Name: Dr. G.

Narsimhulu, Hyderabad

Brief
Introduction

SENIOR CONSULTANT RHEUMATOLOGIST

GVN MEDICAL CENTRE
PROFESSOR AND HOD RHEUMATOLOGY ESI MEDICAL COLLEGE
& SUPERSPECIALITY HOSPITAL HYDERABAD
FORMER PROFESSOR AND HOD RHEUMATOLOGY NIMS HYD
PAST DEAN INDIAN COLLEGE OF PHYSICIAN
FORMER ASSISTANT EDITOR OF JAPI
FORMER PRESIDENT OF IACM
PAST PRESIDENT INDIAN RHEUMATOLOGY ASSOCIATION
PUBLISHED NUMEROUS PAPERS IN VARIOUS JOURNALS AND
CONTRIBUTED CHAPTERS IN VARIOUS UPDATES.
RHEUMATOID ARTHRITIS MANAGEMENT
UPDATES.
DR. G. NARSIMULU
MD,FICP,FIACM

Former Dean
ICP/API
Past President, Indian Rheumatology Association
Sr. Consultant Rheumatologist

GVN Medical Centre, B. K. Guda

S.R. Nagar
Former Prof.& HOD Rheumatology ,NIMS,HYD
Former Chairman Association of Physicians of India AP & Hyderabad
 IgM RF Positive
Rheumatic Diseases : RA, SLE, PSS, MCTD,
Sjogren's syndrome
Viral Infections : AIDS, Mononucleosis, Hepatitis,
influenza,after vaccination
Parasitic : Trypanosomiasis, Kala Azar, Malaria,
Schistosomiasis, Filariasis
Chronic Bacterial Infection : Tuberculosis, leprosy, Yaws, Syphilis,
Brucellosis, Infective endocarditis,
Salmonellosis
Malignancy : Leukemia, Lymphoma after sarcoidosis
Radiation & Chemotherapy
Normal : 5% of general population, especially after the age of 60 years
Hand in early RA Tenosynovial swelling from
tenosynovitis- the ‘Tuck sign’
Fury of Rheumatoid Arthritis
Fury of Rheumatoid Arthritis
Fury of Rheumatoid Arthritis
Fury of Rheumatoid Arthritis
 Problems in Arthritis

• Perception: Nothing can be done

• Priority: Arthritis is non life-threatening cf
Cancer/Heart disease
Not part of NSF
 Problems in Arthritis
Presents late, but irrelevant
As even if could see early
• No accurate diagnosis
• No effective therapy

• All have changed

RA Current Concepts
 RHEUMATOID ARTHRITIS
Disease Progression
Normal
Knee
Joint

Early
Rheumatoid
Arthritis
Established
Rheumatoid
Arthritis

Adapted with permission from:

Choy EHS, Panayi GS. N Engl J Med. 2001;344:907–916.
 TREATMENT OF RHEUMATOID ARTHRITIS
Goals of Therapy
• Relieve symptoms, including fatigue, pain, swelling, and
stiffness
• Prevent joint destruction, loss of joint function,
deformity, disability, and early death
• Preserve quality of life
• Achieve clinical remission
Nodular, erosive rheumatoid arthritis
 Early Treatment of RA and the Goal of
Preventing Long-Term Disability

Inflammation
Function
Severity

Time

Interventions

Ahmed K, Emery P.. Challenges in Rheumatoid Arthritis. Oxford, England: Blackwell Science;
1999:106-115.
 Paradigm
• Inflammation is bad
• Inflammation is treatable

Inflammation x Time = Damage

1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis
1. Morning stiffness Morning stiffness in and around the joints, lasting at
least 1 hour before maximal improvement
2. Arthritis of 3 or more At least 3 joint areas simultaneously have had soft
joint areas 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 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 Demonstration of abnormal amounts of serum
factor 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 posteroanterior hand and wrist radiographs, which
must include erosions or unequivocal bony
decalcification localized in or most marked adjacent to
the involved joints
Size of US lesions seen by radiology (resolution) Wakefield et al A&R1999

• Xray sees 9% of small US lesions

• Xray sees 57% of moderate/large US lesions
i.e. Radiology insensitive for small lesions

Note
• In early RA 90% of all HRUS lesions are small
• In late RA 63% of all HRUS lesions are small
i.e. majority of erosions small (esp. early)
Radiology will miss most cortical breaks
especially in early disease
 Sonography of Subclinical Synovitis
Total number of joints
US synovitis
26 patients with clinical monoarthritis
800 – 35% sonographic oligoarthritis (> 1
700
joint)
Number of joints

600
500 – 25% sonographic
400
300 polyarthritis
200
100
0 Asymptomatic Painful but not Clinical synovitis
swollen
Clinical findings
Prevalence of US detected synovitis in joints which were asymptomatic,
clinically painful but not swollen, and clinically synovitis joints.

Wakefield et al. Ann Rheum Dis 2004; 63:382-388

 Anti-TNFs: A major therapy

Key therapeutics representing a dramatic

improvement in treating RA patients

1930-40 1950 1960 1988 1995 1999+

Gold Steroid NSAID MTX Combo

Penicillamine
Sulfasalazine
Hydroxychloroquine
Anti-TNF
 PREMIER Study

Clinical Remission
by DAS28<2.6

60 Week 52
* Week 104
49
50 *
43
% Patients

40

30 25 25
23 21
20

10

0
Adalimumab + MTX Adalimumab MTX

*p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

PREMIER Study

Change in Total Sharp Score

Adalimumab + MTX
12
Adalimumab 10.4
10
MTX
Change from Baseline

6 5.7 **5.5

4
3.5 **
3
2 ** * 1.9
2.1
*1.3
*0.8
0 0

0 26 52 78 104

* p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

** p<0.001 for adalimumab vs MTX alone
MRI synovial volumes pre- & post- infliximab
 anti-TNF at presentation produces long-lasting
benefit (one year after stopping therapy)
Quinn et al A&R 2005

MTX Treatment
0
0 14 30 46 54 78 104

-20

HAQ MTX + placebo

% change

-40
HAQ MTX + Infliximab
RAQoL MTX + placebo

-60 RAQoL MTX + Infliximab

-80

-100 Anti-TNF treatment 1 years 2

 2010 ACR/EULAR
Classification Criteria for RA
JOINT DISTRIBUTION (0-5)
1 large joint 0
≥6 = definite RA
2-10 large joints 1
1-3 small joints (large joints not counted) 2
4-10 small joints (large joints not counted) 3
>10 joints (at least one small joint) 5 • The Classification criteria has
SEROLOGY (0-3) undergone a radical change
Negative RF AND negative ACPA 0 recently.
Low positive RF OR low positive ACPA 2
High positive RF OR high positive ACPA 3 • This highlights the importance of
SYMPTOM DURATION (0-1) diagnosing the disease early
<6 weeks 0
≥6 weeks 1

ACUTE PHASE REACTANTS (0-1)

Normal CRP AND normal ESR 0
Abnormal CRP OR abnormal ESR 1
 Present differentiation of RA
• Established RA - > 2 years
• Early RA - 1 year
• Very Early RA (VERA) - < 3 months
• Very Very Early RA- < 6 weeks
• Undifferentiated arthritis
– arthritis that could not be classified according
to ACR criteria and lasting <1 year
– Preclinical RA
Hochberg 5 edition
th

Ann Rheum Dis 2011;70:1292–1295. doi:10.1136/ard.2010.142729

Extraarticular Manifestations of RA
30-yr cumulative incidence
Extra-articular manifestation
(%)
Pericarditis 10.9
Pleuritis 9.4
Major cutaneous vasculitis 5.1
Vasculitis-related neuropathy 2.8
Felty syndrome 2.7
Scleritis 1.0
Episcleritis 0.8
Glomerulonephritis 2.9
Amyloidosis 1.0
Secondary Sjögren syndrome 17.1
Pulmonary fibrosis 9.4
Bronchiolitis obliterans 1.2
Subcutaneous rheumatoid
39.4
nodules
 EARLY RA,
LATE COMPLICATIONS
• Cartilage erosions
• Joint subluxation
• Weakness of supporting structures of joints.
• Repair:- Fibrosis and sclerosis
• Joint deformities
 EARLY RA,
LATE COMPLICATIONS
• Fibrous ankylosis
• Bony ankylosis
• Secondary OA
• Atlanto axial sabluxation
• End stage joint damage
• Mechanical pain
• Functional cause deterioration
• Loss of self care
 SYSTEMIC
• ILD
• Infection Pneumonia
• Vasculitis, Rheumatoid Nodule
• Anterial ischaemic optic neuropathy
• Gastritis
• Hepatitis,Nephropathy
• Bone marrow suppression
 Social Complications
• Breakage of marriage
• Loss of job
• Dependancy
• Social isolation
• Depression
• Mortality
 MORTALITY

• Altered lipid profile

• Increased circulating immune complexes
• Endothelial damage
• Increased CAD
• Increased CVA
• PVD
01/25/2023 34
 RA domains

DISEASE ACTIVITY
• DAS 28

DISABILITY
• HAQ

DAMAGE
• Radiographs

01/25/2023 35
 Disease Activity Score- DAS 28
• Tender joint
• Swollen joint
• ESR
• General health
• DAS28=0.56√TJC+0.28 √SJC+0.7 ESR+ 0.014 GA
• ≤ 2.4 ≥ 2.4 - ≤ 5.5 > 5.5

Remission Moderate High

01/25/2023 36
 ACR criteria for clinical remission of RA
1981
• Morning stiffness < 15 minutes
• No fatigue
• No joint pain
• No joint pain or tenderness on motion
• No soft tissue swelling in joints or tendon sheaths
• ESR <30 mm/hr (males) or <20mm/hr (females)
• A minimum of five of the following for atleast 2 consecutive
months

01/25/2023 37
New ACR/EULAR Remission criteria
• < 1/28 swollen and < 1/28 tender

• CRP < 1

• Patient global assessment (VAS) < 1cm

• SDAI < 3.3

 USG

Imaging in RA

MRI

US/ MRI are better than Xrays in early stages

Power Doppler showing synovial
hypertrophy of 2nd MCP joint
41 Medications
• Analgesics
• Anti-inflammatory agents
• Non-biologic Disease-modifying antirheumatic
drugs (DMARDs)
• Biological DMARDs
Therapeutic principles in RA

• Early diagnosis and treatment

• Combination DMARDs therapy

• Anticytokine therapy

• Assessment of treatment outcomes

• Treatment of comorbid condition

• JAK Inhibitors
42
A CENTURY OF ANTIRHEUMATIC THERAPY

01/25/2023 43
Shift in Treatment Paradigm in RA
Disease modifying antirheumatic drugs- DMARDs

• Retard or halt the progression of disease.

Commonly used Less commonly used
Methotrexate (MTX) Chloroquine , Gold
(parenteral and oral ) ,
Hydroxychloroquine Cyclosporine,
(HCQS) Levamisole D-
penicillamine ,
Sulfasalazine (SSZ)
Minocycline ,
Leflunomide Azathioprine,
Cyclophosphamide
01/25/2023 45
 Treatment approaches

The main goal of the therapy – i.e “ tight control of the disease” should
01/25/2023 be achieved , no matter what approach is used. . 46
 Commonly used DMARDs
Name Dose Onset of Monitoring Side effects
action
HCQS 200-400mg/day 2-4 Months Fundoscopy and Skin pigmentation,
perimetry retinopathy,
myopathy, nausea
MTX 7.5- 25 mg once 1-2 Months Blood counts, LFT : Bone marrow
a week 8-12 weekly, suppression,
orally , S/c, CHXR- hepatotoxicity,
IM annually, urea, mucositis, nausea,
creatinine : 3 pulmonary fibrosis,
monthly hair loss
SSZ 2-3 gm/day 1-2 months Blood counts, LFT : Rash myelosuppression,
8-12 weekly may reduce sperm
counts
Lefluno Loading 100mg 1-2 months LFT 8-12 weekly Nausea alopecia,
mide dailyX3 days diarrhea,
then 10- hepatotoxicity,
20mg/day teratogenicity (stop
oral atleast 2 yrs prior to
starting family )
01/25/2023 47
 DMARDs –Shortcomings

• Onset of action takes several months

• Remission induced is partial in many cases.

• Have substantial toxicity which require careful

monitoring

• Have a tendency to lose effectiveness with time “ slip

out ”
01/25/2023 48
AGENT DOSE

Infliximab TNF blocker. 3mg/kg intravenous infusion at weeks 0, 2 and 6 followed by

maintenance dosing every 8 weeks. Has to be combined with MTX.

Etanercept TNF blocker. 50mg subcutaneously once a week. May be given with MTX or as
monotherapy.

Adalimumab Fully humanized TNF blocker. 40mg sub- cutaneously every 2 weeks (fortnightly).
May be given with MTX or as monotherapy.

Anakinra IL-1 receptor anatagonist. 100mg subcutaneous once daily. May be given with
MTX or as monotherapy.

Abatacept T-cell co stimulation modulator. Administered as a 30-minute iv infusion at 0, 2

(12 months) and 4 weeks .then every 4 weeks . Body weight< 60 kg: 500mg & for 60-100 kg :
700mg. may be used as a monotherapy or concomitantly with DMARDs other than
TNF antagonists.

Rituximab (24 Depletes B lymphocytes. Used in combination with Methotrexate to treat severe
weeks) active RA with inadequate response or intolerance to other DMARDs including
one or more TNF inhibitor therapies. Infusions of 1000mg each spaced 2 weeks
apart.
01/25/2023 49
 RESULTS
PARAMETER TREATMENT PLACEBO
GROUP GROUP
PRIMARY 23 / 119 (19%) 21 / 117 (18%)
ENDPOINT
44 / 236 SUBJECTS
REACHED
(27 – ACPA +
17 – ACPA -)

• All participants who developed the primary endpoint were

clinically diagnosed with rheumatoid arthritis
 CONCLUSION

This trial showed that a single intramuscular

glucocorticoid injection and a 1-year course of
methotrexate did not prevent the
development of detectable clinical arthritis,
but could offer new perspectives on lowering
the burden of disease
 VITAMIN D LEVEL IN RHEUMATOID
ARTHRITIS: CORRELATION WITH THE
DISEASE ACTIVITY
§ Naidu AR, Damodaram P, Habibi S, Kanchinadham
S,S.Agrawal Narsimulu G
§ Department of Rheumatology, Nizam’s
Institute of medical sciences, Hyderabad
 Vitamin D & Rheumatoid Arthritis:
Vitamin D receptor
• vitamin D receptor (VDR) in the cells of the immune system is discovered.

• Modulate T cell proliferation and

dendritic cell function:
• It inhibits T-cell proliferation, the expression of IL-2 and IFNγ mrNA and protein in T
cells, and CD8 T-cell-mediated cytotoxicity.
• effect on antigen-presenting DCs, in which it suppresses the synthesis of IL-12, a
cytokine that promotes TH1-cell responses
• 1,25(OH)2VD3 enhances nonspecific T-cell suppressor activity,
• Inhibits the expression of the IL-6, an important factor that stimulates T H17 cells.
TH17 cells are a critical component of the autoimmune reaction
Link between Periodontal disease (PD) and
Rheumatoid arthritis (RA)
• Source of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid
arthritis – Preclinical disease may begin at periodontal pockets.
•
Damodaram P1, Meghana Arunachalam2, Shabina H1, Suresh K, Liza
Rajasekhar1, Bhanumoorthy M2, Narsimulu G1.

• Department of Rheumatology,
• Nizam’s Institute Of Medical Sciences, Hyderabad.
 Traditional pyramidal approach; go slow , go low
Past
( EMPIRICAL )

Present Early, aggressive use of DMARDs in combination

( EVIDENCE BASED )

Future DMARDs + biologic agents (Immuno interventions )

( MECHANISM BASED)

Induction : DMARDs +cytokine antagonists

Consolidation : TCR vaccine , gene therapy
Maintenance and
Tolerance induction

01/25/2023 59
01/25/2023 60
 HIT EARLY

KEEP HITTING

HIT HARD

01/25/2023 61
 Take home message
• Make a very very early diagnosis

• Start combination DMARDS as early as possible.

If required use biologics. Early & Aggressive
therapy

• Recognize and treat co morbid illness

• Strive for remission in all patients

01/25/2023 62
DEPARTMENT OF RHEUMATOLOGY

NIMS
 My Thanks To
Dr.Paul Emery
Leed S Hospital
U.K

Dr.G.Narsimulu
Rheumatologist
GVN Medical Centre
Dean ICP/API
Former Prof & HOD Rheumatology NIMS
President Indian Rheumatology Association
Former President IACM
Hyderabad
Thank u