Instruments to Measure Rheumatoid Arthritis Disease Activity and Define Remission

Patient Activity Scale (PAS) or PAS-II (range: 0-10)
Remission: 0 to 0.25
Low activity: 0.26 to 3.7
Moderate activity: 3.71 to <8.0
High activity: ≥8.0


Routine Assessment of Patient Index Data 3 (range: 0-10)
Remission: 0 to 1.0
Low activity: >1.0 to 2.0
Moderate activity: >2.0 to 4.0
High activity: >4.0 to 10


Clinical Disease Activity Index (range: 0 -76.0)
Remission: ≤2.8
Low activity: >2.8 to 10.0
Moderate activity: >10.0 to 22.0
High activity: >22


Disease Activity Score in 28 joints (range: 0- 9.4)
Remission: <2.6
Low activity: ≥2.6 to <3.2
Moderate activity: ≥3.2 to ≤5.1
High activity: >5.1


Simplified Disease Activity Index (range: 0- 86.0)
Remission: ≤3.3
Low activity: >3.3 to ≤11.0
Moderate activity: >11.0 to ≤26
High activity: >26

Rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) has a typical onset in middle age with a stronger predominance in women. Testing for serum RF and anticyclic citrullinated peptide (CCP) antibodies, a test with higher specificity, may help corroborate or provide a harbinger for clinical diagnosis of RA. It should be noted that serum RF may not be positive in the early stages of RA, in contrast to the anti-CCP antibody, which may predate full-blown RA by months to years.

In regards to the differential diagnosis of RA, various forms of viral arthritis, most notably, arthritis due to parvovirus B19, hepatitis B (in the anicteric phase), hepatitis C, and human immunodeficiency virus (HIV), can present with sudden onset joint pain and/or swelling.

Early disease modifying antirheumatic drug (DMARD) therapy in RA substantially improves signs and symptoms of the disease, limits joint damage, and improves outcomes and long-term prognosis. Methotrexate is the most common first DMARD initiated for RA, and a typical starting dose is between 7.5 to 15 mg weekly. Methotrexate is optimally administered with daily folic acid supplementation. While nonsteroidal anti-inflammatory drugs (NSAIDs), like diclofenac, may provide relief of signs and symptoms, they do not improve outcomes or prognosis in RA.


Disease modifying antirheumatic drug therapy should be started early, ideally within 3 months from the onset of symptoms. The most commonly initiated first DMARD for RA is methotrexate. With the initiation of methotrexate, patients should have baseline liver enzymes and a complete blood count (CBC), and these tests should be monitored at regular intervals to exclude hematologic or hepatic toxicity attributable to methotrexate.


The 2012 ACR recommendations suggest to measure RA disease activity in a quantitative way, and to therapeutically aim for a target of remission or low disease activity; however the recommendations do not specify which specific measurement tools to use.
The RAPID3 (Routine Assessment of Patient Index Data 3 ),
CDAI (Clinical Disease Activity Index),
DAS28 (Disease Activity Score in 28 joints with ESR), and
SDAI (Simplified Disease Activity Index)
are all mentioned in the ACR guidelines, however use of any of these measures as well as the HAQ-DI (Health Assessment Questionnaire Disability Index) are appropriate to use as long as they are used consistently to follow RA disease activity over time.



2012 ACR Recommendations for the Treatment of Early RA (<6 Months)




ACR = American College of Rheumatology; CCP = cyclic citrullinated peptide; DMARD = disease modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire-Disability Index; HCQ = hydroxychloroquine; LEF = leflunomide; MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumor necrosis factor.
aPatients were categorized based on the presence or absence of 1 or more of the following poor prognostic features: functional limitation (eg, HAQ-DI or similar validated tools), extra-articular disease (eg, presence of rheumatoid nodules, RA vasculitis, Felty’s syndrome), positive rheumatoid factor or anti-CCP antibodies, and bony erosions by radiograph.
bCombination DMARD therapy with 2 DMARDs, which is most commonly MTX-based with some exceptions (eg, MTX+HCQ, MTX+LEF, MTX+sulfasalazine, and sulfasalazine+HCQ), and triple therapy (MTX+HCQ+sulfasalazine).




The majority of the clinical trials with the anti-TNF agents have examined patients who had previously failed treatment with nonbiologic DMARDs, where biologic agents were added to methotrexate. These studies have consistently demonstrated, largely across the different anti-TNF agents, that anti-TNF agents have superior efficacy in terms of disease activity and retarding progression of radiographic damage (bone erosions and joint space narrowing) compared to the use of methotrexate alone.


Anti-TNF agents have been associated with a heightened risk for both typical and atypical infections based on both clinical trials and large observational studies. The 2012 ACR guidelines recommend the use of either a TB skin test (purified protein derivative [PPD]) or an interferon gamma release assay (IGRA), commonly called a quantiferon test, for TB screening prior to use of biologic agents.
The IGRA has a particular advantage in patients who have been vaccinated in the past with the Bacillus Calmette-Guérin vaccine.


Evidence has not shown increased efficacy for doubling the frequency of dosing for anti-TNF therapy (i.e if patient having moderate disease activity even with alternate weekly dose of adalimumab 40) and the combination of biologics has been associated with unacceptable toxicity. According to the guidelines, this patient should be switched to either a different anti-TNF agent or to a non-TNF biologic agent (abatacept, rituximab, or tocilizumab)



2012 ACR Recommendations for the Treatment of Established RA Disease (Duration ≥6 Months).


There have been several studies that have examined the additive use of biologic agents and while there may be some synergistic benefit in terms of efficacy, the toxicity, particularly from infections, has been considered unacceptable for the use of combinations of biologic agents. Thus, combination biologic therapy (eg, abatacept plus an anti-TNF agent ) is not recommended based upon the available evidence.



The 2012 ACR guidelines recommend against administering live virus vaccinations including influenza vaccine administered by nasal spray, herpes zoster vaccination, and yellow fever vaccine in patients currently on biologic therapy. Inactivated vaccines including injectable influenza and pneumococcal vaccinations may safely be given to patients receiving biologic agents and nonbiologic DMARDs.

2012 ACR recommendations Regarding the Use of Vaccines in Patients With RA Starting or Currently Receiving DMARDs or Biologic Agents

	Killed Vaccines			Recombinant Vaccine	Live Attenuated Vaccine
	Pneumococcala	Influenza (intramuscular)	Hepatitis Bb	Human papillomavirus	Herpes zoster
Before initiating therapy:
DMARD     monotherapy	√	√	√	√	√
Combination     DMARDs	√	√	√	√	√
Anti-TNF     biologics	√	√	√	√	√
Non-TNF     biologics	√	√	√	√	√
While already taking therapy:
DMARD     monotherapy	√	√	√	√	√
Combination     DMARDs	√	√	√	√	√
Anti-TNF     biologics	√	√	√	√	Not recommended
Non-TNF     biologics	√	√	√	√	Not recommended

Post-meal time glucose spikes are to be prevented because:

• Lowering A1c reduces microvascular complications
• A1c reflects PPG as well as fasting plasma glucose levels (individuals are “postprandial” most of the 24-hour period)
• Control of PPG levels reduces intima-media thickness and decreases cardiac events (as shown in the STOP-NIDDM and other trials)
• Elevated PPG levels are a highly prevalent issue, especially in the elderly.
• Abundant experimental evidence relates acute hyperglycemia and glucose excursions to endothelial dysfunction and increased oxidative load.
• Elevated blood glucose levels 2 hours after a glucose load are associated with an increased risk for death, independent of fasting blood glucose levels (even in non-diabetic persons). The European Prospective Investigation into Cancer Study–Norfolk cohort study further raises questions as to the level of A1c associated with increased risk.

Estimated Average Glucose

Table. Estimated Average Glucose

A1c (%)	mg/dL* (95% confidence intervals)	mmol/L† (95% confidence intervals)
6	126 (100-152)	7.0 (5.5-8.5)
7	154 (123-185)	8.6 (6.8-10.3)
8	183 (147-217)	10.2 (8.1-12.1)
9	212 (170-249)	11.8 (9.4-13.9)
10	240 (193-282)	13.4 (10.7-15.7)
11	269 (217-314)	14.9 (12.0-17.5)
12	298 (240-347)	16.5 (13.3-19.3)

Principles of the AACE/ACE Algorithm for Glycemic Control

Principles of the AACE/ACE Algorithm for Glycemic Control

• Early aggressive glucose control, the importance of which has been demonstrated by the DCCT/EDIC trial
• Targeting PPG excursions, particularly at lower A1c levels (where they comprise a significant component of the A1c)
• Stratified treatment protocols based on presenting A1c in drug naïve patients or A1c on treatment when not at goal
• Combination therapy early in the treatment paradigm initially at an A1c of 7.6%-9.0% or after 2 to 3 months of monotherapy at an A1c of 6.5%-7.5%
• Advancing therapy at 2- to 3-month intervals, addressing the problem of clinical inertia

ADA practice recommendations regarding the prevention and management of diabetes complications

In light of the above strong evidence linking diabetes and CVD and to control and prevent the microvascular complications of diabetes, the ADA has issued practice recommendations regarding the prevention and management of diabetes complications.

Blood pressure should be measured routinely. Goal blood pressure is < 130/80 mmHg. Patients with a blood pressure ≥ 140/90 mmHg should be treated with drug therapy in addition to diet and lifestyle modification. Patients with a blood pressure of 130-139/80-89 mmHg may attempt a trial of lifestyle and behavioral therapy for 3 months and then receive pharmacological therapy if their goal blood pressure is not achieved. Initial drug therapy should be with a drug shown to decrease CVD risk, but all patients with diabetes and hypertension should receive an ACE inhibitor or ARB in their antihypertensive regimen.

Lipid testing should be performed in patients with diabetes at least annually. Lipid goals for adults with diabetes should be an LDL < 100 mg/dl (or < 70 mg/dl in patients with overt CVD), HDL > 50 mg/dl, and fasting triglycerides < 150 mg/dl. All patients with diabetes should be encouraged to limit consumption of saturated fat, trans fat, and cholesterol. Statin therapy to lower LDL by 30-40% regardless of baseline is recommended to decrease the risk of CVD in patients > 40 years of age. Patients < 40 years of age may also be considered for therapy. In individuals with overt CVD, special attention should be paid to treatment to lower triglycerides or raise HDL. Combination therapy with a statin plus other drugs, such as fibrates or niacin, may be necessary to achieve ideal lipid control, but patients should be monitored closely for possible adverse reactions of therapy.

Aspirin therapy (75-162 mg/day) is indicated in secondary prevention of CVD and should be used in patients with diabetes who are > 40 years of age and in those who are 30-40 years of age if other risk factors are present. Patients < 21 years of age should not receive aspirin therapy because of the risk of Reye's syndrome. Patients who cannot tolerate aspirin therapy because of allergy or adverse reaction may be considered for other antiplatelet agents.

In addition to the above pharmacological recommendations, patients with diabetes should be encouraged to not begin smoking or to stop smoking to decrease their risk of CVD and benefit their health in other ways. It should also be noted that statins, ACE inhibitors, and ARBs are strongly contraindicated in pregnancy.

Micro & Macrovascular Diseases

Microvascular disease is a process through which the very small branches of arteries throughout the body become damaged.  Microvascular disease is a common component of other conditions, such as diabetes mellitus and autoimmune diseases.

The very small branches of the arteries are delicate but very important structures.  Damage to these vessels results in occlusion of the vessels and impairment of blood flow.  In many situations the small arteries can re-grow and overcome the blockage, a process called angiogenesis.  This is part of the normal healing process.  In microvascular disease the commonest cause is chemicals within the blood that damage the very delicate lining of the small arteries and causes the blood to clot in the artery and block it.  Sometimes these chemicals are produced by the body itself as part of the immune response and is called an autoimmune microvascular disease.  Occasionally microvascular disease is the result of abnormalities in the cells that form part of the blood.

The commonest symptoms are pain and discoloration of the extremities, usually the fingers and toes, sometimes even leading to gangrene.  These symptoms are very similar to those cause by occlusion of the larger arteries except that it is not associated with muscle pain on exercise (intermittent claudication) and the blood pressure in the larger arteries is normal.

Microvascular disease usually affects the whole body to some degree and the most serious complications are caused by damage to the vital organs (e.g. heart, brain, kidneys, liver).
Treatment for microvascular disease is directed at the underlying cause.  Lifestyle changes to eliminate factors that aggravate the condition, such as smoking, should be the first line of treatment.  A complete medical assessment is required to identify the underlying cause if possible.  If there is an autoimmune element to the condition, then referral to a rheumatologist may be required.  If there is an abnormality in the blood referral to a haematologist is required. Surgery plays only a secondary role in the management of microvascular disease.

• Diabetic retinopathy
• Diabetic nephropathy
• Diabetic neuropathy

Macrovascular disease is a disease of any large (macro) blood vessels in the body. It is a disease of the large blood vessels, including the coronary arteries, the aorta, and the sizable arteries in the brain and in the limbs.
This sometimes occurs when a person has had diabetes for a long time. Fat and blood clots build up in the large blood vessels and stick to the vessel walls.
Three common macrovascular diseases are coronary disease (in the heart), cerebrovascular disease (in the brain), and peripheral vascular disease (in the limbs)