Overlap Bis

8/12/2019 Overlap Bis

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Daniela Opris

Oana Sacu

Sf. Maria Hospital, Carol Davila University of Medicine and Pharmacy,

Research Centr e on the Pathology and Treatment of the Systemic Rheumatic DiseasesBucharest, Romania

Universita di Studi di F irenze, Azienda Ospedal iero Universitari a Careggi,

F irenze, I taly


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Female, 40 ys, DS

Never smoked

: -pulmonary TB, bK +

-6 months treatment

-bilateral wrists, 2-5 MCF, 2-5 PIP

Knees arthritis

-3hs morning stiffness

CRP 77 mg/l (N


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1

0

1

001

0

1

0 0

00

22

0

0 0

mRodnans score: 8

DAS 28= 7.65


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Hands X-ray -Acro-osteolysis of 2,3,4,5 distal phalanges

-Flexion contractures

-Periarticular osteoporosis-Bilateral carpitis


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Laboratory evaluation:

CT-scan -cavitary immages right

VIth segment

Barium radiography:

Esophageal dismotility

SCL70-, U1 RNP(ELISA)

ACA-, ANA + homogenous pattern (IIF on HEp2 cells)

RF 5500 IU (N


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Capillaroscopic patternLATE Scleroderma pattern:

few or absent capillaries and microbleeding, architectural derangement(angiogenesis), ramified/bushy capillaries


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Joint involvement in SS

arthralgias (early-common)

Frank arthritis (rarely)

ContracturesTendon fricture rubs

X-Ray: joint space narrowing 28%, flexioncontractures 27%, erosions 21%, arthritis 18%Radiological hand involvement in Systemic Sclerosis. J Avouac, H Guerini, J Wipff, A Kahn, Y Allanore. Ann Rheum Dis 2006:65


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Particularities:

-RF = 5500 IU/ml

(x 550 H normal level)

-anti CCP = 520 IU/ml(x 25 H normal level)

-ANA +

-anti SCL-

-ACA

-U1RNP-

Hands

X-ray

Joint

involvement

Acro-

osteolysis


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Problems

Positive diagnosis

Worsening of joint involvement after TB

High titers of anti CCP

Positive ANA-homogenous pattern

Treatment


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OVERLAP Syndrome

Positive diagnosis:


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Diagnosis: characteristics of thetwo diseases

Clinical features+ or specific

autoantibodies

Thickening of the skin proximal to the fingers (SSc)

Articular erosions (RA)


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Overlap Syndrome SSc-ARbecause

Raynauds phenomenon

Diffuse skin involvement

ANA positive, RF highly positive, anti CCPhighly positive

Arthritis of hand joints: MCF, IFP, wrist

Arthritis of 3 joints: MCF, IFP, knee, foot

Symmetric arthritis

Imaging: hand x-ray changes typical of RAmust include erosions


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Anti-cyclic citrullinated peptide antibody in systemic sclerosis.Morita Y, Clin ExpRheumatol. 2008 Jul-Aug;26(4):542-7

OBJECTIVES: To determine if anti-cyclic citrullinated peptide (anti-CCP) antibody titers can distinguish the overlap syndrome of

systemic sclerosis and rheumatoid arthritis (SSc-RA) in patientswith systemic sclerosis (SSc) and to investigate the clinical

significance of anti-CCP antibodies in SSc

Elevated serum levels of anti-CCP antibodies wereobserved in 3 of 114 patients (2.6%) with SS, 9 of 14patients (64%) with RA, 6 of 7 patients (86%) with

SS/RA.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22van%20der%20Veen%20MJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22van%20der%20Veen%20MJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


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Anti-CCP antibody titers are areliable marker of SSc-RA

facilitating its distinction fromSS alone.


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Problems

Positive diagnosis


High titers of anti CCP


Treatment


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Worsening of joint involvement

TB arthritis- monoarticular

Poncetsdiseaseaseptic polyarthritis(70%) that occurs during acute TB in whichno mycobacterial involvement can be found.

-self limited-no chronic arthritis reported

-no association reported with anti CCP

-diagnosis of exclusion


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Problems

Positive diagnosis


High titers of anti CCP & RF


Treatment


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Anti-cyclic citrullinated peptide (CCP)antibodies

Relations with RA- sensitivity of 47-76% and specificity of 90-96% for RA

[Nishimura, k, Sugiyama, D, Kogata, Y et al. Meta-analysis: Diagnostic accuracy of anti-CCp and RF for rheumatoid arthritis. AnnIntern Med 2007: 146:797]

-when combined with high RF specificity for RA risefrom 90% to 98%

S. Bas, S. Genevay, O. Meyer1and C. Gabay Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in thediagnosis and prognosis of rheumatoid arthritis. Rheumatology, Vol 42, No5

Relations with SS- positive results can occur in other diseases:

(15% SLE, 14% SjogrensS, 23% PM, 6% scleroderma)

[Matsui, T, Shimada, K, Ozawa, N, et al. Diagnostic utility of Anticitrullinated protein/peptide Ab in early rheumatoidarthritis, J Rheumatol 2006; 33:2390]


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Increased prevalence in patients with active TB (32-39%)

32% (2.6% control, p=0.002)-no correlation found betweenanti CCP+ and any rheumatologic symptoms

No association between anti CCP and RF+

False positivity of anti CCP in TB patients ?

Anti-CCP was inhibited by CCP peptide in sera from RApatients, but not in sera from TB patients.

A slight increase in anti-CCP after initiating treatment for TB,thereafter the anti-CCP level decreased in 1-2 months

A significant proportion of patients with TB present high titer of anti CCP or Ig M RF. O Elkayan, R Segal, M Lidgi & D Caspi; Ann Rheum Dis

doi:10.1136/ard.2005.045229

Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide antibodies, but their sera also react with unmodified arginine-containing peptide (p 1576-1581) P Kakumanu, H Yamagata, E S. Sobel, W H. Reeves, Edward K. L. C May 31 2008 Arthritis and Rheumatism

Anti-cyclic citrullinated peptide (CCP)antibodies

Relation with TB


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Problems

Positive diagnosis


High titers of anti CCPPositive ANA-homogenous pattern

Treatment


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SCL70-, anti centromere-

Anti U1 RNP-

2000ANA-!Drug induced lupus (isoniaside)-Ab anti

histone? (pattern homogenous)


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Problems

Positive diagnosis



Treatment


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Treatment

MTX10mg QW sc

SSZ 2g QD

Medrol 8 mg QD

Aspirin 100mg QD

Nifedipin 20 mg QD

Omeprazole+Metoclopramid

Pulmonary fibrosis Risk of infections/recent TB

Vascular problems

(Raynaud, SRC); ATS

Esophageal dismotility


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Last EUSTAR recommendationsfor SSc related skin involvement

Two RCT have shown that methotrexate

improves skin score in early diffuse SSc.Positive effects on other organ manifestationshave not been established.

Methotrexate may be considered for thetreatment of skin manifestationsof early

diffuse SSc.


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Using MTX for treating the erosive

arthritis

In the literature we found opposed dataregarding the pulmonary fibrosis: There is no evidence to suggest clinically, from

HRCT assessment or serial pulmonary function

tests, that

low-dose methotrexate is associatedwith chronic interstitial lung disease. J. K. DawsonRheumatology 2002; 41: 262-26 (Fifty-five RA patients on methotrexate and 73control patientswith RA were enrolled for the study. Mean doseof methotrexate was 10.7 mg/week (S.D. 2.5mg/week) and meanduration of treatment at entry into the study was 30 (20) months.Twentyper cent of patients with RA treated with methotrexate had pulmonary fibrosis (PF) on initialHRCT compared with 23% in the control group. When the patients with and without PFwerecompared, there was no statistical difference in the duration (mean difference -4.18 months,P=0.237) or dose (mean difference -0.8 mg/week P=0.52) of methotrexate therapy. Meanchanges after2 yr in forced expiratory volume, forced vital capacity, diffusioncapacity for carbonmonoxide and residual volumes were not differentin the methotrexate group compared with thecontrol group.)

Fatal pulmonary fibrosis complicating low dosemethotrexate therapy of 2 aged rheumatoidarthritis patients .van der Veen MJ,J Rheumatol. 1995 Sep;22(9):1766-8
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hirano%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


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TREATMENT?

Absence of large controlled trials

Recommendations are based on conventionaltreatment for associated diseases

BIOLOGICS?


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The rationale for using TNFblockers in SSc

Clinical overlap of Ssc with other rheumaticdiseases in which benefit is well established

Experimental models of lung fibrosis haveresponded to TNF blockers

The inflammatory nature of skin disease inthe early stages of diffuse cutaneous Ssc

The presence of a mononuclear cellinfiltrate including monocytes in skin biopsyspecimens


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An open-label pilot study of infliximabtherapy in difuse cutaneous SscCP Denton, Ann Rheum

Dis published online 9 Sep 2008

a 26 week open-label pilot study in which 16 cases ofdcSSc received 5 infusions of infliximab (5mg/kg)

Clinical assessment included skin sclerosis score,

scleroderma-HAQ, self-reported functional score andphysician global VAS. Collagen turnover, skin biopsyanalysis and full safety evaluation was performed.

In dcSSc infliximab did not show clear benefit at 26 weeksbut was associated with clinical stabilisation and fall in twolaboratory markers of collagen synthesis.

The frequency of suspected infusion reactions maywarrant additional immunosuppression in any futurestudies in SSc.


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High risk of TB reactivation using TNFblockers in patient with a history of activeTB

ANA positive ( high risk of infusionreactions ) and for that the necessity ofcombination therapy

Problems:

f


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A case of lung tuberculosis in a patient withrheumatoid arthritis treated with infliximab after

antituberculosis chemoprophylaxis with

isoniazid. The patient was treated with methotrexate and

prednisolone, but the disease activity remained high. Atuberculin skin test was positive. After antituberculosis

(TB) chemoprophylaxis with isoniazid for four weeks,infliximab was administered. Chemoprophylaxis wascontinued for nine months. Active lung TB was diagnosedat 17 months after the cessation of isoniazid, namely at27 months after starting infliximab treatment.

This case report shows that TB can manifest afterchemoprophylaxis in patients treated withantitumor necrosis factor agents.

Hirano Y, Mod Rheumatol. 2009 Mar 6.


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Tuberculosis in patients receiving anti-

TNF agents despite chemoprophylaxis.

Anti-tuberculosischemoprophylaxis was only ofpartial preventive success inthe pacients receiving TNF

agents.

Sichletidis L,Int J Tuberc Lung Dis. 2006 Oct

Long-term folow up of patients with TB as a


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Long term folow up of patients with TB as acomplication of TNF alfa antagonist therapy: safere-initiation of TNF alfa blockers after appropriate

anti TB treatmentDenis B, Clin. Microbiol. Infec.2008

21 TB cases complicating TNF alfa blocker

therapy

29 % patients had recommenced TNF alfaantagonist treatment after appropriate anti

TB therapy, without reactivation

Conclusions: TNF alfa antagonist can berestarted in TB patients provided thatadequate anti TB treatment has been

completed


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Other possibilities ?

In recent years, clinical trials with B cell

depleting agents, unveiled a role for Blymphocytes in the pathogenesis of severalauto-immune diseases. Multiple elements pointto a role for B cells in Ssc pathogenesis.

B ll d l i i h i i b i


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B cell depletion with rituximab inpatients with diffuse cutaneous

systemic sclerosis (15 pz)

The treatment with rituximab appeared to be safeand well tolerated among patients with dcSSc.Rituximab treatment resulted in both depletion ofcirculating B cells and depletion of dermal B cells buthad little effect on the levels of SSc-associatedautoantibodies. Rituximab treatment did not appear toresult in a significant beneficial effect on skin disease.The potential efficacy of rituximab in other organssuch as the lung could not be clearly evaluated in this

small open-label trial. The modest B cell infiltrates that were present

in most skin biopsy specimens at baseline werecompletely depleted at 6 months in most patientsLafyatis R, Arthritis Rheum. 2009 Feb

Rituximab in diffuse cutaneous systemic


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Rituximab in diffuse cutaneous systemic

sclerosis: an open-label clinical and

histopathological study

Vanessa P Smith,Ann Rheum Dis published online 22 Dec 2008

Ritixumab induced effective B cell depletion in all patients(


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Rituximab for the treatment ofcutaneous involvement in Systemic

sclerosis (10 pz)

Despite limitations of few patients, no

control group and short follow up period,

rituximab seems be a safe therapeuticoption for skin fibrosis and to confirm therole of B cells and autoantibody mediated

fibroblast activation in systemic sclerosis.

P. Fraticelli,Ann. Rheum Dis 2007


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Systemic sclerosis-rheumatoid arthritis

overlap syndrome: literature

77% lcSSc, 23% dcSScThe diagnosis of RA followed that of SS -86.4%

82% erosive poliartritis (xRay)

77% pulmonary fibrosis & 55% oesophageal involv.Genetics: both SSc and RA- associated HLA-DR alleles

Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests s distinct

genetic, serological and clinical entity. G. Szcs1,*,Z. Szekanecz1,*, E. Zilahi2, A. Kapitny2,3, S. Barth2, S.Szamosi1 A. V vri1 Z. Szab1 S. Sznt1 L. Czir k4and C. G r Kiss4Rheumatolo 2007 46:989-993

ANA +: 100%Anti SCL70 +: 22.7%ACA +: 9.1%RF +: 72.7%Anti CCP +: 81.8%

P bl


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Problems

Positive diagnosis



Treatment

Opinions & Suggestions

Documents

Overlap Bis