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Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory condition affecting around 1% of the population, making it the most common inflammatory arthritis seen by physicians [1].

RA affects primarily the small joints of the hands and feet, has a chronic course and if not treated aggressively is a major cause of work loss, decreased quality of life, increased joint replacement surgery and mortality [2]. Patients are usually in their 50’s when diagnosed and there is a slight female preponderance, especially among younger patients [1]. It is a clinical diagnosis for the most part; laboratory and radiographic tests help to confirm the diagnosis and are useful as prognostic factors. RA can sometimes present in large joints like the knees and shoulder but this is less common. There is some evidence that elderly onset RA may present this way more than regular RA [3]. Elderly onset RA has also been grouped with polymyalgia rheumatica (PMR) and has been felt to present a continuum of clinical features of both RA and PMR [4]. Rheumatoid nodules can be seen at baseline in some patients who have very active disease with large numbers of joints involved; these patients also have a higher incidence of rheumatoid vasculitis, presenting mostly as skin manifestations, with ulcerations and other rashes. RA is seen in around 1-2% of any population it has been studied [5].

In younger patients females have a 2:1 predominance but as patient ages this becomes closer to 1:1. The prevalence of RA is around 1% in the US [1], there have been reports suggesting that RA is getting milder, and maybe less common, especially over the last 10-15 years but this is far from conclusive [6]. There are also some suggestions that RA is a “new” disease, being reported since the industrial revolution [7]. Archeological records are lacking in RA findings but this is also controversial, with multiple reasons for the poor preservation of RA bones . There are also studies showing that RA is possibly milder in less advanced countries, again raising the possibility of some new environmental agent maybe more common in industrialized nations [8]. Also one of the explanations for the declining incidence and severity of RA is thought to be improved hygiene [6].

Diagnosis:
Diagnosis of RA is made through the clinical manifestations of the disease. Laboratory tests or radiographic examinations are helpful and can be useful in determining prognostic information but are not necessary for making an RA diagnosis. Patients usually present with more than 6 weeks history of bilateral, symmetric pain and swelling of the small joints of the hands and feet. Morning stiffness lasting more than an hour is commonly reported but can be seen in other inflammatory conditions also. Extra articular features such as rheumatoid nodules over the extensor surfaces of tendons or vasculitic skin involvement can be seen but are rare. In any patient presenting with the above clinical picture RA needs to be considered. For the confirmation of diagnosis and starting disease modifying antirheumatic drug (DMARD) treatment, patients need to be referred to a rheumatologist at this stage.

Once a clinical diagnosis of RA is made, several laboratory tests should be done. Rheumatoid factor is one of the diagnostic criteria and is positive in about 70% of RA patients. When positive it is a poor prognostic factor,; higher the level, poorer the prognosis for most patients. Anti-CCP antibodies are newly described and are found in about 70-80% of RA patients, can be positive when RF is negative. They seem to play more of a pathogenic role in RA development [9]. Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels are also done usually, because they provide a glimpse of the level of inflammation. However, up to 40% of RA patients may have normal levels [10].

Baseline radiographs of the hands and feet should be done and preferably repeated every year. Patients with erosions at baseline, in addition to fulfilling one of the classification criteria for RA, also are at risk for worse disease. DMARD treatment slows down and in some patients halts radiographic progression.

RA is entertained as a diagnosis when symmetric arthritis has been going on for more than 6 weeks. There may be clues that this will turn into RA, such as positive blood tests, or lack of precipitating infections and such but there is still a good chance of undifferentiated polyarthritis of less than 6 weeks duration to subside.
For classification purposes a patient is said to have RA if he/she satisfies at least 4 of these 7 criteria. Criteria 1-4 must have been present for at least 6 weeks. Designation as classic, definite or probable RA is not to be made.

  1. Morning stiffness- lasting at least 1 hour before maximal improvement
  2. Arthritis of 3 or more joint areas – Simultaneously have had soft tissue swelling or fluid, observed by a physician. 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle and MTP joints
  3. Arthritis of hands – At least 1 swollen area in a wrist, MCP or PIP
  4. Symmetric arthritis
  5. Rheumatoid nodules – Subcutaneous nodules over bony prominences or extensor surfaces or in juxtaarticular regions observed by a physician
  6. Serum rheumatoid factor
  7. Radiographic changes – Typical changes in posteroanterior hand and wrist radiographs, must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints.

Treatment:
In the 1980s the general approach to RA treatment was based on appearance of erosions and DMARDs were withheld until erosions were seen on x-rays. However studies in late '80s and early '90s showed that RA was first associated with increased mortality in addition to morbidity and delay in treatment contributed greatly to both.[11]

Current approach can be summarized as early and aggressive treatment. Early RA is defined anywhere from 3 months to 2-3 years of disease [12]. After a diagnosis of RA is made, all patients should be started on a DMARD. Patients with poor prognostic factors, such as more than 20 swollen and tender joints, high RF and/or antiCCP antibodies, and possibly erosive disease at presentation can be treated with a combination of DMARDs but this is not done commonly right from the start. Methotrexate (MTX) is the most commonly used first DMARD. It is also considered the anchor treatment in RA [13]. It is the cornerstone of combination treatments also. MTX is usually started 7.5-10 mg/week, it is taken weekly. Depending on the patient’s response the dose should be increased up to 25 mg weekly, with about every 2 months evaluation.

Laboratory monitoring for liver function test abnormalities should be done every 6-8 weeks at the beginning and when the patient is on a stable dose, it can be done every 3-4 months [14, 15].

One area of controversy is the role of steroids in the treatment of RA. It is the practice of this author to start all patients where there is no contraindication, on 2.5-5 mg of prednisone daily. In addition to working faster than MTX thus providing relief, steroids also have disease modifying effect and hence contribute to overall disease control [16]. Other first line DMARD that are commonly used are leflunomide, sulfasalazine and hydroxycholoroquine. Most other DMARDs are rarely used as initial options.

Hydroxycholoroquine is felt to be a less effective DMARD compared to MTX, leflunomide or sulfasalazine.

Tumor necrosis factor antagonists are currently the choice of DMARDs as the first to add to MTX inadequate responders.  It is not clear if another TNF inhibitor should be tried if a patient fails to respond to the initial TNF inhibitor [17]. Two other medications with different modes of action have been approved recently, abatacept, a T-cell modulator, and rituximab, a B cell inhibitor, and they might be reasonably used after a patient has failed the first TNF inhibitor. The rule of thumb for RA treatment is to treat aggressively and as early as possible to prevent all the long term morbidities and decrease the mortality associated with RA.

Monitoring:
Patients need to be assessed using composite disease activity measures to objectively document improvement or lack thereof to determine the next step in the treatment plan.

Outcome measures, some based on patient reported outcomes (RAPID-Rheumatology Assessment Patient Index Data), some a combination of laboratory, and physician derived measures (DAS-Disease Activity Score, SDAI-Simplified Disease Activity Index, CDAI-Clinical Disease Activity Index), should be used in routine care for providing optimum care for RA patients.

If a patient has not reached a level of low disease activity defined by any of the tools that the rheumatologist uses after 3 months of a DMARD, it is time to add another DMARD to the treatment regimen.

References:

  1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-11
  2. Pincus T, Sokka T. How can the risk of long-term consequences of rheumatoid arthritis be reduced? Best Pract Res Clin Rheumatol. 2001 Mar;15(1):139-70.
  3. Kavanaugh AF. Rheumatoid arthritis in the elderly: is it a different disease? Am J Med. 1997 Dec 29;103(6A):40S-48S. Review.
  4. Yazici Y, Paget SA. Elderly-onset rheumatoid arthritis. Rheum Dis Clin North Am. 2000 Aug;26(3):517-26. Review
  5. Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006 Dec;36(3):182-8. Epub 2006 Oct 11. Review.
  6. Silman AJ. The changing face of rheumatoid arthritis: why the decline in incidence? Arthritis Rheum. 2002 Mar;46(3):579-81. Review. No abstract available.
  7. Hansen SE. William Musgrave's (1655-1721) system of arthritides. Did it include rheumatoid arthritis? Scand J Rheumatol. 1995;24(5):274-8.
  8. Kalla AA, Tikly M. Rheumatoid arthritis in the developing world. Best Pract Res Clin Rheumatol. 2003 Oct;17(5):863-75. Review.
  9. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC,Verweij CL, Toes RE, Huizinga TW. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 2004 Mar;50(3):709-15.
  10. Wolfe F, Michaud K. The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol. 1994 Jul;21(7):1227-37.
  11. Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriously--predictive markers, socioeconomic status and comorbidity .J Rheumatol. 1986 Oct;13(5):841-5.
  12. Pincus T. The case for early intervention in rheumatoid arthritis. J Autoimmun. 1992 Apr;5 Suppl A:209-26. Review.
  13. Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003 Sep-Oct;21(5 Suppl 31):S179-85. Review.
  14. Yazici Y, Erkan D, Paget SA. Monitoring by rheumatologists for methotrexate-, etanercept-, infliximab-, and anakinra-associated adverse events. Arthritis Rheum. 2003 Oct;48(10):2769-72.
  15. Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines? J Rheumatol. 2002 Aug;29(8):1586-9. Review. No abstract available.
  16. van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis:  clinical efficacy, disease-modifying properties, and side effects: a randomized,  double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002 Jan 1;136(1):1-12.
  17. Carmona L, Ortiz A, Abad MA. How good is to switch between biologics? A systematic review of the literature. Acta Reumatol Port. 2007 Apr-Jun;32(2):113-28.