What is the role of conventional DMARD in rheumatoid arthritis treatment

DMARD are disease modifying antirheumatic drugs, they are so called because of their ability to prevent and slow the structural damage to joint and save the joint in rheumatoid arthritis.These are known as slow-acting "second-line drugs.Prior to the invention of these drugs treatment is aimed to reduce the pain and discomfort to people than slow the actual underlying disease process.DMARD have thus revolutionized the treatment and elevated treatment goal. 

What are the advantages of DMARDS in RA?

1.These agents substantially reduce the inflammation in joints.

2.Prevent or slow down the joint damage.

3.Help to preserve the joint structure and function so the affected person can lead normal life and enable to do all daily activities as far as possible.

When to start DMARD?

Since the critical period in RA is first year of onset of disease, bone and joint damage occurs early, DMARDS cannot reverse the existing damage already occurred, they can only protect the joint from further progression of disease process.It is better to start them early to avoid joint destruction.As soon as the person is diagnosed with this disease Rheumatologists now start with a DMARD.Methotrexate is the most commonly prescribed drug.The faster the patient is strated on DMARD sooner it slow down the joint damage.

How they act in RA?

They will act on specific part of immune system and bring down the abnormally increased immune response.Basic pathology in RA is abnormal immune response which damage the joints.Earlier treatment with them have improved the function and reduced the structural damage to joint that is even within months of diagnosis.Most people need aggressive secondline drugs to treat the situation that is methotrexate.

How long it take to get improvement in disease?

The time requied to produce improvement varry depending on individual agent.

4 to 6 weeks of treatment with methotrexate

1 to 2months with salfasalazine

2 to 3 months for hydroxychloroquine

Sometime they need to take for years at varying doses to get optimal results

Conventional DMARDS  in Rheumatoid arthritis treatment 

DMARDS come in variety of forms and are listed below. 

Methotrexate (Trexall, Rheumatrex, Otrexup),leflunomide (Arava), hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine)

Methotrexate 

This is the initial DMARD of choice and is the main drug for combination therapy.This is an immune suppressing agent and decreases the joint inflammation.Since 1986 it is approved for treatment of RA.This is the initial second-line drug because of the following. 

1.Methotrexate is effective and it has infrequent side effects compared to other DMARDS.

2.Dose adjustment of methotrexate is flexible.Dose adjustment done as per need.

Side effects of this drug are ,it may affect bonemarrow and liver  rarely cause cirrhosis of liver and allergic reaction in lung.So regular monitoring of liverfunction and complete blood count is required in all people  while on this drug.Taking folic acid recommended to  reduce the risk of methotrexate side effects.

Dose of methotrexate is 10–25 mg/week orally or SQ Folic acid 1 mg/d to reduce toxicities.Other common side effects are mouth ulcers fatigue, hair loss ,vomiting and loose stool.Before starting treatment check CBC, LFTs Viral hepatitis panel and Chest x-ray.

Monitor CBC, creatinine, LFTs every 2–3 months while on treatment.

Leflunomide (Arava) 

Helps to relieve the symptoms and slowdown the progression of the RA.Clinical efficasy similar to methotrexate.Common side effects of this dugs are hair loss, diarrhea, rash in some people.Serious side effects include increased susceptibility to infection,liver damage, bone marrow suppression.This drug is not safe in pregnancy.As it produces birth defects it should not be taken during pregnancy and those women who want to become pregnant while on drugs.Dose is 10–20 mg/d.Before starting therapy blood count,liver function test and viral hepatitis panel should be done. While on this agent regular monitoring of CBC, creatinine, LFT every 2–3 months is recommended.

Hydroxychloroquine  (Plaquenil) 

It has been used for long periods  to treat RA..But it wont produce radiographic improvement.Dosage of this drug is 200–400 mg/d orally(=6.5 mg/kg)

This is used  in early mild cases and in combination therapy with other DMARD. The common side effect of this drug include upset of stomach, diarrhea,vomiting ,headache. muscle weakness ,skin rashes, and vision changes.Prior to starting this drug eye examination is done in all people who are more than 40 years old and those with past history of eye disease.People on this drug require regular monitoring of vision by an eye doctor (ophthalmologist) every year after starting drug.Other serious adverse reactions of this drugs are toxicity of heart and abnormality in blood count.

Sulfasalazine (Azulfidine)

This is an oral drug used to treat RA along with other antiinflammatory agents.This drug is usually well tolerated by people.The common side effects are stomach upset rash,vomiting and diarrhea.The serious side effect is low blood count thus predispose to infection.As Azulfidine  contain  sulfa and salicylate compounds this should  be avoided in people with past history of allergy to sulfa.Initial dose of drug is 500 mg orally twice daily and maintenance dose is 1000–1500 mg twice daily.Before starting these drugs blood count,liver function test and G6PD level need to be tested.For people on salfasalazine blood count should be monitored every 2–4 weeks for first 3months,then every3 months

Conventional  agents may be used alone or in combination in the treatment of RA 

Immunosuppressants in the treatment of RA

Immunosuppressants are used in the treatment of refractory aggressive case of RA , where all other therapy fails.Also in those people with severe complication of RA that is blood vessel inflammation.They include azathioprine (Imuran), cyclophosphamide(Cytoxan), cyclosporine and chlorambucil(Leukeran), 

These agents may suppress the bonemarrow and produce anemia,low platelet count and low toatal WBC  count.Thus increases the risk for infection,and bleeding.

Agents like Gold ,Pencillamine are rarely used nowadays due to poor clinical efficacy and toxic profile. 

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Clinical features of osteoarthritis

Most common manifestation of osteoarthritis is joint pain and it is activity related pain occur during activity or immediately after the use of joint and it decreases gradually.

Site of pain - example

1. Hip and knee pain going up and down stairs.
2. Pain in weight bearing joints  while walking.
3. Hand osteoarthritis - pain while cooking.

Nature of pain.

Early in the disease, pain is present only when the affected joint is overused, but later the pain become constant and present even at night. This is associated with stiffness of joint. If early morning stiffness is present, it is very brief usually less than 30 minutes.

Osteoarthritis of knee joint.

In osteoarthritis of knee joint, pain occur on bending the knee. Some people experience buckling, catching and locking of the knee joint. Osteoarthritis of knee joint is the most common cause of chronic knee pain in persons over 45 yrs. In hip osteoarthritis restriction of hip movements will occur.

Investigation in osteoarthritis.

No blood test is required for evaluation of patients with osteoarthritis.

Tests that may be done.

1. Synovial fluid analysis.
2. Xray of joint.
3. MRI test.

Synovial fluid analysis.
If the WBC count more than 1000 it indicate inflammatory arthritis or gout

Xray

Correlate poorly with disease activity and joint pain .It may be normal in the early disease.It is indicated if the joint pain does not respond to usual management.

White arrow indicates joint space reduction compared to opposite side

MRI

Not a routine part of osteoarthritis evaluation.

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Clinical feature of gout

Gout is a disease in which body uric acid pool is increased. This will lead to deposition of urate crystals in the joints. Most people with hyperuricemia are asymptomatic. Gout is typically seen in middle aged men. Attacks may be precipitated by excessive food, alcohol, dehydration and diuretic therapy.

Clinical syndrome caused by hyperuricemia

1. Acute urate synovitis –acute gout.
2. Chronic urate polyarticular gout.
3. Chronic tophaceous gout. 
4. Urate renal stone formation.

Commonest clinical presentation is sudden onset pain in a single joint. Common sites affected are the following. In 50% of cases it involves big toe (metatarsophalangeal joint) as shown in figure.

Podagra. Acute gout with  swelling and erythema

Other sites affected are 

1. Ankle
2. Midfoot
3. Knee
4. Small joints of hands
5. Wrist
6. Elbow

Large joints of limbs and axial skeleton (spinal joints) are rarely affected.

Acute gout

Characteristic features of pain in acute gout are given below

1. Sudden onset of pain, which reach maximum severity in 2 to 6 hours, it may wake up the patient in early morning.
2. Patients describe the pain as very severe and ‘worst pain ever’.
3. On touching the area severe tenderness occur, patient cannot even wear a sock or let bedding rest on the joint.
4. There can be marked swelling with overlying skin become red and shiny.
5. The disease is self-limiting, pain resolves over 5 to 14 days, with complete resolution.
6. Once the attack subsides, pruritus (itching) and desquamation of skin is seen.
7. Along with the above features there can be fever, malaise and confusion particularly if large joints are affected.
8. Some patients experience only milder attack. More than one joint may be affected. Cluster attack can occur ,in such case other joint is affected after a few days. But polyarticular involvement is unusual.

Chronic gout

Chronic pain and damage to joints occur which may lead to severe disability and functional impairment. If the hyperuricemia is uncontrolled repeated attack can occur  and progress to chronic gout. 

Tophus with white monosodium urate monohydrate

Chronic poly articular gout is rare, it is seen in elderly on long duration of diuretic therapy and chronic renal failure. 

Chronic tophaceous gout - Urate crystal may be deposited in joints and soft tissues to produce tophi, which appear as irregular firm nodule white in colour. Common sites affected are extensor surfaces of fingers, hands, forearm, elbows, Achilles tendons (back of the ankle joint) and the helix of the ear. Tophi may undergo ulceration and infection.

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