Table 5.
Randomized controlled trials assessing skin outcome in SSc: interventions, end points, results and relevant post hoc analyses
| Study | Active arm: intervention, sample size | Control arm: intervention, sample size | Skin manifestation as primary end point (outcome measure used) | Skin manifestation as secondary end point (outcome measure used) | Result on skin-related end points | Relevant post hoc analyses |
|---|---|---|---|---|---|---|
| Domiciano (2011) [82] | CYC i.v. with monthly infusions of 1 g/m2/dose, + prednisolone (60 mg then reduced), n = 9 | CYC i.v. with monthly infusions of 1 g/m2/dose, n = 9 | – | Change in mRSS | Tend to improve | – |
| Ostojic (2011) [83] | Antioxidants (α-tocopherol 400 IU/day and ascorbic acid 1000 mg/day) and CYC (500 mg/m2 of body surface monthly), n = 6 | CYC (500 mg/m2 of body surface monthly), n = 7 | mRSS, skin thickness progression rate (change in mRSS in a year) | – | No effect | – |
| Rubén et al. [6] | Oral ciprofloxacin (250 mg), n = 15 | Placebo, n = 15 | mRSS 17 sites | – | Tend to improve | – |
| Daoussis et al. [20] | Rituximab, n = 8 | Continue previous drugs (no additional treatment), n = 6 | mRSS | HAQ (0.2 point decrease), skin histology from affected and adjacent skin sites | Tend to improve | – |
| Su (2009) [84] | Rapamycine, n = 8 | MTX, n = 9 | – | mRSS, proportion of patients achieving minimal clinically important difference (for mRSS: ≥5.3), HAQ, tendon friction rubs | No effect | – |
| Khanna et al. [7] | Recombinant human relaxin, two arms (10 and 25 μg/kg/day): n = 42, n = 95 | Placebo, n = 94 | mRSS 17 areas (mRSS traininga) | Oral aperture, maximal hand extension, HAQ, SF-36 | No effect | Amjadi et al. [28]; Kaldas et al. [33]; Khanna et al. [30] |
| Postlethwaite et al. [8] | Oral Type I collagen, n = 83 | Placebo, n = 85 | Change of mRSS (17 areas) between baseline and 12 months (mRSS traininga) | – | No effect | Amjadi et al. [28]; Kaldas et al. [33]; Khanna (2007) [85] |
| Denton et al. [21] | CAT-192, three arms (0.5, 5 and 10 mg/kg): n = 11, n = 11, n = 10 | Placebo, n = 11 | – | Change of mRSS (17 sites) at weeks 12 and 24; proportion of patients with no change in mRSS (mRSS traininga); HAQ, serum biomarkers, skin biopsy from affected skin sites | No effect | Merkel et al. [44] |
| Tashkin et al. [9] | CYC, n = 79 | Placebo, n = 79 | – | Skin thickening score (range 0–51) | Tend to improve | Tashkin, 2007 [86] |
| Knobler et al. [10] | Photopheresis, n = 27 | Sham photopheresis, n = 37 | Decrease in skin thickening score (20 areas) with range of 0–66 (investigator traininga) | Joints with contractures | Tend to improve | – |
| Genovese et al. [11] | PVAC injection, two arms (15 and 50 mg injections), n = 6, n = 6 | Placebo, n = 6 | Change in mRSS at week 24 | Post-baseline mRSS response, hand expansion, oral aperture, HAQ-DI, serum E-selectin and thrombomodulin | Tend to improve | – |
| Scorza (2001) [78] | Iloprost, n = 29 | Nifedipine, n = 17 | mRSS 17 areas | RP severity score | Tend to improve | – |
| Pope et al. [12] | MTX, n = 35 | Placebo, n = 36 | mRSS 26 areas, UCLA skin score 10 sites (investigator traininga) | Oral opening, grip strength, flexion index, HAQ-DI | Tend to improve | Sultan 2004 [87]; Johnson et al. [24] |
| Seibold et al. [13] | Recombinant human relaxin, two arms (25 or 100 μg/kg/day), n = 23, n = 26 (efficacy analysis: n = 21, n = 24) | Placebo, n = 19 | mRSS 17 areas (investigator traininga) | Maximal oral aperture, hand extension | Significant improvement in the 25 mg/kg/day group | – |
| Enomoto et al. [58] | Photopheresis, n = 10 | Cross-over, n = 9 | Average change in four-scale skin score (74 areas) after 1 year, oral aperture, hand mobility | Blood tests, biopsy | Tend to improve | – |
| Filaci et al. [48] | Iloprost, n = 10 | Iloprost + CYC, n = 10 | Plicometry | Capillarmicroscopy, serum IL-6 concentration | Tend to improve | – |
| Clements et al. [16] | D-Pen 125 mg/day, n = 68 | D-Pen 750–1000 mg/day, n = 66 | Change of mRSS (17 areas), rate of responders (responder: ≥25% lower score compared with baseline) | Active hand spread, fit closure, maximal oral aperture, HAQ-DI |
|
Amjadi et al. [28]; Khanna et al. [32]; Clements et al. [34]; Khanna, 2010 [79]; Sultan, 2004 [87]; Clements, 2001 [88]; Clements, 2004 [89] |
| Black et al. [14] | IFN-α, n = 19 | Placebo, n = 17 | mRSS (17 sites) | Skin biopsy, PINP and ICTP | No effect. Tend to harm | – |
| Grasseger et al. [22] | IFN-γ, n = 27 | Control group, n = 17 | RSS (15 areas), mouth aperture, grip strength | Tend to improve | – | |
| Della (1997) [90] | Iloprost, n = 19 | Nifedipine, n = 12 | – | Rodnan score, nailfold capillaroscopy | Tend to improve | – |
| Van den Hoogen et al. [15] | MTX, n = 17 (at week 24: dose increase or switching to active treatment) | Placebo, n = 12 | Total skin score (26 sites), global health VAS. Responders: improvement of ≥ 30% | Hand extension, grip strength, maximal oral opening | Tend to improve | – |
| Wilson et al. [17] | Recombinant human tPA, n = 14 | Placebo (cross-over) | RSS | – | Tend to improve | – |
a
Investigators underwent pre-study standardization training. HAQ-DI: HAQ-Disability Index; ICTP: carboxyterminal cross-linked telopeptide of type I collagen; mRSS: modified Rodnan skin score; PINP: blood amino-terminal propeptide; PVAC: therapeutic agent derived from delipidated, deglycolipidated Mycobacterium vaccae; RSS: Rodnan skin score; SF-36: short form 36 questionnaire; UCLA: University of California Los Angeles; VAS: visual analog scale.