Behçet’s disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-)
Behçet’s disease (BD) is a chronic and relapsing multisystemic inflammatory disorder which can be localized on the borderline between autoimmune and autoinflammatory diseases [
BD clinical course is highly irregular and erratic, ranging from simple localized mucocutaneous symptoms, that may or may not be associated with uveitis, to severe forms associated with eye and neurological involvement linked to less favourable outcomes. Thus, therapy is mainly based on the type and severity of clinical manifestations and disease duration, as well as number of flares [
Infliximab, a chimeric mouse-human anti-TNF-
In the management of gastrointestinal involvement, prior to surgery, sulfasalazine, corticosteroids, azathioprine, thalidomide, and anti-TNF
There is currently no gold standard therapy for BD, and increasing evidence of molecular and cellular pathways involved in its pathogenesis continues to emerge. Recent data have spread the promising therapeutic targets other than TNF in patients with severe and refractory BD (Figure
Mechanisms of actions of anakinra, canakinumab, gevokizumab, tocilizumab, ustekinumab, and rituximab, based on the different mechanisms of antagonizing cytokine receptors, cytokines, and cellular antigens.
We found 44 cases of BD patients in therapy with biological agents other than anti-TNF-
Studies reporting on patients with Behçet’s disease treated with anti-IL1
First author (reference, year) |
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Clinical and laboratory features | HLA-B51 | Previous biologic agents and causes of withdrawal | Dosage and eventual cotherapies | Followup | Outcome |
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Botsios (2008) [ |
1 | Fever, mucosal involvement, colon ischemic perforation, necrotizing lymphocytic venulitis, thrombosis, serositis, increase of inflammatory markers, and SPR | Negative | IFX: mucosal abdominal abscesses | ANA 100 mg/day + PDN 5 mg/day | 20 months | CR and improvement of inflammatory markers in 7–10 days. Disease-free at 20-month followup |
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Bilginer (2010) [ |
1 | Fever, mucosal involvement, EN, arthritis, secondary amyloidosis, increase of inflammatory markers, and SPR overlapping with FMF | NR | None | ANA 1 mg/kg/day | 18 months | CR and improvement of inflammatory markers; patient free of clinical symptoms at 18-month followup; however proteinuria gradually increased (from 1,8 to 2,4 g/day) |
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Gül (2012) [ |
7 | Acute posterior or panuveitis and/or retinal vasculitis | NR | None | GEV: 0.3 mg/kg (single infusion) | Up to disease relapse | Improvement in visual acuity from day 1 in 5 out of 7 patients. Complete resolution of retinal findings achieved in 4–21 days (median 14 days). No detailed assessments of extraocular manifestations were performed. Recurrence of folliculitis and oral aphtosis. Median duration of response: 49 days (range: 21–97 days) |
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Ugurlu (2012) [ |
1 | Mucosal involvement, EN, bilateral panuveitis, retinal vasculitis, and SPR | NR | INF- |
CAN 150 mg (single dose) | 8 weeks | CR for 8 weeks; resolution of ocular inflammation and rapid VA improvement. |
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Emmi (2013) [ |
1 | Mucosal and gastrointestinal involvement, arthritis, pseudofolliculitis, and bilateral retinal vasculitis | NR | IFX: ADR (diffuse urticaria with angioedema); |
ANA 100 mg/day | 12 months | CR after 12 months of followup; rapid and persistent disappearance of joint pain, mucocutaneous and bowel manifestations; VA improvement, clearing of the vitreous opacity and no active retinal inflammation |
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Cantarini (2013) [ |
9 | Mucosal involvement, EN, headache, retinal vasculitis, low-back pain, and increase of inflammatory markers | Positive | ETN and IFX: loss of efficacy | ANA 150 mg/day + |
9 months | PR; PDN was reduced to 7.5 mg/day |
Fever, mucosal involvement, skin lesions, headache, arthritis, abdominal pain, and increase of inflammatory markers | Positive | None | ANA 100 mg/day | 19 months | CR at 12-month followup; | ||
Fever, mucosal involvement, skin lesions, headache, and increase of SAA | Positive | ANA (100 mg/day): inefficacy | ANA 150 mg/day + |
19 months | DVT not resolved with heparin at 6 months; CYC (5 mg/kg/day) was added; | ||
Mucosal involvement, bilateral panuveitis, retrobulbar optic neuritis, papillophlebitis, headache, arthralgia, DVT, and increase of SAA | Positive | ETN: loss of efficacy | ANA 100 mg/day + |
6 months | Flare of panuveitis after 3 months; ANA was withdrawn; CR with ADA (40 mg twice monthly) + MTX (10 mg/weekly) + PDN (25 mg/day) | ||
Mucosal involvement, bilateral panuveitis, arthralgia, and increase of inflammatory markers | Positive | None | ANA 100 mg/day + AZA 50 mg/day + PDN 7.5 mg/day | 8 months | CR after 12 months | ||
Fever, mucosal involvement, venous thrombosis, arthritis, panuveitis, headache, pseudofolliculitis, and increase of ESR and SAA | Positive | None | ANA 100 mg/day | 12 months | Flare of uveitis after 8 months; ANA was increased to 150 mg/day + MTX (15 mg/weekly) + colchicine (1 mg/day); PR at 17 months of followup | ||
Mucosal involvement, skin lesions, abdominal pain, photophobia, and increase of SAA | Positive | ADA: inefficacy | ANA 2 mg/kg/day + PDN 15 mg/day | 9 months | CR at first; relapse after 4 months requiring an increased dosage of ANA (2.5 mg/kg/day); PR after 7 months | ||
Fever, mucosal involvement, EN, arthritis, anterior uveitis, pseudofolliculitis, and increase of CRP | Positive | None | ANA 100 mg/day + |
6 months | PR; CYC (5 mg/kg/day) was added after 8 months of followup | ||
Fever, mucosal and gastrointestinal involvement, headache, anterior uveitis, and arthralgia | Positive | ETN and ADA: loss of efficacy | ANA 100 mg/day | 9 months | Inefficacy after 8 weeks; | ||
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Caso (2014) [ |
1 | Mucosal and ocular involvement, pseudofolliculitis, sacroiliitis, and increase of inflammatory markers | Positive | IFX: loss of efficacy | ANA 100 mg/day + |
12 months | CR in few days; PDN was tapered to 5 mg/day |
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Cantarini (2012) [ |
3 | Fever, mucosal involvement, skin lesions, arthritis, abdominal pain, headache, and increase of inflammatory markers and SAA overlapping with granuloma annulare | Positive | SSZ, MTX, CYC, AZA and LFN: inefficacy; |
CAN 150 mg every 8 weeks | 16 months | CR in few months; |
Fever, mucosal and gastrointestinal involvement, headache, anterior uveitis, and arthralgia | Positive | ETN and ADA: loss of efficacy; ANA: inefficacy | CAN 150 mg every 6 weeks | 12 months | CR after few months | ||
Fever, mucosal involvement, DVT, panuveitis, headache, arthritis, pseudofolliculitis, and increase of ESR and SAA | Positive | ANA: ADR (urticarial skin lesions) | CAN 150 mg every 6 weeks | 6 months | CR within few days |
Abbreviations: ADA: adalimumab; ADR: adverse reactions; ANA: anakinra; AZA: azathioprine; BD: Behcet's disease; CAN: canakinumab; CYC: cyclosporine; CMO: cystoid macular oedema; CR: complete remission; CRP: C-reactive protein; CS: corticosteroids; DVT: deep venous thrombosis; EN: erythema nodosum; ESR: erythrocyte sedimentation rate; ETN: etanercept; FMF: familial Mediterranean fever; GEV: gevokizumab; HLA: human leukocyte antigen; Ig: immunoglobulin; IFX: infliximab; INF-
Studies reporting on patients with Behçet’s disease treated with tocilizumab and ustekinumab.
First author (reference, year) |
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Main BS clinical and laboratory features | HLA-B51 | Previous biologic agents with causes of withdrawal | Dosage and eventual cotherapies | Followup | Outcome |
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Hirano (2012) [ |
1 | Mucosal involvement, EN, and uveitis | NR | IFX: loss of efficacy | TCZ 8 mg/kg every 4 weeks | 12 months | VA improvement and resolution of EN and genital aphtosis. Partial improvement of oral aphtosis |
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Shapiro (2012) [ |
1 | Mucosal and neurologic involvement, bilateral uveitis, and cutaneous vasculitis | NR | IFX: concomitant onset of IgA nephropathy | TCZ 8 mg/kg every 4 weeks |
7 months | CR after the 2nd infusion; PDN was tapered off; complete resolution of ocular, neurological, and skin manifestations; oral ulcers recurred |
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Urbaniak (2012) [ |
1 | Mucosal and neurologic involvement, EN, DVT, and thrombophlebitis | NR | IFX: worsening of the gait disturbance and relapse of myelitis | TCZ 8 mg/kg every 4 weeks |
8 months | Improvement of clinical signs and symptoms; after the 4th infusion TCZ was discontinued due to a scrotal abscess |
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Caso (2013) [ |
1 | Fever, mucosal involvement, myalgia, bilateral uveitis, optic neuritis, EN, SPR, and increase of inflammatory markers overlapping with refractory pemphigus foliaceus | Positive | IFX and ADA: inefficacy; |
TCZ 480 mg every 4 weeks | 14 months | CR with improvement of inflammatory markers within few days |
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Redondo-Pachón (2013) [ |
1 | Mucosal involvement, EN, iridocyclitis, secondary amyloidosis, and increase of CRP | Positive | None | TCZ 8 mg/kg every 4 weeks |
12 months | CR with decrease of proteinuria and CRP after the 2nd infusion. |
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Diamantopoulos (2013) [ |
2 | Mucosal involvement, pseudofolliculitis, and cutaneous vasculitis | NR | IFX and ETN: short efficacy and ADR (not specified) | TCZ 8 mg/kg every 4 weeks |
Unknown | Inefficacy; worsening of mouth and genital ulcers |
Mucosal involvement, increase of inflammatory markers | NR | IFX and ADA: incomplete response and ADR (not specified) | TCZ 8 mg/kg every 4 weeks | 3 months | Initial PR with loss of efficacy after the 3rd infusion; recurrence of genital ulcers | ||
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Baerveldt (2013) [ |
1 | Mucosal involvement, anterior uveitis, arthritis, and pathergy reaction overlapping with psoriasis vulgaris and hidradenitis suppurativa | NR | None | Ustekinumab 45 mg at weeks 0 and 4 and every 12 weeks | 36 months | CR within few months, clinical improvement of psoriasis |
ADA: adalimumab; ADR: adverse reactions; ANA: anakinra; AZA: azathioprine; BD: Behçet’s disease; CR: complete remission; CRP: C-reactive protein; DVT: deep venous thrombosis; EN: erythema nodosum; ETN: etanercept; HLA: human leukocyte antigen; IFX: infliximab; MRI: magnetic resonance imaging; MTX: methotrexate;
Studies reporting on patients with Behçet’s disease treated with anti-CD20 monoclonal antibody (rituximab).
First author (reference, year) |
|
Main BD clinical and laboratory features | HLA-B51 | Previous biologic agents and causes of withdrawal | Dosage and eventual cotherapies | Followup | Outcome |
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Sadreddini (2008) [ |
1 | Mucosal involvement, arthritis, posterior uveitis, retinal vasculitis, and chronic renal failure (of unknown origin) | NR | ETN: ADR (fever, urticaria, macular rushes, angioedema, transient new lymphopenia, and positive antinuclear antibody test) | RTX 1 g every two weeks for two doses + PDN 1 mg/kg/day | 24 months | CR of retinal vasculitis within few months and PDN was tapered to 5 g/day |
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Davatchi (2010) [ |
10 | Mucosal, ocular, and articular involvement; skin manifestations | NR | None | RTX 1 g every two weeks for two doses + PDN 0.5 mg/kg/day + MTX 15 mg/week | 6 months | Improvement of ocular manifestations after 6 months. TADAI significant improvement on RTX. VA improved in two patients, remained unchanged in 1, and worsened in 7. Significant improvement of retinal, disc, and macular oedema in all patients |
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Zhao (2014) [ |
1 | Fever, mucosal involvement, arthritis, EN, leukocytoclastic vasculitis, increase of CRP | NR | IFX: inefficacy; |
RTX 1 g every two weeks for two doses + PDN 15 mg/day + MTX 20 mg/week + colchicine | 12 months | CR after the 3rd infusion; improved clinical control of disease activity and reduction in steroids requirements (PDN tapered to 8 mg/day) |
ADR: adverse reactions; BD: Behçet’s disease; CR: complete remission; CRP: C-reactive protein; EN: erythema nodosum; ETN: etanercept; HLA: human leukocyte antigen; IFX: infliximab; MTX: methotrexate;
The IL-1 superfamily comprises a group of 11 cytokines which regulate many intracellular signaling pathways: IL-1
Canakinumab is a human monoclonal IgG1 that selectively neutralizes IL-1
Gevokizumab is a recombinant humanized anti-IL-1
IL-6 is a pleiotropic cytokine secreted by various cell types, including T and B lymphocytes, macrophages, osteoblasts, fibroblasts, keratinocytes, and endothelial cells, involved in many immune pathways and playing a pivotal role in the regulation of various immune responses, in the amplification of acute inflammation, and in its progression into relapsing or chronic inflammatory reactions [
Two studies have shown increased serum levels of IL-12 and IL-23 in BD patients and also descripted a relationship of serum IL-23 levels with ocular inflammatory activity [
With regard to ustekinumab, a human monoclonal antibody against the common p40 subunit of IL-12 and IL-23 [
Although there is more extensive evidence of T cell involvement in BD, several studies have suggested a possible pathogenetic role of B cells and a potential close interaction between T and B cells [
In a single-blind randomized controlled trial related to 20 patients with refractory BD involving the eye, 10 patients were treated with rituximab (1 g × 2/infusions, 2 weeks apart) and methotrexate (15 mg/week) and 10 with cyclophosphamide (monthly intravenous infusions of 1000 mg), azathioprine (2-3 mg/kg/day), and prednisone (0.5 mg/kg/day): rituximab and methotrexate were found to be more effective than traditional drugs in improving all the most dreadful ocular manifestations [
The final goal in the treatment strategies of BD is to prevent irreversible multisystemic damage: an ideal therapy should be tailored according to the extent and severity of BD heterogeneous clinical manifestations [
Luca Cantarini received grant/research support from Novartis, SOBI, where he serves as consultant.
Francesco Caso and Luisa Costa equally contributed to the present paper.