Are You Sure the Patient Has Rheumatoid Arthritis?

Revised American Rheumatology Association Criteria for the Classification of Rheumatoid Arthritis (RA):

For classification purposes, a patient is said to have RA if he or she has satisfied at least 4 of the following 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded:

  • morning stiffness

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  • arthritis of 3 or more joints simultaneously

  • arthritis of hand joints

  • symmetric arthritis

  • rheumatoid nodules

  • rheumatoid factor

  • radiographic changes

Morning stiffness is characterized as in and around the joints, lasting at least 1 hour before maximal improvement.

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 joint areas are right or left proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, wrist, elbow, knee, ankle, and metatarsophalangeal (MTP) joints.

Arthritis of hand joints: At least 1 area swollen (as defined above) in a wrist, MCP or PIP joint.

Symmetric arthritis: Simultaneous involvement of the same joint areas (see 2 above) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry).

Rheumatoid nodules: Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician.

Positive serum rheumatoid factor.

Positive anti-citrullinated protein antibodies (ACPAs).

Radiographic changes: Radiographic changes typical of RA on poster anterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized to, or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify).

Involvement of the thoracic and lumbar spine are very uncommon in RA; the most common causes of severe back pain in RA patients are degenerative joint disease and corticosteroid induced compression fractures.

Hips are often spared in RA, however when it does occur and the symmetric erosive process becomes established, bilateral protrusion of the acetabulae is inevitable.

Knee involvement is common in early and progressive RA.

In the foot subtalar and talonavicular joints are commonly affected as is disease of the metatarsal heads.

What Else Could the Patient Have?

The differential diagnosis of a patient with polyarthritis includes: rheumatoid arthritis, postviral arthritis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, and polyarticular gout/pseudogout, and infectious arthritis. Blood tests, clinical exam, and duration of symptoms determine the ultimate diagnosis. Rarely inflammatory arthritis can represent a paraneoplastic syndrome.

Key Laboratory and Imaging Tests

Blood tests and x-rays may be negative early on in RA, however recognized prognostic factors include: rheumatoid factor, anticyclic citrullinated protein (anti-CCP), acute phase reactants (ESR, CRP) female sex, joint damage seen by radiologic images, functional impairment – health assessment questionnaire (HAQ).

Rheumatoid factors are antibodies directed against the Fc portion of IgG; the RF most commonly measured is an IgM RF, although others have been described. Sensitivity of the RF test for RA has been reported as high as 90%, but RF positivity is seen in a variety of rheumatic diseases.

Anti-CCP antibodies are directed against a filaggrin antigen and has a specificity of approximately 95% among patients meeting the criteria for RA. Anti-CCP is also very useful in the early diagnosis of rheumatoid arthritis in high-risk groups, such as relatives of RA patients.

In rheumatoid arthritis, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.

Ultrasound is used to assess inflammatory arthritis: these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound, which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of rheumatoid arthritis, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.

Magnetic resonance imaging (MRI) also may detect bone erosions earlier in the course of the disease than is possible with plain films. Decreased signal from the bone marrow on T1-weighted images and enhancement of the marrow with gadolinium administration is interpreted as bone marrow edema. The presence of marrow edema on MRI is predictive of later development of erosive disease.

Other Tests That May Prove Helpful Diagnostically

Antinuclear antibody testing maybe helpful to determine if there is overlap of RA with other autoimmune disorders.

Management and Treatment of the Disease

American College of Rheumatology/European League Against Rheumatism Criteria for Clinical Remission of RA in Clinical Trial (2011). At any point, patient must satisfy all of the following:

  • tender joint count = 1 or less

  • swollen joint count = 1 or less

  • C reactive protein = 1 mg/dl or less

  • patient global assessment = 1 ( on a 0-10 scale)

Treatment of Rheumatoid Arthritis

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Numerous NSAIDs are available and individual response can vary. Long acting preparations should be preferred for efficacy and to reduce morning stiffness. NSAIDs do not affect underlying pathophysiologic damage to joints.

Disease Modifying Agents (DMARDs)

Early introduction of DMARDs is common practice now and is supported from studies comparing early versus delayed DMARD use in early RA and also placebo controlled trials. In an analysis of 1435 patients from 11 different studies, 53% of patients with disease duration less than 1 year responded to DMARD therapy, whereas patients with longer disease showed diminished response. Selection of the first disease modifying agent is commonly hydroxychloroquine and/or methotrexate.

Methotrexate is considered to be the “anchor drug” for RA. The recently conceived European League Against Rheumatism (EULAR) recommendation is that methotrexate be part of the first treatment strategy in RA; when methotrexate is contraindicated (or intolerance is present) then leflunomide or sulfasalazine should be considered.


Corticosteroids have been shown to have both anti-inflammatory and disease modifying properties; they are very effective in suppressing Cox-2 and proinflammatory cytokines and proteases. Steroids are used as a part of an induction treatment, as rescue treatment during an acute flare, and at low doses as part of maintenance therapy. There is evidence that low dose prednisone (5.0mg) in combination with DMARDs slows radiographic progression. Intra-articular steroids, as adjunctive therapy, can also effectively suppress local synovitis. Long-term steroid use is limited by its side effects; rate of bone loss is proportional to steroid dose exposure. In fact, early exposure correlates with bone loss at 2 years, even after steroids have been discontinued. Additional side effects include hypertension, diabetes, atherosclerosis, and adrenal suppression which can be more difficult to quantify.

Biologic Agents

Biologic agents i.e., Tumor necrosis factor inhibitors (TNF) are recommended if DMARDs have failed. Unless, contraindicated, they should be used in combination with methotrexate (or other DMARDs) since the combination has greater efficacy than monotherapy with most biologic agents. Best efficacy is available presently for eight biological agents (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab). The pharmacokinetics each differ from each other; in slightly varying degrees all have been shown to relieve the signs and symptoms of RA, prevent joint space narrowing and erosions, and improve physical function. Due to the risk of infection, skin cancer, and possibly lymphoma patients on TNF inhibitors need to be followed closely.

Of note is that tofacitinib, the first oral biologic medication and an oral Janus kinase inhibitor was approved for RA in November 2012.

Of note is that Hellgren K et al reported no increased risk of malignancy in patients on TNF inhibitors treated for: spondyloarthropathy; psoriatic arthritis; and ankylosing spondylitis/site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6.

Osteoporosis in Rheumatoid Arthritis

Haugeberg et al have demonstrated a 2-fold increase in osteoporosis in female RA patients aged 20-70 years as measured by bone density. Vis et al studied one hundred fifty female RA patients with RA, mean age 61 years, disease duration 17 years. Fifteen percent were treated with bisphosphonates, 25 percent received calcium and 20 percent received vitamin D at baseline. At 5 year follow-up 16% had a new nonvertebral fracture and 19 % had new vertebral fractures identified on spinal x-ray.

Ghazi, et al found vertebral fractures in RA were inversely related to DMARD and glucocorticoid use.

The key mediator of joint inflammation and bone resorption in inflammatory arthritis is TNF. TNF both promotes bone destruction and inhibits bone formation. Bone loss in RA may occur as a result of direct disease; the bone loss is most pronounced in areas immediately surrounding the affected joints, most likely due to local release of inflammatory cytokines. Periarticular osteoporosis, in fact, is also the first radiographic disease related sign before joint erosions and joint space narrowing take place in RA, and is more commonly seen in the hands as compared to the hip and spine. Because of this phenomenon it is recommended that DEXA testing in RA include the forearm. Joint pain and swelling can also result in inactivity causing generalized bone loss.

Corticosteroids, although undoubtedly effective in RA, are limited by long-term toxicity. Rate of bone loss is proportional to steroid use, and early exposure to steroids correlates with bone loss at two years. The American College of Rheumatology has guidelines for prevention and treatment of glucocorticoid-induced osteoporosis:

  • Calcium and vitamin D (800 IU/day or an activated form of vitamin D should be given to all steroid patients.

  • Supplementation has been shown to prevent bone loss in low-to-medium dose glucocorticoid therapy; there is no data to support anti-fracture efficacy.

  • Bisphosphonates are effective for both prevention and treatment of glucocorticoid bone loss.

  • Treatment with bisphosphonates is recommended to prevent bone loss in all men and postmenopausal women in whom > or = 5mg of prednisone is initiated for more than three months in whom the T score at the lumbar spine or hip is below normal.

  • Teriparatide injection for the treatment of osteoporosis associated with sustained systemic glucocorticoid injection ( > or = to 5mg/day of prednisone); patients in this category often include those with multiple risk factors for fracture and those who have been intolerant to other available treatments for osteoporosis.

  • There are no data on the use of denosumab in steroid induced osteoporosis.

What’s the Evidence?/References

Haugeberg, G. “Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis.”. Arthritis and Rheum. vol. 43. 2000. pp. 522-30. (An analysis of disease activity and demographic factors affecting bone loss in early RA.)

Ghazi, M. “Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids.”. Osteoporosis Int 2010.. (An important article highlighting disease activity and treatment affects the incidence of vertebral fracture in RA patients.)

Pinals, RS. “Criteria for Clinical Remission in RA.”. Bull Rheum Dis. vol. 2. 1992. pp. 7-10. (Six criteria identified for clinical remission in RA regarding morning stiffness, fatigue, joint tenderness, joint pain, joint swelling, ESR.)

Felson, DT. “American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials.”. Annals Rheum Dis. vol. 70. 2011. pp. 404-13. (The authors propose two new definitions of remission and recommend that one of these be selected as an outcome measure in each RA trial and that the results on both be reported for each trial.)

Singer, O. “Methotrexate versus leflunomide in rheumatoid arthritis: what is new.”. Curr Opinion Rheum. vol. 23. 2011. pp. 288-92. (Leflunomide offers an alternative with comparable efficacy to MTX as both monotherapy and, as preliminary data suggest, in combination with certain biologics agents. Addition of Leflunomide to MTX in RA patients who have failed MTX monotherapy also has added therapeutic benefit.)

Arnett, FC. “The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis (1987).”. Arthritis Rheum.. vol. 31. (1988). pp. 315-24. (For classification purposes, a patient is considered to have rheumatoid arthritis if he/she has satisfied at least 4 of 7 criteria. Criteria 1 through 4 (morning stiffness, 3 joints or more involvement, hand involvement, and symmetry) must have been present for at least 6 weeks.)

McInnes, I. “Cytokines in the pathogenesis of rheumatoid arthritis.”. Nat Rev Immunol. vol. 7. 2007. pp. 429-442. (A discussion of the role of cytokines in the immunological process in RA)

Schueller-Weidekamm, C. “Modern ultrasound methods yield stronger arthritis workup 2010 Diagnostic Imaging:”. pp. 20-22. (A physiologic review of cytokines and their effects on fatigue, articular damage, and anemia.)

McQueen, FM. “The Use of MRI in early RA.”. Rheumatology (Oxford).. vol. 47. 2008. pp. 1597-9.

Wassenberg, S. “Very low does prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo controlled trial.”. (2005) Arthritis Rheum:. vol. 52. pp. 3371-80. (Bone edema, erosions and synovitis are very early MRI findings of RA and MRI of the hand and wrist in clinical diagnosis of RA is useful to assess the degree of involvement.)

Vis, M. “High incidence of vertebral and non-vertebral fractures in the OSTRA cohort study: a 5-year follow-up study in postmenopausal women with rheumatoid arthritis (2011) Osteoporosis Int:”. vol. 22. pp. 2413-9. (The authors found a high incidence rate of vertebral and non-vertebral fracture rates during a follow-up of 5 years in patients with established RA compared to the general population. The study only revealed well-known risk factors for new vertebral fractures and new non-vertebral fractures, respectively baseline non-vertebral fractures and BMD of the hip at baseline.)

Goeldner, I. “Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil.”. Rheumatology (Oxford).. vol. 49. 2010. pp. 1590-3.

Hellgren, K. “Extended report: Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers (2016) Annals of Rheumatic Dis:”.

Fleischmann, R. “Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis.”. N Engl J Med. vol. 367. 2012. pp. 495-507.