RHEUMATOID ARTHRITIS AND

ACUTE RHEUMATIC FEVER

INTRODUCTION
• Rheumatoid arthritis (RA) is the most common form of chronic
inflammatory arthritis.

• Rheumatoid arthritis (RA) is a chronic inflammatory disease of

unknown etiology characterized by a symmetric polyarthritis
with varied systemic manifestations.
EPIDEMIOLOGY
• RA affects ~0.5–1% of the adult population worldwide
• In INDIA, the prevalence is 0.5 to 0.7 % of adult population
• RA occurs more commonly in females than males with a ratio of 3:1
• The incidence of RA increases between 25 and 55 years of age, after which it
plateaus until the age of 75 and then decreases.
ETIOLOGY
A)GENETIC CONSIDERATIONS
• First-degree relative of RA patient carries 2–10 fold risk of developing RA.
• Most of the risk is associated with HLA-DRB1 gene(encoded by MHC II β)
• Non-MHC genes contributing to the risk of RA is protein tyrosine phosphatase non-
receptor 22 (PTPN22). It is exclusively seen in anti CCP positive disease.
• The peptidyl arginine deiminase type IV (PADI4) gene is another risk allele seen in
only Asian population.
• In India, HLA-DRB1 *0405 allele has been shown to confer highest risk followed by
*0401.
B)ENVIRONMENTAL FACTORS
• Smoking confers a relative risk for developing RA of 1.5–3.5.
• The risk from smoking is almost exclusively related to RF and anti-CCP antibody-
positive disease.
• Certain viruses such as Epstein-Barr virus (EBV) , parvo virus etc have been linked to
cuasation of RA.
• Microbial dysbiosis of the oral or gut microbiome(Prevotella copri) may predispose
to the development of RA in at risk population.
• Periodontitis caused by P. gingivalis may play a role in the pathogenesis of RA.
• P gingivalis contains PADI 4 enzyme which converts arginine to citrulline.
PATHOLOGY
• The pathologic hallmarks of RA are synovial inflammation and proliferation , focal
bone erosions, and thinning of articular cartilage.
• Chronic inflammation leads to synovial lining hyperplasia and the formation of
pannus, a thickened cellular membrane containing fibroblast-like syno-viocytes and
granulation-reactive fibrovascular tissue that invades the underlying cartilage and
bone.
• The inflammatory infiltrate is made up of six cell types: T cells, B cells, plasma cells,
dendritic cells, mast cells, and, to a lesser extent, granulocytes.
• Growth factors secreted by synovial fibroblasts and macrophages promote the
formation of new blood vessels in the synovial sublining that supply the increasing
demands for oxygenation and nutrition required by the infiltrating leukocytes and
expanding synovial tissue.
• The structural damage to the mineralized cartilage and subchondral bone is
mediated by the osteoclast.
• Another form of bone loss is periarticular osteopenia that occurs in joints with active
inflammation. It is associated with substantial thinning of the bony trabeculae along
the metaphyses of bones, and likely results from inflammation of the bone marrow
cavity.
PATHOGENESIS
• The pathogenic mechanism implicated is dysregulation of the immune system and a
breakdown in self-tolerance.
• The pathogenesis of RA is built upon the concept that self-reactive T cells drive the
chronic inflammatory response. In theory, self-reactive T cells might arise in RA from
abnormal central (thymic) selection or intrinsic defects lowering the threshold in the
periphery for T cell activation.
EVIDENCE OF CD4+ T CELLS
CD4 on the surface of T cells binds to invariant sites on MHC class II molecules,
stabilizing the MHC- peptide–T cell receptor complex during T cell activation.
• Thus CD4+ T cells play an important role in orchestrating the chronic inflammatory
response in RA.
• Activated B cells are also important players in the chronic inflammatory response. B
cells give rise to plasma cells, which in turn, produce antibodies, including RF and
anti-CCP antibodies. RFs may form large immune complexes inside the joint that
contribute to the pathogenic process by fixing complement and promoting the
release of proinflammatory cytokines and chemokines.
• RA is often considered to be a macrophage-driven disease because this cell type is
the predominant source of proinflammatory cytokines inside the joint. Key
proinflammatory cytokines released by synovial macrophages include TNF-α, IL-1, IL-
6, IL-12, IL-15, IL-18, and IL-23.
CLINICAL FEATURES

• RA typically produces inflammation of the joints, tendons, and bursae.

• Patients often complain of early morning joint stiffness lasting more than 1 hr that
eases with physical activity.
• The earliest involved joints are typically the small joints of the hands and feet.
• Involvement may be monoarticular, oligoarticular (≤4 joints), or polyarticular (>5
joints), usually in a symmetric distribution .
• Once the disease process of RA is established, the wrists, metacarpophalangeal
(MCP), and proximal interphalangeal (PIP) joints stand out as the most frequently
involved joints
• Ulnar deviation results from subluxation of the MCP joints, with subluxation, or
partial dislocation, of the proximal phalanx to the volar side of the hand.
• Hyperextension of the PIP joint with flexion of the DIP joint (“swan-neck deformity”)
• Flexion of the PIP joint with hyperextension of the DIP joint (“boutonnière
deformity”),
• Subluxation of the first MCP joint with hyperextension of the first interphalangeal
(IP) joint (Z-line deformity)
• Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris
may cause subluxation of the distal ulna, resulting in a “piano-key movement ” of
the ulnar styloid.
• Although metatarsophalangeal (MTP) joint involvement in the feet is an early
feature of disease, chronic inflammation of the ankle and midtarsal regions usually
comes later and may lead to pes planovalgus (“flat feet”).
• Atlantoaxial involvement of the cervical spine is clinically noteworthy because of
its potential to cause compressive myelopathy and neu- rologic dysfunction
EXTRAARTICULAR MANIFESTATIONS
• Extraarticular manifestations may develop in up to 40% of patients, even prior to the
onset of arthritis .
• Patients most likely to develop extraarticular disease have a history of cigarette
smoking, have early onset of significant physical disability, and test positive for serum
RF or anti-CCP antibodies.
1. SUBCUTANEOUS NODULES –
Subcutaneous nodules have been reported to occur in 30–40% of patients.
When palpated, the nodules are generally firm; nontender; and adherent to
periosteum, tendons, or bursae; developing in areas of the skeleton subject to
repeated trauma or irritation such as the forearm, sacral prominences, and Achilles
tendon.
They may also occur in the lungs, pleura, pericardium, and peritoneum.
• 2. SJOGRENS SYNDROME
Secondary Sjögren’s syndrome is defined by the presence of either
keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with
another connective tissue disease, such as RA. Approximately 10% of patients with
RA have secondary Sjögren’s syndrome.
3. CARDIAC
The most frequent site of cardiac involvement in RA is the pericardium. However,
clinical manifestations of pericarditis occur in <10% of patients with RA.
Cardiomyopathy, another clinically important manifestation of RA, may result from
necrotizing or granulomatous myocarditis, coronary artery disease, or diastolic
dysfunction.
Mitral regurgitation is the most common valvular abnormality in RA.
• 4. PULMONARY
Pleuritis, the most common pulmonary manifestation of RA, may produce
pleuritic chest pain and dyspnea, as well as a pleural friction rub and
effusion.
Pleural effusions tend to be exudative with increased numbers of monocytes
and neutrophils and pleural fluid glucose less than 30mg/dl usually.
ILD may also occur in patients with RA and is generally found in patients
with higher disease activity
Caplan’s syndrome is a rare subset of pulmonary nodulosis characterised by
the development of nodules and pneumoconiosis following silica exposure..
• 5. VASCULITIS
Rheumatoid vasculitis typically occurs in patients with long-standing disease, a
positive test for serum RF or anti-CCP anti- bodies, and hypocomplementemia.
The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene,
livedo reticularis, and in severe cases large, painful lower extremity ulcerations.
Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in
association with systemic rheumatoid vasculitis.
• 6. HAEMATOLOGICAL MENIFESTATIONS

• A normochromic , normocytic anemia often develops in patients with RA

and is the most common hematologic abnormality.
• Felty’s syndrome is defined by the clinical triad of neutropenia,
splenomegaly, and nodular RA .
• There is two- to four fold increased risk of lymphoma in RA patients
compared with the general population. The most common type being
diffuse large B cell lymphoma.
ASSOCIATED CONDITIONS
1. CARDIOVASCULAR DISEASES
• The most common cause of death in patients with RA is cardiovascular disease.
• The incidence of coronary artery disease and carotid atherosclerosis and congestive
heart failure is higher in RA patients than in the general population.
2. OSTEOPOROSIS
Osteoporosis is more common in patients with RA than an age- and sex-matched
population.Chronic use of glucocorticoids and disability-related immobility also
contributes to osteoporosis.
DIAGNOSIS
• 2010 ACR-EULAR criteria
LABORATORY FINDINGS
• There will be elevated nonspecific inflammatory markers such as an ESR
or CRP.
a) RF -
• IgM, IgG, and IgA isotypes of RF occur in sera from patients with RA,
Serum IgM RF has been found in 75–80% of patients with RA; therefore, a
negative result does not exclude the presence of this disease.
• It is also found in primary Sjögren’s syndrome, systemic lupus
erythematosus, and type II mixed essential cryoglobulinemia, as well as
chronic infections such as subacute bacterial endocarditis and hepatitis B
and C.
• Serum RF may also be detected in 1–5% of the healthy population.
b) ANTI CCP ANTIBODIES
The presence of serum anti-CCP antibodies has about the same sensitivity as serum
RF for the diagnosis of RA.
However, its diagnostic specificity approaches 95%, so a positive test for anti-CCP
antibodies in the setting of an early inflammatory arthritis is useful for
distinguishing RA from other forms of arthritis.
The isomer of Anti-CCP antibody, which is Anti-CCP 2, has specificity of more than
98%.
• C) ANTI MUTATED CITRULLINATED VIMENTIN ANTIBODY (ANTI-MCV)
DETECTION OF THIS ANTIBODIES IS USEFUL ESPECIALLY IN SERONEGATIVE RA
WITH SENSITIVITY OF 72% AND SPECIFICITY OF 99.7%.

• D) OTHER ANTIBODIES
Approximately 30% of patients with RA test positive for antinuclear antibodies (ANAs),
and some sera from some patients contain antineutrophil cytoplasmic antibodies
(ANCAs; particularly p-ANCA)
c) SYNOVIAL FLUID ANALYSIS
Synovial fluid white blood cell (WBC) counts can vary widely, but generally range
between 5000 and 50,000 WBC/μL compared to <2000 WBC/μL for a
noninflammatory condition such as osteoarthritis. the predominant cell type in the
synovial fluid is the neutrophil.

d) X RAY-
the initial radiographic finding is periarticular osteopenia. Other findings include
soft tissue swelling, symmetric joint space loss, and subchondral erosions, most
frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs). X-ray
imaging of advanced RA may reveal signs of severe destruction, including joint
subluxation and collapse.
e) MRI –
MRI offers the greatest sensitivity for detecting synovitis and joint effusions, as well
as early bone and bone marrow changes.

f) ULTRASOUND-
Ultrasound, including power colour Doppler, has the ability to detect more erosions
than plain radiography, especially in easily accessible joints. It can also reliably
detect synovitis, including increased joint vascularity indicative of inflammation
CLINICAL COURSE
VARIANTS OF RA
1. VERA (VERY EARLY ONSET RA)
2. LORA (LATE ONSET RA)
3. PALINDROMIC RA

DIFFRENTIAL DIAGNOSIS
4. VIRAL ARTHRALGIA
5. POLYMYALGIA RHEUMATICA
6. SLE
7. RS3PE SYNDROME
8. SERONEGATIVE POLYARTHRITIS
TREATMENT
• PHARMACOLOGICAL
• SURGICAL
• PHYSICAL THERAPY AND ASSISTIVE DEVICES
 DRUGS

BRIDGING
NON-BIOLOGICALS BIOLOGICALS
METHOTREXATE NSAIDS TNF-α INHIBITORS
HYDROXYCHLROQUINE STEROIDS INTERLEUKIN 6 INHIBITORS
SULFASALAZINE JAK INHIBITORS
LEFLUNAMIDE CD-20 ANTAGONISTS
IL 1 INHIBITORS
GOLD CD 28/80-86 INHIBITORS
D-PENICILLAMINE
MINOCYCLINE
AZATHIOPRINE
NSAIDS

• NSAIDs exhibit both analgesic and anti-inflammatory properties. The anti-

inflammatory effects of NSAIDs derive from their ability to nonselectively inhibit
cyclooxygenase (COX)-1 and COX-2.
• Chronic use should be minimized due to the possibility of side effects, including
gastritis and peptic ulcer disease as well as impairment of renal function.
GLUCOCORTICOIDS

• Administered in low to moderate doses to achieve rapid disease control before the
onset of fully effective DMARD therapy, which often takes several weeks or even
months.
• High-dose glucocorticoids may be necessary for treatment of severe extraarticular
manifestations of RA, such as ILD.
• If a patient exhibits one or a few actively inflamed joints, the clinician may consider
intraarticular injection of an intermediate-acting glucocorticoid such as
triamcinolone acetonide.
• Methylprednisolone depot preparations can also be used.
DMARDS

• DMARDs are so named because of their ability to slow or prevent structural

progression of RA.
• The conventional DMARDs include hydroxychloroquine, sulfasalazine, methotrexate,
and leflunomide; they exhibit a delayed onset of action of ~6–12 weeks.
• Methotrexate is the DMARD of choice for the treatment of RA and is the anchor
drug for most combination therapies
• Abatacept : It is a soluble fusion protein of human CTLA-4 linked to the modified
portion of human IgG.
• It inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions
and may also inhibit the function of antigen-presenting cells.
• Rituximab: Rituximab is directed against CD20.
• Rituximab has been approved for the treatment of refractory RA in combination
with methotrexate.
• Tocilizumab : It is directed against IL-6 receptor.
• Tofacitinib: primarily inhibits JAK1 and JAK3, which mediate signaling of the
receptors for cytokines.
2. PHYSICAL THERAPY AND ASSISTIVE DEVICES
All patients with RA should receive a prescription for exercise and physical activity.
• Dynamic strength training, community based comprehensive physical therapy, and
physical-activity coaching (emphasizing 30 min of moderately intensive activity most
days a week) have all been shown to improve muscle strength and perceived health
status
• . Foot orthotics for painful valgus deformity decrease foot pain.
3. SURGERY
• For large joints, such as the knee, hip, shoulder, or elbow, the preferred option for
advanced joint disease may be total joint arthroplasty.
• MCP silicone arthroplasty, arthrodesis , wrist arthroplasty can be tried for patients
with substantial pain and functional impairement.
PREGNANCY
• Up to 75% of female RA patients will note overall improvement in symptoms during
pregnancy, but often will flare after delivery.
• Flares during pregnancy are generally treated with low doses of prednisone;
hydroxychloroquine and sulfasalazine.
• Methotrexate and leflunomide therapy are contraindicated during pregnancy due to
their teratogenicity in animals and humans.
ALGORITHM
(2015)
REMISSION IN RA
DAS 28 SCORE
• The DAS28 score is arrived at using: The number of swollen joints (out of the 28), The
number of tender joints (out of the 28), Global Health Assesesment and The C
reactive protein (CRP) or erythrocyte sedimentation rate (ESR) lab test results
ACUTE RHEUMATIC FEVER

• Acute rheumatic fever (ARF) is a

multisystem disease resulting from an
autoimmune reaction to infection with
group A streptococcus.
EPIDEMIOLOGY
• ARF is mainly a disease of children age 5–14 years. Initial episodes become less
common in older adolescents and young adults and are rare in persons aged >30
years. This pattern contrasts with RHD, which peaks at 25-40 years.
• There is no clear gender association for ARF, but RHD more commonly affects
females, sometimes up to twice as frequently as males.
• Worldwide 4.7 lakh new ARF cases with 2.7 lakh deaths are attributed to RHD.
• INDIA is home to 40% of the global RHD population.
PATHOGENESIS
Organism
• Based on currently available evidence, ARF is exclusively caused by infection of the
upper respiratory tract with group A streptococci
HOST FACTORS
• Approximately 3–6% of any population may be susceptible to ARF.
• ARF is an inherited characteristic, with 44% concordance in mono- zygotic twins
compared to 12% in dizygotic twins, and heritability more recently estimated at 60%.
• Some human leukocyte antigen (HLA) class II alleles, particularly HLA-DR7 and HLA-
DR4, appear to be associated with susceptibility.
• Associations have also been described with polymorphisms at TNF-α-308 and TNF-α-
238, high levels of circulating mannose-binding lectin, and Toll-like receptors.
The immune response
• The most widely accepted theory is based on the concept of molecular mimicry,
whereby an immune response targeted at streptococcal antigens (mainly thought to
be on the M protein and the N-acetylglucosamine of group A streptococcal
carbohydrate) also recognizes human tissues.
• In this model, cross- reactive antibodies bind to endothelial cells on the heart valve,
leading to activation of VCAM-1, which results in recruitment of activated
lymphocytes and lysis of endothelial cells in the presence of complement.
• The latter leads to release of peptides including laminin, keratin, and tropomyosin,
which, in turn, activates cross-reactive T cells that invade the heart, amplifying the
damage.
Clinical features
• There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A
streptococcal infection and the appearance of the clinical features of ARF.
• Although many patients report a prior sore throat, the preceding group A
streptococcal infection is commonly subclinical; in these cases, it can only be
confirmed using streptococcal antibody testing.
• The most common clinical features are polyarthritis (present in 60–75% of cases)
and carditis (50–60%).
Diagnosis
HEART INVOLVEMENT
• Up to 60% of patients with ARF progress to RHD.
• The endocardium, pericardium, or myocardium may be affected.
• Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always
affected, sometimes together with the aortic valve.
• Early valvular damage leads to regurgitation . Over ensuing years, usually as a result of
recurrent episodes of leaflet thickening, scarring, calcification, and valvular stenosis may
develop.
• Therefore, the characteristic manifestation of carditis in previously unaffected individuals
is mitral regurgitation, sometimes accompanied by aortic regurgitation.
• Myocardial inflammation may affect electrical conduction pathways, leading to P-R
interval prolongation (first-degree atrioventricular block or rarely higher level block) and
softening of the first heart sound.
JOINT INVOLVEMENT
• The most common form of joint involvement in ARF is arthritis, i.e., objective
evidence of inflammation, with hot, swollen, red, and/or tender joints, and
involvement of more than one joint (i.e., polyarthri tis). Polyarthritis is typically
migratory, moving from one joint to another over a period of hours. ( IT LICKS THE
JOINTS BUT BITES THE HEART)
• ARF almost always affects the large joints—most commonly the knees, ankles, hips,
and elbows—and is asymmetric. The pain is severe and usually disabling until anti-
inflammatory medication is commenced.
 CHOREA/St Vitus Dance
• Sydenham’s chorea commonly occurs in the absence of other manifestations ,
follows a prolonged latent period after group A streptococcal infection, and is found
mainly in females.
• The choreiform movements affect particularly the head (causing characteristic
darting movements of the tongue) and the upper limbs.
• They may be generalised or restricted to one side of the body (hemi-chorea)
OTHER SIGNS
1. MILKMAID SIGN
2. PRONATOR SIGN
3. JACK IN THE BOX SIGN
4. BAG OF WORMS SIGN
SKIN MANIFESTATIONS
• The classic rash of ARF is erythema marginatum ,which begins as pink macules that
clear centrally, leaving a serpiginous, spreading edge. Seen in 5% of patients.
• The rash is evanescent, appearing and disappearing before the examiner’s eyes. It
occurs usually on the trunk, sometimes on the limbs, but almost never on the face.
• Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile lumps beneath
the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput,
and occasionally the vertebrae. Seen in less than 5% of cases.
TREATMENT
• There is no treatment for ARF that has been proven to alter the likelihood of
developing, or the severity of, RHD. With the exception of treatment of heart failure,
which may be life-saving in cases of severe carditis, the treatment of ARF is
symptomatic.
• ANTIBIOTICS
Penicillin is the drug of choice and can be given orally 500 mg [250 mg for children ≤27
kg] PO twice daily,
or amoxicillin, 50 mg/kg [maximum, 1 g] daily, for 10 days
or as a single dose of 1.2 million units (600,000 units for children ≤27 kg) IM
benzathine penicillin G.
Salicylates and NSAIDS
• These may be used for the treatment of arthritis, arthralgia, and fever, once the
diagnosis is confirmed.
• Aspirin is the drug of choice, delivered at a dose of 50–60 mg/kg per day, up to a
maximum of 80–100 mg/kg per day (4–8 g/d in adults) in 4–5 divided doses.
• Naproxen at a dose of 10–20 mg/kg per day is a suitable alternative to aspirin and
has the advantage of twice-daily dosing.
ROLE OF GLUCOCORTICOIDS
• The use of glucocorticoids in ARF remains controversial .
• Many clinicians treat cases of severe carditis (causing heart failure) with
glucocorticoids in the belief that they may reduce the acute inflammation and result
in more rapid resolution of failure.
• If used, prednisone or prednisolone is recommended at a dose of 1–2 mg/kg per day
(maximum, 80 mg), usually for a few days or up to a maximum of 3 weeks.
CHOREA
• Medications to control the abnormal movements do not alter the duration or
outcome of chorea.
• Milder cases can usually be managed by providing a calm environment.
• In patients with severe chorea, carbamazepine or sodium valproate is preferred .
• There is recent evidence that corticosteroids are effective and lead to more rapid
symptom reduction in chorea. They should be considered in severe or refractory
cases.
PREVENTION
• PRIMARY PREVENTION
Ideally, primary prevention would entail elimination of the major risk factors for
streptococcal infection, particularly overcrowded housing.
The mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the
timely and complete treatment of group A streptococcal sore throat with antibiotics).
If commenced within 9 days of sore throat onset, a course of penicillin will prevent
almost all cases of ARF that would otherwise have developed.
• SECONDARY PREVENTION
they should receive long-term penicillin prophylaxis to prevent recurrences.
The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million
units, or 600,000 units if ≤27 kg) delivered every 4 .
Oral penicillin V (250 mg) can be given twice daily instead but is less effective than
benzathine penicillin G.
Penicillin-allergic patients can receive erythromycin (250 mg) twice daily.
THANK YOU.