Oana Sacu

Universita di Studi di Firenze, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy

Daniela Opris
Sf. Maria Hospital, Carol Davila University of Medicine and Pharmacy, Research Centre on the Pathology and Treatment of the Systemic Rheumatic Diseases Bucharest, Romania

Female, 40 ys, DS Never smoked

: malaise, fingers oedema -global swollen fingers and arthralgias, Raynauds Phenomenon: diagnosed with RA (treatment Tauredon)

-sclerodactily, mycrostoma, digital pitting scarrs

-d SS was diagnosed

ANA -, SCL70-, anti centromere-

positive skin biopsy Hidroxicloroquin 400mg/day (6ys), Sulfasalasine 3 g/day (2007), low doses of steroids

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<3mg/l) ESR 94 mm/h

mRodnans score: 8
1 1

0 0 0 2 0

0 0 0 0 2

DAS 28= 7.65

0 1 0 1

Hands X-ray

-Acro-osteolysis of 2,3,4,5 distal phalanges -Flexion contractures -Periarticular osteoporosis -Bilateral carpitis

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<10IU), antiCCP2 495 IU (N<20IU) DLCO 66%, Normal respiratory function tests PAP-ECHO 34 mmHg, normal ECG

Capillaroscopic pattern LATE Scleroderma pattern: few or absent capillaries and microbleeding, architectural derangement (angiogenesis), ramified/bushy capillaries

Joint involvement in SS
arthralgias

(early-common) Frank arthritis (rarely) Contractures Tendon fricture rubs

X-Ray:

joint space narrowing 28%, flexion contractures 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

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-

Joint involvement

Acroosteolysis

Hands X-ray

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP Positive ANA-homogenous pattern Treatment

Positive diagnosis:

OVERLAP Syndrome

Diagnosis: characteristics of the two diseases

Articular erosions (RA)

Clinical features

+ or specific autoantibodies

Thickening of the skin proximal to the fingers (SSc)

Overlap Syndrome SSc-AR because

Raynauds phenomenon Diffuse skin involvement ANA positive, RF highly positive, anti CCP highly 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 RA must include erosions

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

OBJECTIVES: To determine if anti-cyclic citrullinated peptide (antiCCP) antibody titers can distinguish the overlap syndrome of systemic sclerosis and rheumatoid arthritis (SSc-RA) in patients with systemic sclerosis (SSc) and to investigate the clinical significance of anti-CCP antibodies in SSc

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

Anti-CCP antibody titers are a reliable marker of SSc-RA facilitating its distinction from SS alone.

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP Positive ANA-homogenous pattern Treatment

Worsening of joint involvement

TB

arthritis- monoarticular Poncets disease aseptic polyarthritis (70%) that occurs during acute TB in which no mycobacterial involvement can be found.
-self limited -no chronic arthritis reported -no association reported with anti CCP -diagnosis of exclusion

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP & RF Positive ANA-homogenous pattern Treatment

Anti-cyclic citrullinated peptide (CCP) antibodies

Relations
[Nishimura,

with RA

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

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

-when
S.

combined with high RF specificity for RA rise from 90% to 98%

Bas, S. Genevay, O. Meyer1 and C. Gabay Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology, Vol 42, No5

Relations

with SS

- positive results can occur in other diseases:

(15% SLE, 14% Sjogrens S, 23% PM, 6% scleroderma)
[Matsui, T, Shimada, K, Ozawa, N, et al. Diagnostic utility of Anticitrullinated protein/peptide Ab in early rheumatoid
arthritis, J Rheumatol 2006; 33:2390]

Relation with TB

Anti-cyclic citrullinated peptide (CCP) antibodies

Increased prevalence in patients with active TB (32-39%) 32% (2.6% control, p=0.002)-no correlation found between anti CCP+ and any rheumatologic symptoms No association between anti CCP and RF+
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

False positivity of anti CCP in TB patients ? Anti-CCP was inhibited by CCP peptide in sera from RA patients, 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
Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide antibodies, but their sera also react with unmodified argininecontaining peptide (p 1576-1581) P Kakumanu, H Yamagata, E S. Sobel, W H. Reeves, Edward K. L. C May 31 2008 Arthritis and Rheumatism

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP Positive ANA-homogenous pattern Treatment

Positive ANA-homogenous pattern

SCL70-,

anti centromere Anti U1 RNP 2000 ANA-! Drug induced lupus (isoniaside)-Ab anti histone? (pattern homogenous)

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP Positive ANA-homogenous pattern Treatment

Treatment
MTX10mg SSZ

QW sc

Pulmonary fibrosis Risk of infections/recent TB

2g QD

Medrol
Aspirin

8 mg QD

100mg QD Nifedipin 20 mg QD Esophageal dismotility

Omeprazole+Metoclop

Vascular problems (Raynaud, SRC); ATS

ramid

Last EUSTAR recommendations for SSc related skin involvement

Two RCT have shown that methotrexate improves skin score in early diffuse SSc. Positive effects on other organ manifestations have not been established.
Methotrexate may be considered for the treatment of skin manifestations of early diffuse SSc.

Using MTX for treating the erosive arthritis

In the literature we found opposed data regarding the pulmonary fibrosis: There is no evidence to suggest clinically, from HRCT assessment or serial pulmonary function tests, that low-dose methotrexate is associated with chronic interstitial lung disease. J. K. Dawson

Rheumatology 2002; 41: 262-26 (Fifty-five RA patients on methotrexate and 73 control patients with RA were enrolled for the study. Mean dose of methotrexate was 10.7 mg/week (S.D. 2.5 mg/week) and mean duration of treatment at entry into the study was 30 (20) months. Twenty per cent of patients with RA treated with methotrexate had pulmonary fibrosis (PF) on initial HRCT compared with 23% in the control group. When the patients with and without PF were compared, 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. Mean changes after 2 yr in forced expiratory volume, forced vital capacity, diffusion capacity for carbon monoxide and residual volumes were not different in the methotrexate group compared with the control group.)

Fatal pulmonary fibrosis complicating low dose methotrexate therapy of 2 aged rheumatoid arthritis patients . van der Veen MJ,J Rheumatol. 1995 Sep;22(9):1766-8

TREATMENT?
Absence

of large controlled trials Recommendations are based on conventional treatment for associated diseases

BIOLOGICS?

The rationale for using TNF blockers in SSc

Clinical overlap of Ssc with other rheumatic
diseases in which benefit is well established Experimental models of lung fibrosis have responded to TNF blockers The inflammatory nature of skin disease in the early stages of diffuse cutaneous Ssc The presence of a mononuclear cell infiltrate including monocytes in skin biopsy specimens

An open-label pilot study of infliximab therapy in difuse cutaneous Ssc

Dis published

CP Denton, Ann Rheum

online 9 Sep 2008

a 26 week open-label pilot study in which 16 cases of

dcSSc received 5 infusions of infliximab (5mg/kg) Clinical assessment included skin sclerosis score, scleroderma-HAQ, self-reported functional score and physician global VAS. Collagen turnover, skin biopsy analysis and full safety evaluation was performed. In dcSSc infliximab did not show clear benefit at 26 weeks but was associated with clinical stabilisation and fall in two laboratory markers of collagen synthesis. The frequency of suspected infusion reactions may warrant additional immunosuppression in any future studies in SSc.

Problems:

High risk of TB reactivation using TNF

blockers in patient with a history of active TB ANA positive ( high risk of infusion reactions ) and for that the necessity of combination therapy

A case of lung tuberculosis in a patient with rheumatoid arthritis treated with infliximab after antituberculosis chemoprophylaxis with isoniazid.

The patient was treated with methotrexate and

prednisolone, but the disease activity remained high. A tuberculin skin test was positive. After antituberculosis (TB) chemoprophylaxis with isoniazid for four weeks, infliximab was administered. Chemoprophylaxis was continued for nine months. Active lung TB was diagnosed at 17 months after the cessation of isoniazid, namely at 27 months after starting infliximab treatment.

This case report shows that TB can manifest after

chemoprophylaxis in patients antitumor necrosis factor agents.
Hirano Y, Mod Rheumatol. 2009 Mar 6.

treated

with

Tuberculosis in patients receiving antiTNF agents despite chemoprophylaxis.

Anti-tuberculosis chemoprophylaxis was only of partial preventive success in the pacients receiving TNF agents.
Sichletidis L,
Int J Tuberc Lung Dis. 2006 Oct

Long-term folow up of patients with TB as a complication of TNF alfa antagonist therapy: safe re-initiation of TNF alfa blockers after appropriate anti TB treatment
21

TB cases complicating TNF alfa blocker therapy 29 % patients had recommenced TNF alfa antagonist treatment after appropriate anti TB therapy, without reactivation Conclusions: TNF alfa antagonist can be restarted in TB patients provided that adequate anti TB treatment has been completed

Denis B, Clin. Microbiol. Infec.2008

Other possibilities ?
In recent years, clinical trials with B cell
depleting agents, unveiled a role for B lymphocytes in the pathogenesis of several auto-immune diseases. Multiple elements point to a role for B cells in Ssc pathogenesis.

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis (15 pz)

The treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc. Rituximab treatment resulted in both depletion of circulating B cells and depletion of dermal B cells but had little effect on the levels of SSc-associated autoantibodies. Rituximab treatment did not appear to result in a significant beneficial effect on skin disease. The potential efficacy of rituximab in other organs such 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 were completely depleted at 6 months in most patients
Lafyatis R, Arthritis Rheum. 2009 Feb

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

(<5 CD19+ cells/l blood) There was a significant change in skin score at week 24 (p<0.001) Significant improvements were measured in the dermal hyalinised collagen content (p=0.014) and dermal myofibroblast numbers (p=0.011). Rituximab appears to be well-tolerated and may have potential efficacy for skin disease in dc-SSc.

Rituximab for the treatment of cutaneous involvement in Systemic sclerosis (10 pz)
Despite limitations of few patients, no control group and short follow up period, rituximab seems be a safe therapeutic option for skin fibrosis and to confirm the role of B cells and autoantibody mediated fibroblast activation in systemic sclerosis.
P. Fraticelli, Ann. Rheum Dis 2007

Systemic sclerosis-rheumatoid arthritis overlap syndrome: literature

77%

lcSSc, 23% dcSSc The 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 ANA +: 100% Anti SCL70 +: 22.7% ACA +: 9.1% RF +: 72.7% Anti CCP +: 81.8%
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. Vgvri1,Z. Szab1, S. Sznt1, L. Czirjk4 and C. Gyrgy Kiss4 Rheumatology 2007;46:989-993

Problems
Positive

diagnosis Worsening of joint involvement after TB High titers of anti CCP Positive ANA-homogenous pattern Treatment Opinions & Suggestions