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  • Collagenoses at EULAR 2016

New disease-modifying therapeutic approaches in systemic sclerosis.

    • Congress Reports
    • Rheumatology
    • RX
    • Studies
  • 4 minute read

At the EULAR congress in London, one of the topics was the treatment of collagenoses and in particular early diffuse systemic sclerosis. New approaches that have the potential to act on the disease itself address B-cell depletion, the interleukin-6 pathway, and intravenous immunoglobulin.

John Varga, MD, Chicago, spoke on new disease-modifying approaches in systemic sclerosis (SSc). This is a rare autoimmune disease characterized by inflammation, fibrosis, and vascular changes that can lead to manifestations on the skin and internal organs. Several phenotypes with differences in clinical course and prognosis have been described. There is probably a causal relationship between the inflammatory changes of the early stages of the disease and the later fibrosis. Numerous immunosuppressive therapeutic approaches have therefore been investigated – with overall rather disappointing results. Depending on the spread of the skin thickening, a limited form (skin below the elbows or knee joints) is distinguished from a diffuse form (additional involvement of the skin closer to the center of the body and the trunk). In addition, the lung tissue (interstitial lung disease, ILD) or the blood vessels of the lungs (pulmonary arterial hypertension) may be affected. The approach to SSc with diffuse skin involvement (with or without associated ILD) in particular is poorly established. Methotrexate has been tested, but the results regarding skin manifestations or overall status in early diffuse SSc are not encouraging [1,2]. Cyclophosphamide-established in SSc-associated ILD-also provides insufficient relief from dermatologic symptoms. New disease-modifying approaches with acceptable safety profiles over a longer period of time are therefore highly sought after.

B-cell depletion

There is evidence for B-cell dysregulation or hyperactivation in systemic sclerosis. Since B cells are critically involved in the maintenance of fibrosis and vasculopathy, it seems reasonable to target them therapeutically, e.g. with the anti-CD20 antibody Rituximab [3]. This was administered to 20 patients with (mainly early) diffuse systemic sclerosis – 80% of whom had failed cyclophosphamide therapy, 35% with ILD – in a small, non-randomized trial (follow-up duration four years) [4]. Significant improvements were observed in the activity and severity of skin manifestations and in the mean skin score at 12 months and at final follow-up (compared to baseline). Rituximab also appears to have a positive or stabilizing effect on lung function.

A case-control study with a total of 63 treated SSc patients who received rituximab over a follow-up of five to nine months reached a similar conclusion. The mRS score, a parameter for skin fibrosis, was 25 at baseline, and again there were significant improvements in skin fibrosis with rituximab compared with controls and baseline. Worsening of pulmonary fibrosis was prevented. The safety profile was good according to the authors [5].

Interleukin-6

Interleukin-6 (IL-6) may also be a therapeutic target, as shown by the so-called faSScinate study [6]. This randomized, controlled phase II trial tested weekly subcutaneous tocilizumab vs. placebo for a total follow-up of 48 weeks in 87 patients with diffuse cutaneous SSc with a mean MRSS of 25 and disease duration of 17 months. After this time, there was a trend toward improved mRSS in the tocilizumab group. On average, the anti-IL-6 antibody reduced the score by 6.33 vs. 2.77 with placebo (p=0.0579). Thus, while this result narrowly “missed” significance, the decline in lung function was significantly less with tocilizumab than with placebo (p=0.0373).

The results are not exactly outstanding, yet a corresponding phase III trial is currently underway to definitively clarify the benefit-risk profile.

Intravenous immunoglobulin

Intravenous immunoglobulin (containing human IgG antibodies) is already used in other autoimmune diseases – even though the exact mechanism regarding reduction of autoimmunity is highly complex and not yet conclusively clarified. The effect in scleroderma has also been studied for some time.

An open-label study of 30 patients who had refractory, active diffuse cutaneous SSc for an average of two years and had an mRSS of 30 tested six-month cycles of intravenous immunoglobulin (2 g/kg/month) as add-on therapy. The mean duration of therapy was 8.5 cycles. From 30, the mRSS decreased to 24.1 ± 9.6 at six months, to 22.5 ± 10.0 at one year, and to 15.3 ± 6.4 at two years. All these differences were significant compared with baseline [7].

Source: EULAR Congress, June 8-11, 2016, London.

Literature:

  1. Pope JE, et al: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 2001 Jun; 44(6): 1351-1358.
  2. van den Hoogen FH, et al: Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 1996 Apr; 35(4): 364-372.
  3. Sakkas LI, Bogdanos DP: Systemic sclerosis: New evidence re-enforces the role of B cells. Autoimmune Rev 2016 Feb; 15(2): 155-161.
  4. Bosello SL, et al: Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum 2015 Feb; 44(4): 428-436.
  5. Jordan S, et al: Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis 2015 Jun; 74(6): 1188-1194.
  6. Khanna D, et al: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 2016 May 5. DOI: 10.1016/S0140-6736(16)00232-4 [Epub ahead of print].
  7. Poelman CL, et al: Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 2015 Feb; 42(2): 236-242.

DERMATOLOGIE PRAXIS 2016; 26(5): 46-47

Autoren
  • Andreas Grossmann
Publikation
  • DERMATOLOGIE PRAXIS
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  • B-cell depletion
  • Collagenoses
  • EULAR
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