Epidemiology of Adult Rheumatoid Arthritis

By | April 8, 2023
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Definition :

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of undetermined aetiology involving primarily the synovial membranes and articular structures of multiple joints. The disease is often progressive and results in pain, stiffness, and swelling of joints. In late stages deformity and ankylosis develop.

Incidence and Prevalence:

Worldwide prevalence is approx 1%. Its incidence and prevalence is more in developed countries and less in developing countries except India. There is now some evidence that prevalence and severity of this disease is decreasing.

 

Morbidity and MortalityIt is now not considered as a benign disease .Patients of  rheumatoid arthritis experience lower  life expectancy than general healthy population. Risk of infections ,cardiovascular disease and other co-morbid conditions like depression  is also high. Approx 50% patients stop working after 10 years of diagnosis of disease.  Risk Factors: Female gender, old age ,positive family history, heavy smoking  and ethnicity (Pima Indians) are established risk factors for onset of this disease.  

Protective Factors.

Pregnancy, Oral contraceptive pills ,Fish ,Olive oil and vegetarian diet  are  considered as protective factors but evidence is not so strong and more research is needed to be done in these areas.

Detection and Conclusion.

Public awareness regarding the diagnosis of this disease as early as possible is needed. Because early diagnosis and  early start of aggressive treatment by disease modifying agents is important in slowing the progression of rheumatoid arthritis.

References

Epidemiology of Adult Rheumatoid Arthritis.

Introduction

Rheumatoid arthritis is a chronic systematic inflammatory disorder of unknown cause. It affects the peripheral joints in a systemic manner. Within 10 years of onset it causes great disability. Arthritis is the dominant clinical manifestation, involving many joints, especially those of the hands and feet. The course is variable, but often chronic and progressive, leading to deformity and disability. In most cases of RA, the patient has remissions and exacerbations of the symptoms. 

This means that there are periods of time when the patient “feels good” and times when the patient “feels worse”. There will likely be times that a patient with RA “feels cured”. It is important to understand that there are very few patients that have complete remission of the disease and it is essential that the RA patient does not stop the treatment program

 Methods and definitions

 The method of searching the topic was through internet by medical databases like Pubmed, medical magazines in science direct.com and http://scholar.google.com (a new feature of google search engine for searching only academic papers. It’s in beta version)

 Keywords used  for searching were Epidemiology of adult rheumatoid arthritis, Mortality and morbidity of rheumatoid arthritis, Nutrition and rheumatoid arthritis, Pregnancy and rheumatoid arthritis, Rheumatoid arthritis in developing countries.

Definitions.

Rheumatoid factor.

The test for rheumatoid factor (RF) is used to help diagnose rheumatoid arthritis (RA

Environmental factors

The term ‘environment’ is frequently used to describe all those susceptibility factors leading to disease that are not  explicable on the basis of an identifiable genetic marker.

1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis

In 1958 American college of Rheumatology [1]presents the diagnostic criteria for rheumatoid arthritis . Then in 1987 it presents another diagnostic criteria. the reason being “improved clinical knowledge and other forms of arthritis misdiagnosed as RA are now separately classified”[2]

Criterion Definition
1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement
2. Arthritis of 3 or more joint areas At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints
3. Arthritis of hand joints At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides fo the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)
5. Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician
6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
7. Radiographic changes Radiographic changes typical of rheumatoid arthritis on poster anterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

·         ·       *   For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 or these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.

·    Table no 1 .[2]

 

  International Classification of Diseases-10 (ICD-10) OF ADULT RHEUMATOID ARTHRITIS.[3]

 Adult rheumatoid arthritis attracts the coding in ICD-10 from  M05-M06

 M05.3

 

 Rheumatoid arthritis with involvement of other organs and systems

 

M05.9

 

Seropositive rheumatoid arthritis, unspecified

 

M06

 

Other rheumatoid arthritis

 

M06.0

 

Seronegative  rheumatoid arthritis

 

M06.4

 

Inflammatory  Polyarthropathy

 

M06.9

 

Rheumatoid arthritis, unspecified  

 

Routine data and descriptive studies .

Prevalence is Approx 1%  worldwide. However the prevalence is not same across the world. Women are affected 2-3 times more than men. Prevalence  increases with age and sex differences diminish with increase in age. It affects all races but it is more common in certain races like Pima Indians[4] (prevalence 5.3-6.0) and in the Chippewa Indians (6.8%)[5].

It is rare in rural parts of China, Hong Kong [6] ,Indonesia, Japan .One study fails to find  even a single case of Rheumatoid arthritis in Nigeria.[7] Prevalence in Northern Europe and North America is 0.5 -1.1%.[9][10][11][12][13]Southern Europe=0.3-0.7%.[14][15]There is higher incidence if we go from south to north Europe. Prevalence in developing countries is 0.1 -0.5% [16][17]. But in India ,the prevalence of rheumatoid arthritis is .75% ,is similar to the developed countries. 

  Reason might be north Indian population is genetically closer to the Caucasians than to other ethnic groups.[18]

 Prevalence and incidence rates of RA worldwide (cases per

100 inhabitants)

Population   Prevalence rates Incidence rates
North America • USA (general population) 0.9–1.1 0.02–0.07
  • USA (native-Americans) 5.3–6.0 0.09–0.89
North Europe • England 0.8–1.10 0.02–0.04
  • Finland 0.8 0.03–0.04
  • Sweden 0.5–0.9  
  • Norway 0.4–0.5 0.02–0.03
  • Netherlands 0.9 0.05
  • Denmark 0.9  
  • Ireland 0.5  
South Europe • Spain 0.5  
  • France 0.6 0.01
  • Italy 0.3  
  • Greece 0.3–0.7 0.02
  • Yugoslavia 0.2  
South America • Argentina 0.2  
  • Brazil 0.5  
  • Colombia 0.1  
Asia • Japan 0.3 0.04–0.09
  • China 0.2–0.3  
  • Taiwan   0.3
  • Indonesia 0.2–0.3  
  • Philippines 0.2  
  • Pakistan 0.1  
Middle East • Egypt 0.2  
  • Israel 0.3  
  • Oman 0.4  
  • Turkey 0.5  
  • Africa 0–0.3  

 

TABLE NO 2  TAKEN FROM [19] 

 

Incidence and prevalence of rheumatoid arthritis is decreasing  in developed world .[12][13] But especially in women not in men and proposed causes are

Use of oral contraceptives by females after 1960s .[20]

There is decrease in severity of disease .[21][22]

Change in classification criteria of rheumatoid arthritis .[23]

Birth cohort effect.

Norfolk study.[13]

The first study in uk for prevalence of rheumatoid arthritis was done in 1958 by Lawrence JS.[24]Since then the classification criteria had changed and to see whether there is any decrease in prevalence of disease Norfolk study was  conducted in primary setting . By stratified  randomization according to seven  age and gender bands,7050 patients were mailed and then positive responders for disease were examined by rheumatologist. The overall response rate was 82%. Sixty-six cases of RA were identified. Extrapolated to the population of the UK, the overall minimum prevalence of RA is 1.16% in women and 0.44% in men. If we look at fig.2 which  compares the data from  both studies, it is clear that prevalence in women is decreasing in all age groups except in 75+group.but the prevalence in men had increased.

 

 

Figure 1 and 2 taken from [44]

 

MORTALITY AND MORBIDITY

It is now considered as a malignant disease and with  increase mortality and morbidity and poor prognosis. Life expectancy decreases by 3-10 years  according to severity and age of onset of disease. It is debilitating disease and limit the patient daily activities. It is also associated with serious co morbid conditions like infections ( common cause of death in developing countries) cardiovascular disease[25], respiratory disease [26]etc.

Drugs taken for this disease are associated with serious side effects. Depression is more common in rheumatoid arthritis patients due to pain ,economic burden ,lose of work which ultimately leads to suicide.

Suicide and RA

A  prospective study[27] with  13-yr follow-up ,data taken from national hospital discharge registers of all suicides (1296 males, 289 females) committed during the years 1988–2000 in Finland.

Results show 52.6% women with rheumatoid arthritis committed suicide as against 17.3%  women with non RA. 90% of RA women were suffering from depressive disorders before suicide. RA males were less depressive but committed suicide after short period of disease.

Disability and RA.[28]

Cohort  study done to  determine the impact of rheumatoid arthritis on employment status in the early years of diagnosis. Two  cohorts of patient were chosen  with similar employment status and cohort 1 with 162 patients and disease onset between 1989 and1992 and cohort 2 with 134 patients and disease onset between 1994 and 1997. The rates for work disability for the RA cases 1, 2, 5 and 10 yr after symptom onset were 14, 26, 33 and 39% respectively. For cohort 2, the rates for work disability 1 and 2 yr from onset were 23 and 33% respectively. This shows the aggressive nature of this disease.

 ECONOMIC BURDEN OF DISEASE .

 Rheumatoid arthritis posses great economic burden on  patients due to expensive drugs ,multiple hospitalisation, rehabilitation costs and absence from work. A systemic review by Cooper NJ. of University of East Anglia, Norwich , UK estimates average cost of UK£3575-£3638  per patient per year.

Risk factors

 It is multi factorial disease with interaction of both genetic and environmental factors. Exact cause is still unknown.

Gender.

It is 2-3 times more common in women.

Age

Incidence of this disease increases with age but it can occur at any age.

Genetic factors

Persons with positive family history of disease are more prone to develop this disease. It  Contributes about 60 % in aetiology of RA.[29].It shows that environmental factors also contribute in aetiology of disease.

Socio-economic factors.

Some evidence in U.K. that poor prognosis in socially deprived people.[13]

Infectious agents.

Some infectious agents are implicated but evidence is poor .The probable agents are Parvovirus, rubella virus, Epstein-Barr virus, borrelia burgdorferi etc.[19]

Lifestyle.

Smoking is now established risk factor. It also  aggravate the disease course.A study in Sweden concludes that smoking causes RF positive RA in both sexes.[30] 

Hormonal factors

As this disease is more common in women so it seems that some hormonal factors might be involved. Many studies have been done to know the relationship between oral contraceptive pills and pregnancy  with rheumatoid arthritis . Spector TD did the case control study(1990)[31] and suggest  that oral contraceptives and parity is protective against rheumatoid arthritis. But in the same year he did metaanalysis on protective effect of OCP on RA[32] and  he  select  6 case control and  3 longitudinal. studies and concluded that OCP might not have any protective effect but may change the course of disease.

Prospective cohort study[33] of 140 women were followed from last trimester of pregnancy and 6 months postpartum. This study concluded that there was little effect of pregnancy on rheumatoid arthritis outcome plus great variability of disease. Researcher criticise the previous studies and make argument that many  previous  studies were retrospective (recall bias) without any validated methods and sample size was small.

This study was followed by another study in Netherlands[34] and came up with same conclusions but they followed cohorts for 12 years and ascertain that multiple pregnancies and ocp use before symptoms was associated with good outcome (less radiographic joint damage and a better functionallevel).

 Dietary factors.

Some dietary factors also been implicated as risk factors but the evidence is not strong .Some dietary factors are also investigated for its beneficial role in alleviating the symptoms of rheumatoid arthritis but  according to NICE guidelines [35]if we put patient  on diet for long time the patient will develop some nutritional deficiencies.

Fish oil ,olive oil are beneficial for patients. [36][37][38]

Fasting and vegetarian diet also improves the pain score. [39]

Tea ,coffee and caffeine consumption .[40]

A cohort study was done in Birmingham, USA, started in 1986 in older women 31,336 women from age range of  55-69 years were selected without rheumatoid arthritis . By 1997 156 cases of rheumatoid arthritis were diagnosed. Results show  the relative risk of  2.58, 95% CI 1.63-4.06 for women who consume >4 cups of decaffeinated coffee  while for women with daily consumption of >3 cups of tea show RR of  0.39, 95% CI 0.16-0.97) compared with women who were never drinker of tea.

Ethnicity

More common in native Americans. But now there is evidence that incidence and prevalence is decreasing in this group as well.[41]

Detection and prevention.

 Early diagnosis of disease  is key in slowing the progression of rheumatoid arthritis. The diagnosis of disease is purely on clinical grounds. The only screening test or rheumatoid arthritis is detection of rheumatoid factor in blood. But it is non specific and can also be present in normal patients especially in older patients.

High risk patients especially with strong family history should be screened for RF and should be warned of smoking , becoming obese and taking balanced diet.

 As we don’t know the exact cause of rheumatoid arthritis so unfortunately   it  cannot be prevented . efforts should be directed  at early diagnosis of disease and then early start of aggressive treatment by disease modifying drugs .

 Conclusion.

 Rheumatoid arthritis is a destructive disease with no known cause  and no  cure and great variability in its expression and prevalence . Drugs are given to slow the progression of disease . Risk factors include positive family history , heavy smoking with long duration and ethnicity.

 Recommendations.

  1.  Efforts should be directed at improving the quality of life of patients .
  2. Decrease the waiting time for patients with rheumatoid arthritis.
  3.  More rheumatologist should be trained and recruited in developing countries. (In Kenya of 16 million population there is only one rheumatologist)
  4.  Drugs at cheaper rates should be supplied to developing countries.
  5.  Educate the people  about early symptoms of disease and instructions regarding smoking cessation,   weight reduction, exercise  and balanced diet.

Future Research questions.

  1. To know the exact cause of disease.
  2. To know the exact relationship between diet and rheumatoid arthritis.
  3. More studies need to be done in developing countries to know the exact incidence and prevalence .

References.

 

1.ROPES,M.W.; BENNETT,G.A.; COBB,S.; JACOX,R.; JESSAR,R.A.1958 Revision of diagnostic criteria for rheumatoid arthritis.Bull.Rheum.Dis., 1958, 9, 4, 175-176

 

2.Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315—24.

 

3.Statistics Canada.2004  [Table 102-05331,2,3,4,5 – Deaths, by cause – Chapter XIII: Diseases of the musculoskeletal system and connective tissue (M00-M99), age group and sex, Canada, annual (Number):WHO  .Available at :< http://cansim2.statcan.ca/cgi-win/CNSMCGI.EXE> [7th decemebr 2004]

 

4.Del Puente A, Knowler WC, Pettitt DJ, Bennett PH .High incidence and prevalence of rheumatoid arthritis in Pima Indians.
Am J Epidemiol. 1989 Jun;129(6):1170-8

 

5.Harvey J, Lotze M, Stevens MB, Lambert G, Jacobson D.Rheumatoid arthritis in a Chippewa Band. I. Pilot screening study of disease prevalence.Arthritis Rheum. 1981 May;24(5):717-21.

 

6.Lau E, Symmons D, Bankhead C, MacGregor A, Donnan S, Silman A.Low prevalence of rheumatoid arthritis in the urbanized Chinese of Hong Kong.J Rheumatol. 1993 Jul;20(7):1133-7.

 

7.Silman AJ, Ollier W, Holligan S, Birrell F, Adebajo A, Asuzu MC, Thomson W, Pepper L.Absence of rheumatoid arthritis in a rural Nigerian population.J Rheumatol. 1993 Apr;20(4):618-22.

 

8.Cimmino MA, Parisi M, Moggiana G, Mela GS, Accardo S. Prevalence of rheumatoid arthritis in Italy: the Chiavari Study. Ann Rheum Dis. 1998 May;57(5):315-8.

9.Malaviya AN, Kapoor SK, Singh RR, Kumar A, Pande I. Prevalence of rheumatoid arthritis in the adult Indian population. Rheumatol Int. 1993;13(4):131-4.

10.Simonsson M, Bergman S, Jacobsson LT, Petersson IF, Svensson B. The prevalence of rheumatoid arthritis in Sweden. Scand J Rheumatol. 1999;28(6):340-3.

 

11.Power D, Codd M, Ivers L, Sant S, Barry M. Prevalence of rheumatoid arthritis in Dublin, Ireland: a population based survey. Ir J Med Sci. 1999 Jul-Sep;168(3):197-200.

12. Michele F. Doran, Gregory R. Pond, Cynthia S. Crowson, W. Michael O’Fallon, Sherine E. Gabriel. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum. 2002 Mar;46(3):625-31.

13. Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M, Scott D, Silman A. The prevalence of rheumatoid arthritis: new estimates for a new century. Rheumatology 41 (2002), pp. 793–800

14. Drosos AA, Alamanos I, Voulgari PV, Psychos DN, Katsaraki A, Papadopoulos I, Dimou G, Siozos C. Epidemiology of adult rheumatoid arthritis in northwest Greece 1987-1995. J Rheumatol. 1997 Nov;24(11):2129-33.

15. Carmona L, Villaverde V, Hernandez-Garcia C, Ballina J, Gabriel R, Laffon A; EPISER Study Group. The prevalence of rheumatoid arthritis in the general population of Spain. Rheumatology (Oxford). 2002 Jan;41(1):88-95.

 

16. Dans LF, Tankeh-Torres S, Amante CM, Penserga EG. The prevalence of rheumatic diseases in a Filipino urban population: a WHO-ILAR COPCORD Study. World Health Organization. International League of Associations for Rheumatology. Community Oriented Programme for the Control of the Rheumatic Diseases. J Rheumatol. 1997 Sep;24(9):1814-9.

17. Darmawan J, Muirden KD, Valkenburg HA, Wigley RD. The epidemiology of rheumatoid arthritis in Indonesia. Br J Rheumatol. 1993 Jul;32(7):537-40.

 18. Malaviya AN, Kapoor SK, Singh RR, Kumar A, Pande I. Prevalence of rheumatoid arthritis in the adult Indian population. Rheumatol Int. 1993;13(4):131-4.

 

19. Drosos AA, Alamanos I, Voulgari PV, Psychos DN, Katsaraki A, Papadopoulos I, et al. Epidemiology of adult rheumatoid arthritis in northwest Greece 1987-1995. J Rheumatol 1997; Nov;24(11):2129-33

 

20. Spector TD, Hochberg MC. The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytic epidemiological studies using meta-analysis. J Clin Epidemiol 1990;43(11):1221-30

 

21. . Silman A, Davies P, Currey HL, Evans SJ. Is rheumatoid arthritis becoming less severe?. J Chronic Dis 1983;36(12):891-7.

 

22. Aho K, Tuomi T, Palosuo T, Kaarela K, Von Essen R, Isomaki H. Is seropositive rheumatoid arthritis becoming less severe? Clin Exp Rheumatol. 1989 May-Jun;7(3):287-90.

 

23. Arnett FC. Revised criteria for the classification of rheumatoid arthritis. Orthop Nurs 1990; Mar-Apr;9(2):58-64

 

24. LAWRENCE JS. Prevalence of rheumatoid arthritis. Ann Rheum Dis. 1961 Mar;20:11-7.

 

25. Sacks JJ, Helmick CG, Langmaid G. Deaths from arthritis and other rheumatic conditions, United States, 1979-1998. J Rheumatol. 2004 Sep;31(9):1823-8.

 

26. Carmona L, Hernandez-Garcia C, Vadillo C, Pato E, Balsa A, Gonzalez-Alvaro I, Belmonte MA, Tena X, Sanmarti R; EMECAR Study Group. Increased risk of tuberculosis in patients with rheumatoid arthritis.

 

27. Timonen M, Viilo K, Hakko H, Sarkioja T, Ylikulju M, Meyer-Rochow VB, Vaisanen E, Rasanen P. Suicides in persons suffering from rheumatoid arthritis. Rheumatology (Oxford). 2003 Feb;42(2):287-91.

 

28. Barrett EM, Scott DGI, Wiles NJ, Symmons DPM. The impact of rheumatoid arthritis on employment status in the early years of disease: a UK community-based study. Rheumatology (Oxford) 2000;39:1403–9

 

29. Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993; Oct;32(10):903-7.

 

 

 30. Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L; EIRA study group. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003 Sep;62(9):835-41.

 

 

31. Spector TD, Roman E, Silman AJ. The pill, parity, and rheumatoid arthritis. Arthritis Rheum. 1990 Jun;33(6):782-9.

 

32. Spector TD, Hochberg MC. The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytic epidemiological studies using meta-analysis. J Clin Epidemiol. 1990;43(11):1221-30

 

 

33. Jennifer H. Barrett *, Paul Brennan, Magdalen Fiddler, Alan J. Silman. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Arthritis and Rheumatism 42 (1999), pp. 1219–1227

 

34. Drossaers-Bakker KW, Zwinderman AH, van Zeben D, Breedveld FC, Hazes JMW. Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis. Ann Rheum Dis 2002;61:405–8

 

35. SIGN Publication No. 48, Published December 2000. Management of Early Rheumatoid Arthritis.[online] Edinburgh.Available at http://www.sign.ac.uk/guidelines/fulltext/48/index.html  [6th august 2004]

 

36. Cleland LG, Hill CL, James MJ. Diet and arthritis. Baillieres Clin Rheumatol 1995;8:771–85

.

 

37.Cleland LG, French JK, Betts WH, Murphy GA, Elliot M. Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J Rheumatol 1988;15:1471–5

 

 

38. Kremer JM, Lawrence DA, Jubiz W, et al. Dietary fish oil and olive oil supplement in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:810–20

 

 

39. Muller H, de Toledo FW, Resch KL. Fasting followed by vegetarian diet in patients with rheumatoid arthritis: a systematic review. Scand J Rheumatol. 2001;30(1):1-10.

 

 40. Mikuls TR, Cerhan JR, Criswell LA, Merlino L, Mudano AS, Burma M, Folsom AR, Saag KG. Coffee, tea, and caffeine consumption and risk of rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum. 2002 Jan;46(1):83-91.

 

41. Jacobsson LT, Hanson RL, Knowler WC, Pillemer S, Pettitt DJ, McCance DR, Bennett PH. Decreasing incidence and prevalence of rheumatoid arthritis in Pima Indians over a twenty-five year period. Arthritis and Rheumatism 37 (1994), pp. 1158–1165.

 

42. Cooper NJ. Economic burden of rheumatoid arthritis: a systematic review. Rheumatology (Oxford). 2000 Jan;39(1):28-33.

 

43. Debashis Singh.2004 Merck withdraws arthritis drug worldwide[Online]. BMJ  2004;329:816 (9 October),Available at < > [7th december 2004]

 

44.Deborah P.M, Symmons MD . Epidemiology of rheumatoid arthritis:determinants of onset ,persistence ans outcome.

 

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