Nuovi Farmaci Biotecnologici nelle Patologie Reumatiche

e AutoimmuniC. Salvarani, N Pipitone,

MG Catanoso, L Magnani, F Muratore,Unità di Reumatologia,

Ospedale di Reggio Emilia

Topics

• TNF-blockers and Tocilizumab in Giant Cell Arteritis and Takayasu Arteritis

• TNF-blockers and Rituximab in ANCA-• TNF-blockers and Rituximab in ANCA-associated Vasculitis

• Rituximab in IgG4-related Systemic Disease

TNF-BLOCKERS AND TOCILIZUMB IN GIANT CELL ARTERITIS AND IN GIANT CELL ARTERITIS AND

TAKAYASU ARTERITIS

B.G., Maschio, 63 aa, iperteso, BMI 35.6

Cefalea di nuova insorgenza in sede fronto-temporale dx

e occipitale

Astenia e febbricola serale (37,5 °C – 38 °C )

Caso Clinico

Astenia e febbricola serale (37,5 °C – 38 °C )

Tosse stizzosa e secca

Incremento indici di flogosi: VES 120 mm/h, PCR 4,25 mg/dl

Caso Clinico: Diagnosi

BIOPSIA A. TEMPORALE DX

DIAGNOSI ISTOLOGICA

Sezioni di vaso arterioso con marcata flogosi linfomonocitaria transparietale con

cellule giganti cellule giganti

Reperto istologico diagnostico di

Arterite a Cellule Giganti

Inizia terapia steroidea con Prednisone 50 mg/die

Caso Clinico: Follow-up Clinico (2007-2010)Inizia terapia con prednisone 50 mg/dì

Recidiva di malattia con prednisone < 15 mg/dì

Comparsa di diabete e frattura vertebrale dorsale

Persistenza elevati indici di flogosi (VES: 80-120 mm/h)

Associazione con MTX 15 mg/sett.

Per inefficacia del MTX come risparmiatore di steroide

dopo 1 anno si associa anti-TNFα (prima Infliximab 5 mg/kg,

quindi dopo 12 mesi per inefficacia passa a Etanercept 50 mg/sett)

Aprile 2010: CT-PET positiva e VES 110 mm/ora

CT-PET Whole Body April 2010

patologico accumulo del FDG a livello delle carotidi interne (prevalente a sx), dell’arco dell’aorta e dell’aorta ascendente espressione

di persistente flogosi vascolare in dette sedi

Caso clinico: inizio Tocilizumab 8 mg/Kg ogni 4 sett .

VESmm/1h 120 25 18 20 8

PCR(mg/dl) 4,70 0,28 0,16 0,36 0,30

Giugno Luglio Agosto Settembre Ottobre

(mg/dl) 4,70 0,28 0,16 0,36 0,30

Prednisone (mg/dì) 12,5 12,5 12,5 10 7,5

Segni/Sintomi Costituzionali SI NO NO NO NO

Glucocorticoids are the treatment of choice for GCA

• Adequate GC doses quickly suppress clinical manifestations of GCA and prevent ischemic complications

• If visual loss has occurred before starting • If visual loss has occurred before starting therapy, it is usually not reversed

• An empiric initial dose of 40-60 mg daily of prednisone (or equivalent) as a single or divided dose is recommended

Salvarani et al, Lancet 2008

Glucocorticoids are the treatment of choice for GCA

• The needed duration of GC therapy is variable, but in most patients it can be discontinued within 1-2 years

• Some patients have a chronic relapsing course and may require low doses of GCs for several years or even indefinitely

Salvarani et al, Lancet 2008

Points to consider in the therapy of GCA

• vision loss or cerebrovascular accidents occur in a minority of patients and are very unusual once GC therapy has been initiated

• The potentially catastrophic thoracic aneurysm and dissection occur only in 7.6% and 1% of patients, years after the onset of the disease

Salvarani et al, Lancet 2008 and Arthritis Rheum 2005

Points to consider in the therapy of GCA

• The morbidity of GCA is related to the impact of long-term therapy with glucocorticoids in elderly patients, who glucocorticoids in elderly patients, who often have many comorbidities

Gucocorticoid-related side-effects in GCA• In a population based study: adverse events

associated with GCs were recorded in 103 (86%) of 120 patients and 2 or more events occurred in 70 patients (58%)

• Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects

Proven et al, Arthritis Rheum 2003

Major adverse events that occurred in 103 of 120 patients with giant cell arteritis

Type of adverse event Patients with the event, numbe r (%)

Diabetes mellitus 11 (9)

Total fractures 46 (38)

Hip fracture 19 (16)

Vertebral fracture 27 (23)Vertebral fracture 27 (23)

Colles' fracture 3 (2.5)

Other fractures 11 (9)

Gastrointestinal bleeding 5 (4)

Hypertension 26 (22)

Infection 37 (31)

Posterior subcapsular cataract

49 (41)

Therapy of GCA

We need effective treatments inGCA to reduce the exposure GCA to reduce the exposure to glucocorticoids

Steroid-sparing agents in GCA: evidence from RCTs

• Methotrexate: 3 RCTs with different results and 1 meta-analysis

• Azathioprine: 1 RCT• Azathioprine: 1 RCT

• Infliximab: 1 RCT

• Etanercept: 1 RCT

• Alternate day GC treatment: 1 RCT

• Pulse GC therapy: 2 RCTs

What is the evidence from randomized controlled trials (RCTs)?

• MTX may have a small steroid-sparing effect• MTX is effective only after a latency period of

24-36 weeks• High MTX dosages (20 -25 mg/week) have not • High MTX dosages (20 -25 mg/week) have not

been adequately studied • MTX does not decrease the incidence of

steroid-related side effects• Azathioprine may have a small steroid-sparing

effect and it may be tried if MTX is contro-indicated or not tolerated

What is the evidence from randomized controlled trials (RCTs)?

• Infliximab does not have a steroid-sparing effect in newly diagnosed patients

• Etanercept could have a steroid-sparing effectin patients with relapsing disease

• Infliximab and etanercept do not reduce the incidence of steroid-related side effects in the short-term

• A GC-sparing effect for infliximab may not be completely excluded: the study was too small to definitively identify small benefits

What is the evidence from randomized controlled trials (RCTs)?

• Before completely excluding a potential therapeutic role for TNF-blockers, a large RCT should be performed enrolling only GCA patients with relapsing diseasepatients with relapsing disease

• Alternate-day GC regimen is not recommended

• Additional investigations are needed on the use of pulse GC at the onset of treatment for GCA to confirm whether this regimen reduces GC toxicity

Future directions in GCA therapy Salvarani et al, Lancet 2008

• RCTs are needed to assess new therapeutic agents

• Strong evidence suggest that IL-6 has a major role in sustaining disease activity in GCA

IL-6 and Disease Activity in GCA• IL-6 concentrations, but not TNF alpha, are

increased in GCA patients• GCs rapidly suppress IL-6 production• There is a close correlation of plasma IL-6

concentrations with clinical symptomsconcentrations with clinical symptoms• Vasculitic lesions in GCA samples are

characterized by in situ production of IL-6, IL-1 beta, and TGF-beta1 mRNA, indicative of macrophage activation

Roche et al, Arthritis Rheum 1993;

Weyand et al, Ann Intern Med 1994

IL-6 and Disease Activity in GCA• Plasma IL-6 is more sensitive than

ESR for indicating disease activity

• Circulating IL-6 may persist • Circulating IL-6 may persist elevated in GCA patients after long-term followup and remain higher in patients with more relapsing disease

Weyand et al, Arthritis Rheum 2000Garcia-Martinez et al, Arthritis Rheum 2010

Points to consider in the therapy of Takayasu Arteritis

• 20% of patients have a self-limited, monophasic inflammatory episode

• 80% have a progressive or relapsing/remitting cours e• Serial angiographic studies show that new lesions c an

be found in 61% of patients, even when the arteriti s is be found in 61% of patients, even when the arteriti s is thought to be in remission

• Fixed vascular lesions are not reversed by drug the rapy • GCs constitute the first line of treatment, with

suggested initial dosages of 0.5 to 1 mg/Kg/dayKerr et al, Ann Intern Med 1994; Liang and Hoffman, Current Opin Rheumatol 2004

Limitations of therapy and a guarded prognosis in an American cohort of TA patients

Maksimowicz-McKinnon et al, Arthritis Rheum 2007

• Results:93% of patients attained disease remission of any duration, but only 28% had sustained remission of at least 6 months' duration after remission of at least 6 months' duration after prednisone was tapered to <10 mg daily

• Conclusion:although improvement of symptoms in TA usually follows GC therapy, relapses and anatomic progression usually occur with dosage reduction

Role of Immunosuppressive Agents in TA

They are addded to GCs:

• Halting disease progression

• Reducing GC-related morbidity

Traditional immunosuppressive agents

• Only open-label pilot studies in GC-resistant cases:- methotrexate- micophenolate mofetil- azathioprine- azathioprine- oral cyclophosphamide

Hoffman et al, Arthritis Rheum 1994; Daina et al, Ann Intern Med 1999;

Shinjo et al, Clin Rheumatol 2007; Valsakumar et al, J Rheumatol 2003;

Shelhamer et al, Ann Intern Med 1985; Hoffman et al, Arthritis Rheum 2004;

Molloy et al, Ann Rheum Dis 2008

Anti- TNF therapy in patients with refractory TA: long-term follow-up

Molloy et al, Ann Rheum Dis 2008

• Methods: Retrospective single-centre study of 25 patients with refractory TA treated with infliximab (21) or etanercept (9) for up to 7 years

• Results: Following anti -TNF therapy remission was • Results: Following anti -TNF therapy remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%)

• Conclusions: anti-TNF therapy may lead to durable remission and reduction in glucocorticoid requirements in most patients with refractory TA

IL-6R inhibition in refractory TA

• IL-6R inhibition with tocilizumab improved the clinical manifestations and the abnormal laboratory findings in one patient who needed a daily prednisone dosage of 30 mg/day and was daily prednisone dosage of 30 mg/day and was refractory to several immunosuppressive agents

Nishimoto et al, Arthritis Rheum 2008

IL-6 and Disease Activity in TA

• IL-6 is strongly expressed in aortic tissue of TA patients

• IL-6 is probably locally produced at the site of aortic inflammation

• All patients with active disease have • All patients with active disease have elevated serum IL-6 levels

Seko et al, Circulation 1996Noris et al, Circulation 1999Salvarani et al, Clin Exp Rheumatol 2003Park et al, Rheumatology 2006

IL-6 and Disease Activity in TA

• Clinical improvement was associated with a marked reduction in serum IL-6 levels

• A positive correlation was found between • A positive correlation was found between IL-6 levels and the disease activity score (NIH criteria for disease activity)

Noris et al, Circulation 1999Salvarani et al, Clin Exp Rheumatol 2003Park et al, Rheumatology 2006

Take-Home Messages

•• TNFTNF--blockers as steroidblockers as steroid--sparing agents sparing agents are not effective in GCAare not effective in GCA

•• TNFTNF--blockers are effective in refractory blockers are effective in refractory Takayasu arteritisTakayasu arteritisTakayasu arteritisTakayasu arteritis

•• ILIL--6 inhibition with tocilizumab might be a 6 inhibition with tocilizumab might be a logical target for future RCTs in GCA and logical target for future RCTs in GCA and Takayasu arteritisTakayasu arteritis

Therapy of AAV: RCTs

• Biologic agents- TNF-blockers (etanercept)- TNF-blockers (etanercept)- Rituximab

Wegener’s granulomatosis: Early Outcomes

• Natural History:- Mean survival time: 5 months- Mortality: 82% in 1 year

• Glucocorticoid-treated generalized WG- Mean survival time: 12.5 months

Fauci S and Wolff SM, Medicine 1973

The Fauci-Wolff Protocol: NIH Longitudinal Series (began 1968)

• Cyclophosphamide (CYC) 2 mg/Kg/day• Glucocorticoids:

- Pulse methylprednisolone (1g/day X 3)

- Prednisone 1 mg/Kg/day- Prednisone 1 mg/Kg/day- Tapered to qod after 3 months

• Typical duration of therapy:- Glucocorticoids: 12 months

- CYC: Remission + 12 monthsHoffman GS et al, Ann Intern Med 1992

CYC Therapy for AAV The Good/The Bad

• 91% marked improvement

• 42% permanent morbidity- 46% serious infections- 43% hemorrhagic cystitis- 33-fold risk of bladder CA

• 75% complete remission

- 33-fold risk of bladder CA- 11-fold risk of lymphoma- 57% infertility

Steroid-induced damage:Cushingoid features, weight gain, hypertension, cataracts, fractures

Hoffman et al, Ann Intern Med 1992

Conventional therapy for AAV

• How can we minimize exposure to CYC?

• How can we avoid CYC?

Take-Home Points from RCTs• A short course of CYC for remission induction,

followed by a longer course of methotrexate or azathioprine is an effective treatment strategy for AAV

• The pulse CYC (15 mg/kg pulse q2wkX3, then • The pulse CYC (15 mg/kg pulse q2wkX3, then q3wk) induces remission as well as the daily oral regimen at a reduced cumulative CYC dose and causes fewer cases of leukopenia

Jayne D et al, N Engl J Med 2003 (CYCAZAREM);Pagnoux C et al, N Engl J Med 2008 (WEGENT); de Groot K et al, Ann Intern Med 2009 (CYCLOPS);

Biologic AgentsBiologic Agents

Wegener’s Granulomatosis Etanercept Trial (WGET)

• Etanercept in addition to standard therapy is not effective for the maintenance of remission in pts with WG

- No difference in time to remission- No difference in frequency of remission- No difference in duration of remission- No difference in severity or frequency of flares- Increased risk of cancer in patients treated with

etanercept (6 vs 0, P = 0.01)WGET Research Group, N Engl J Med 2005

Pathogenic immune mechanisms in AAV

Chen M & Kallenberg CGM, Nat Rev Rheumatol 2010

RTX versus CYC in ANCA-Associated Renal Vasculitis (RITUXVAS) Jone RB et al, N Engl J Med 2010

• Randomized (3:1), controlled, open-label• 44 patients• All ANCA-positive, all new diagnosis• All had severe renal disease• Comparing:� RTX plus 2 infusions of CYC (n=33)� Intravenous CYC for 6 months, followed by oral AZA

(n=11)• Everybody remained on ~ 10 mg/day of prednisone• Primary endpoints: sustained remission at 12 months

and severe adverse events

Main RITUXVAS ResultsNo difference between treatment arms of:• Mortality: 18% in each arm• Sustained remission at 12 months:

- RTX 76% vs CYC 82% • Time to remission: RTX 90 days vs CYC 94 days• Relapse rate• Time to relapse• Improvement of renal function• Adverse events rate

Conclusion: over 12 months one course of RTX achieves the same results as 6 months of CYCfollowed by AZAJone RB et al, N Engl J Med 2010

RTX versus CYC for ANCA-Associted Vasculitis (RAVE) Stone JH et al, N Engl J Med 2010

• Randomized (1:1), double blind• 197 patients (newly diagnosed or relapsing disease)• All ANCA-positive• Limited disease (not requiring CYC) and too severe disease

(mechanical ventilation because of alveolar hemorrhage or serum creatinine > 4 mg/dL) were excluded

• Comparing:� RTX plus daily placebo-CYC (n=99), then placebo-AZA for pts in

remission between 3-6 months� Daily CYC (2 mg/Kg) plus placebo-RTX infusions (n= 98), then daily

AZA (2 mg/Kg) for pts in remission between 3-6 months• Primary endpoint: remission without the use of prednisone at 6

month

Main RAVE ResultsNo difference between treatment arms of:• Remission without the use of prednisone at 6 months:

- RTX 64% vs CYC 53%- RTX 67% vs CYC 42% (p=0.01) for relapsing disease

• Improvement of renal function• Adverse events rate• Loss of proteinase 3-ANCA production occurred more frequently

with RTX than with CYC

Conclusion: RTX was not inferior to daily CYC for induction of remission and may be superior inrelapsing disease

Stone JH et al, N Engl J Med 2010

Rituximab Dosage

• RITUXIVAS and RAVE trials used rituximab at a dose of 375 mg per square meter per week for 4 consecutive weeks

• However, in a retrospective evaluation of 65 sequential • However, in a retrospective evaluation of 65 sequential patients receiving RTX for refractory AAV there was no difference in efficacy between 4 infusions of 375 mg/m2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart

Jones RB et al, Arthritis Rheum 2009

Take-Home Messages• Available data do no support the use of anti-TNF therapy

in AVV• Results from 2 RCTs comparing RTX to CYC complement

each other:- RTX is effective as CYC for newly diagnosed pts with

severe AAVsevere AAV- RTX seems to be superior for pts with severe relapses- RTX is preferable for young patients who want to preserve their fertility

• More data on RTX for maintaining remission in AAV are needed

Rituximab in IgG4-related Systemic DiseaseSystemic Disease

IgG4-related systemic disease (IgG4-RSD)

• IgG4-RSD is a recently recognized systemic conditions characterized by unique pathological features:

- extensive lymphoplasmacytic infiltration- abundant IgG4+ plasma cells

- extensive fibrosis

• Increased numbers of IgG4+ plasma cells (more than 10/hpf) strongly support the diagnosis of IgG4-RSD

Smyrk TC et al, Curr Opin Rheumatol 2011

Organ involvement in IgG4-RSDKhosroshahi and Stone, Curr Opin Rheumatol 2011

• Pancreas• Bile duct• Liver• Gastrointestinal tract• Salivary and lacrimal glands

• Mesentery• Aorta• Thyroid• Breast• Lung• Salivary and lacrimal glands

• Orbit• Retroperitoneum• Skin• Lymphonodes

• Lung• Kidney• Pituitary glands• Meninges• Prostate• Pericardium

Conditions recognized to be explained at least part ly by the IgG4-RSD spectrum

Khosroshahi and Stone, Curr Opin Rheumatol 2011Previous name• Mikulicz’s disease• Küttner’s tumor• Riedel’s tyroiditis• Chronic sclerosing aortitis

Target organ(s)• Salivary and lacrimal glands• Submandibular glands• Thyroid• Aorta• Chronic sclerosing aortitis

• Inflammatory abdominal aortitis• Retroperitoneal fibrosis• Autoimmune pancreatitis• Sclerosing cholangitis• Orbital pseudotumor• Eosinophilic angiocentric fibrosis• Multifocal fibrosclerosis

• Aorta• Abdominal aorta• Retroperitoneum• Pancreas• Biliary tree• Orbital adnexa• Sinuses and nasal cavities• Various organs

IgG4-associated sclerosing mesenteritis Salvarani et al, Arthritis Rheum submitted

Rituximab therapy leads to rapid decline of serum I gG4 levels and prompt clinical improvement in IgG4-RSD

Khosroshahi et al, Arthritis Rheum 2010

• Glucocorticoids have become a standard therapy for AIP

• AIP relapses in one third of patients treated with glucocorticoidsglucocorticoids

• Experience with traditional DMARDs as steroid sparing agents is limited

• Treatment with rituximab led to prompt clinical and serological improvement in 4 patients with refractory IgG4-RSD

Take-home message

• Rituximab is a viable treatment option for patients with IgG4-RSD that is refractory to conventional refractory to conventional immunosuppressive therapy

RingraziamentiReumatologiaDr GL Bajocchi, Dr PL Macchioni, Dr N Pipitone,Dr.ssa F Rossi, Dr G Germanò, Dr.ssa L Dardani,Dr.ssa MG Catanoso, Dr A Caruso, Dr.ssa I Chiarolanza, Dr.ssa G Restuccia, Dr.ssa A Ghinoi, Dr L Magnani, Dr F MuratoreAnatomia PatologicaAnatomia PatologicaDr A CavazzaOculisticaDr L CiminoMedicina NucleareDr A VersariRadiologiaDr G Zuccoli, Dr A Levrini

Grazie per l’attenzione