocorticoids: Some authorities consider them as DMARDs as they interfere in all aspects of inflammation. Injectable preparations are sometimes preferred because misuse is relatively infrequent and bioavailability is ensured. In RA, mythylprednisolone in depot preparation 40-80 mgat 2-3 wkly intervals is used as bridge therapy for the period DMARDs take to act and at the time of flare-ups. Oral prednisolone at greater than 7.5 mg/d should not be used for long time in R.A. unless there is vasculitis, due to fear of adenohypophysial axis suppression.
In SLE, it is the mainstay of treatment in most patients. Dose: 1-1.5 mg/kg/d x 6 wks followed by tapering by 5 mg every 2 wks is used. At time of severe disease, methylprednisolone 500-1000 mg I.V. bolus x 3 d is often very effective.
Polymyositis (PM) or Dermatomyositis (DM) require higher dose, prednisolone 1.5-2 mg/d is needed at first.
Glucocorticoids as the only drug are rarely effective in optimal control of any severe chronic inflammatory disease including RA, SLE. Another immunomodulator is usually needed.
Adverse effect are largely related to dose and duration. Some believe that maintaining low dose is better than discontinuing in most patients.
Cyclophosphamide : This alkylates DNA and remains drug of choice for most patients with systemic necrotizing vasculitis or severe cases of SLE. In lupus nephritis IV preparation is more effective than oral preparation, whereas in Wegeners granulomatosis oral preparation is better.[9] Apart from infection, cystitis and pulmonary toxicity may occur. There are some chance of increased malignancy and decreased fertility.
Azathioprine: This antimetabolite is used mainly as steroid sparing agent, particularly effective in skin manifestations of SLE. Also used in Behcet's disease, psoriatic arthritis, Reiter's disease, vasculitis, PM/DM and RA. Dose is 50 mg/d, if tolerated increased to 2-2.5 mg/kg after 2 wks. Adverse effects are hepatic dysfunction, myelosuppression, G.I. intolerance.
Mycophenolate mofetil: This inhibits de novo synthesis of purines. Promising results are obtained in SLE particularly in patients with renal manifestations, PM/DM and RA. MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.[10] For the treatment of diffuse proliferative lupus nephritis, the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prdnisolone followed by azathioprine and prednisolone but is less toxic.[12]
| Biological Agents | | |
TNF-a orchestrates proniflammatory cytokines inducing inflammatory synovitis. Trials have shown that TNF-a neutralising agents like infliximab (TNF-a antagonist), etanercept (TNF-a receptor IgG fusion protein), adalimumab (fully human antibody to TNF-a) are remarkably effective at controlling signs and symptoms in RA, in patients who failed DMARD therapy as well as in DMARD naοve patients. Repetitive therapy is effective with or without MTX. They also slow the rate of progression of joint damage. In ankylosing spondylitis (AS) they have shown striking improvement in disease activity and function. At present, it is not definitely known whether this therapy will halt the progression of the disease or can reverse ankylosis or other damage. Anecdotal evidence supports the use of these agents in severe chronic reactive arthritis also. Side effects include serious infections, hematological disorders, demyelinating disorders, exacerbations of congestive cardice failure, SLE and hypersensitivity. Though they are costly and are usually used in resistant cases, studies are coming up which shows that prognosis may be better if used early.
Abbreviated summary of the "updated consensus statement on biological agents for the treatment of rhumatic diseases, 2004" are as follows:[12]
| Indications | | |
TNF blockers are recommended for the treatment of active RA, PsA, AS and juvenile chronic arthritis after using another DMARD.
TNF blockers can be added to preexisting therapy or when appropriate, may replace previous DMARDs or other biologicals.
TNF blockers are effective in MTX naοve patients.
At present, TNF blocking agents for the treatment of RA should be limited due to consideration of long-term safety. Cost consideration should be included when considering the use to TNF blocking agents.
When other DMARDs are containdicated TNF blockers may be considered as the first DMARD.
Etanercept has been approved for juvenile idiopathic arthritis of the polyarticular type as well as PsA and AS.
Infliximab is approved in Europe for AS.
Adalimumab and infliximab are being tested in PsA.
There is no evidence that any one TNF blocking agent should be used before another or that any TNF blocker is more effective than another is, although individual differences may exist between patients.
TNF blocking agents are being evaluated in Wegener's granulomtoses, Takyasu's arteritis, adult onset Stills disease, Sjogrens syndrome; hepatitis C, SLE but more work is needed.
Others
Anakinra: It inhibits IL-1. Dose is 100 mg S.C. daily. Improves signs and symptoms of R.A, decrease disability, slow progression of articular damage. It can be used as monotherapy or in combination with MTX.
Thalidomide
Thalidomide is an immunomodulatory agent, has shown the ability to suppress tumor necrosis factor alpha (TNF alpha) production and to modify the expression of TNF alpha induced adhesion molecules on endothelial cells and on human leukocytes. It is finding its place in the treatment of ankylosing spondylitis, juvenile rheumatoid arthritis, Behcet's disease, even SLE and RA. Adverse reactions are somnolence, rash, peripheral neuropathy, deep vein thrombosis and of course, teratogenicity. Usual dose is upto 40 mg/day.[13],[14]
| (b) Non-pharmacological Treatment | | |
Improved sympathetic discussion and patient enducation programs have been shown to reduce pain, depression and disability.[15] Rest, exercise, physical and occupational therapy are part of rheuma-tologic diseases.
Exercise: Regular exercise like walking, swimming improves muscle function, joint stability and sense of well being.
Physical therapy: Comprises of rest and splinting to reduce pain, splinting to prevent deformity, application of heat or cold to relief pain, passive and active exercises to maintain joint mobility.
| Individual Disease Management Strategies | | |
Management of Rheumatoid Arthritis
In a typical case of Rheumatoid Arthritis, treatment is usually started with methotrexate, sulphasalazine and hydroxychloroquine along with NSAIDs. The starting dose of metrotrexate is usually 10-15 mg per week. Relatively severe cases are put on injection metrotrexate 15-25 mg per week. The dose of sulphasalazine is 1-2 gm per day. Steroids are often used as bridge therapy initially. Injectable steroids are usually preferred as they are quick to act. NSAIDs are used for a symptomatic benefit and patients are put on exercise program as early as possible. A few patients experience significant pain, even after full dose of DMARDs for three months or have frequent flare-ups. They are considered for the combination of leflunomide (100 mg per day for three days as loading dose, then 20 mg per day) and methotrexate orally. In all cases opinion of the Department of Physical Medicine are taken for muscle strengthening and deformity limitation. Patients are usually followed initially at the interval of 11/2 months for three visits with blood reports of at least SGPT and ESR. A next visit is usually scheduled at three to six months interval or earlier if emergency occus. The juvenile rheumatoid arthritis patients are more difficult to treat. The patient compliance is less, so frequent follow-ups are planned.
Management of Psoriatic Arthritis
In management of psoriatic authutis (PsA) NSAIDs namely ibuproren, naproxen or diclofenic remain the mainstay of initial management aspecially in significant peripheral arthritis and spondyloarthroputty with prolonged morning stiffness. Among DMARDs methotroxate, sulphasalazine, cyclosporin A, leflenomide, etratinate or biologic response modifier (BRM) like etanercept, infliximal and alefacept are used. All patients of PsA must be screened for HIV infection before starting DMARD therapy. Methotrexate and salazopyrine are the only two agents among DMARDs which have been shown by meta-analysis to be the well-effective in management of PsA. Each and every patient of psoriasis should be screened thoroughly by the dermatologists, if required by referral to rheunstologists, so that early intervention can be done to ensure better therapeutic outcome. Reverse is also true; each case of arthoritis to be excluded for PsA by the rherutologist.
Management of Spondyloarthropathy
It is surprising to note that a significant number of patients who were previously put in the category of 'Non specific Rheumatism' or 'Degenerative Spinal disease', have in fact detectable Sacroilleitis by Digital X-ray or MRI. Even carefully done conventional X-ray often takes out the diagnosis in a sizeable number of patients.
All of them are put on physical therapy, after carefully explaining the disease to the patient. If the patient has peripheral arthritis, sulphasalazine is prescribed first. Methotrexate is added if necessary. Patients are subjected to infliximab (Dose is 5 mg/kg at 0, 2. 6 weeks and then 8 weekly) or Inj. pamidronate (60 mg monthly injection for 6 doses) confirming their ability to afford high cost.
Management of Scleroderma
Management of scleroderma is not very satisfying. For Raynaud's Phenomenon patients are advised to dress warmly, avoid cold exposure and avoid vasoconstrictor drugs. Amlodipine or sustained release preparation of nifedipine are used. Other drugs we use include prazosin, losartan and fluoxetine. Pentoxifylline improves microcirculation. Skin care is very important. Dryness of skin should be avoided. Occlusive dressing over a noninfected ulcer may promote healing and protect the finger. Local nitroglycerine paste may be beneficial. In patients with G.I. symptoms, we use H2 blockers or ppi along with metoclopramide. Patients are advised to take frequent small meals, not to lie down after a meal, to avoid tea, coffee or alcohol. Articular symptoms are treated with NSAIDs. Physical therapy is advised in all edema associated with early skin involvement and may be useful in relieving joint and tendon pain. In early active alveolitis, inflammatory arthritis and pericarditis 20-30 mg/d prednisolone is used. They are reduced as early as possible and steroid sparing agents like azathioprine are sometimes added. Glucocorticoids are reported to be associated with renal crisis. We do not use penicillamine nowadays as studies failed to show any benefit. Immunosuppressives like cyclophosphamide or cyclosporine are being tried in randomized controlled trails. For pulmonary hypertension, bosentan and iloprost are being increasingly used in patients who can afford.
Management of Lupus Erythematosus [Table - 1]
It must be decided, first, whether management of the patient of SLE requires immunosuppression. If the delay is not a life or organ threatening, analgesics, local steroids, sunscreeens, NSAIDs may suffice. Low-dose glucocorticoids are usually adequate if these measures fail. when there is life or organ theatening illness, the disease may or may not respond to immunosuppression. If responsive, high-dose glucocorticoids followed by tapering (as tolerated) are administered. In case of inadequate response or unacceptable toxicity, cytotoxics (cyclophosphamide / azathioprine) are used. Complications not responsive to immuno-suppression may respond to other measures (anticoagulation, splenectomy).[15]
For mild disease, analgesics, NSAIDS or salicylates may provide adequate relief. Glucocorticoids however are most effective.[16] A trial of antimalarials is warranted in cases not controlled on NSAIDs. Hydroxychloroquine is less effective than chloroquine but has less retinal toxicity.[17] If used for more than six months, ophthalmologic examination is mandatory. For uncontrolled disease, institution of low dose glucocorticoids may be necessary.
| References | | |
| 1. | Wolfe MM, Lichtensteine DR, Gastro intestinal toxicity of NSAIDs New Eng J. Medicine 1999; 340:1888-99.  |
| 2. | Guidelines for monitoring drug therapy in R.A. Arthritis Rheum 1996; 39:723-31. |
| 3. | Felson DT anderson JJ. Use of short-term efficacy/toxicity tradeoffs to select second line drugs in R.A. A Meta analysis, Arthritis Rheum 1992; 35:1117. |
| 4. | Sokka T, Pincus T. Contemporary disease modifying antirheumatic drugs (DMARD) in patients with recent onset rheumatoid arthritis in a US private practice: methotrexate as the anchor drug in 90% and new DMARD in 30% of patients. J. Rheumatol 2002; 29:2521-4. [PUBMED] [FULLTEXT] |
| 5. | Kremer M, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trail. Ann Intern Med 2002; 137:726-33. |
| 6. | Mladenovic V, Domlan Z, Rozman B, et al. Safety and effectivenss of leflunomide in the treatment of patients with active rheumatoid arthritis: results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995; 38:1595-603. |
| 7. | Stone M, Fortin PR et al. Should tetracycline treatment be used more etensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol. 2003; 30:2112-22. |
| 8. | Pardy CK, Matyas JR et al. Doycycline effects on mechanical and morphometrical properties of early and late-stage osteoarthritic bone following anterior cruciate ligament injury. J. Appl Physiol. 2004; 97:1257-60. |
| 9. | Guillevin L, Cordin JF et al , A prospective multicenter randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in generalized Wegeners Granulomatosis. Arthritis Rhem 1997; 40:2187. |
| 10. | Karim MY, Alba P et al. Rheumatology Oxford 2002; 41:876-82. |
| 11. | Chan TM; Li FK et al. N. Engl J Med. 2000; 19; 343:1156-62. |
| 12. | Furst DE, Breedveld FC et al. Updated consensus statement on biologic agents, specifically TNF-a blocking agent and IL-1 receptor antagonist, for the treatment of Rheumatic diseases. Ann Rheum Dis 2004; 63:II2-II12. |
| 13. | Ossandon A, Cassara EA, Priori R, Valesini G. Thalidomide focus on its employment in rheumatologic diseases. Clin Exp. Rheumatol. 2002; 20(5):709-18. |
| 14. | Laffitte E, Revuz J. Thalidomide: an old drug with new clinical applications. Expert Opin Drug Saf. 2004; 3(1):47-56. |
| 15. | Hahn BH. Management of systemic lupus erythematosus. Kelley's Textbook of Rheumatology 6th Ed, W.B. Saunders; 2001; 1125-43. |
| 16. | Kimberly RP. Treatment: Corticosteroids and anti-inflammatory drugs. Rheum Dis Clin North Am. 1988, 14:203. [PUBMED] |
| 17. | Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin North Am. 1994; 20:243. [PUBMED] |
Tables
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