OT2 - Improvement of hand dysfunction by arthritis

Protocol Summary                                          PI: László CZIRJÁK

 Investigative objective

Background: The major contributors to hand dysfunctiony are skin involvement, DU, hand arthritis, tendinitis, calcinosis and flexion contractures. Of these, presence of hand arthritis is a major contributor to impairment of hand function [32]. There are several drugs used in SSc and other rheumatic diseases, including methotrexate, leflunomide, azathioprine, mycophenolate mofetil and low-dose corticosteroids, which can potentially improve arthritis and consequently hand function. Hand function can be assessed by HAQ-DI (CHAQ-DI in jSSc) and CHFS, which are validated tools in SSc [41, 36-39, 92, 93]. For the assessment of arthritis, the CDAI is validated in rheumatoid arthritis [43] and may prove useful for SSc-related arthritis as well

Objectives: To investigate the efficacy and safety of different treatments on hand dysfunction in SSc patients with hand arthritis and to validate the CDAI for arthritis in SSc

 Primary endpoint(s)

Improvement of HAQ-DI (CHAQ-DI in jSSc) by at least -0.21 (moderate improvement) in one year

Secondary endpoint(s)

• Improvement of the CHFS in one year 
• Improvement of the CDAI in one year 
• Improvement of the SDAI in one year 
• Improvement of the DAS28(We) ) in one year 
• Improvement of the DAS28(CRP) ) in one year 
• Improvement of the 28 (±hand distal interphalangeal) joint tenderness count in 
  one year 
• Improvement of the 28 (±hand distal interphalangeal) joint swelling count in 
  one year

 Exploratory endpoints

• Validation of the CDAI 
• Validation of the SDAI in SSc 
• Validation of the DAS28(We) in SSc 
• Validation of the DAS28(CRP) in SSc 
• Validation of the 28 joint (±hand distal interphalangeal) joint tenderness count 
• Validation of the 28 joint (±hand distal interphalangeal) joint swelling count 
• Evaluation of the incidence and potential predictors of deterioration of hand dysfunction and progression of arthritis in SSc 

 Safety endpoints

Incidence of drug-related adverse events, incidence of withdrawal from treatment due to drug-related adverse events

 Participants

Study population justification

 The study population is adult and juvenile systemic sclerosis patients from the EUSTAR cohort (MEDSonline database) and the jSScWG cohort.

 Inclusion criteria

•  Juvenile and adult Systemic sclerosis patients, with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria respectively
• Clinical signs of arthritis (defined as ≥2 tender and swollen joints)

• Presence of significant, long standing articular pain due to other cause than autoimmune disease 
• Presence of significant hand disability due to other causes than autoimmune disease 

Trial design

 Observational trial with 4 treatment arms

 Treatment arms

Four different groups will be observed for analysis:

1. methotrexate with or without low-dose corticosteroids
2. Other DMARDs (leflunomide, azathioprine, mycophenolic acid) with or without low-dose corticosteroids
3. Low-dose corticosteroids without DMARDs
4. No DMARD or corticosteroid treatment

Patients, who receive drug(s) related to the observational treatment arms at a dose lower than the minimally efficient dose defined in the table below, will be excluded from the observational treatment arms for primary analysis but will be followed within OT2 for explorative analysis.

In case of therapy changes during the follow-up, only patients who continuously received the drug(s) − related to the observational treatment arms − for at least 9 months during the 1 year follow-up will be included in the observational treatment arms for primary analysis, otherwise they will be excluded from primary analysis but will be followed within OT2 for explorative analysis.

In case of rarely used combination therapies, depending on the period of use and the dose of the respective therapies, the in- or exclusion of patients from the observational treatment arms will be decided one-by-one.

Patients, who received a biologic therapy 3 to 12 months before the baseline visit* and/or a concomitant biologic therapy during the follow-up period, will be excluded from the observational treatment arms for primary analysis but will be followed within OT2 for explorative analysis.

*3 months before baseline in case of Abatacept, Tocilizumab and TNF-alfa antagonists, 12 months in case of Rituximab and “other biologic therapy”.