Scleroderma Lung

Incidence

Pathology

Cellular NSIP versus fibrotic NSIP

UIP Scleroderma Lung

Natural History

Risk prediction model 

It has been shown that three-year mortality risk in SSc-ILD can be estimated using the SADL model (ever Smoking history, Age, and percent predicted Diffusing capacity of the Lung for carbon monoxide) developed in two independent cohorts of patients with SSc-ILD with a total of 225 patients. [1]

Lab

Autoantibodies

The 3 most common antibodies associated with scleroderma are

• centromere
• anti-topoisomerase-1
• RNA polymerase 3.

Anti-CCP antibodies and rheumatoid factor are not uncommon in patients with systemic sclerosis. In a study published in Adv Clin Exp Med. 2018;27(9):1253–1257, prevalence of CCP antibody was 10 in 100 (10%) and RF was 71 of 100 (71%). 6 of the 100 were considered to have an overlap of RA and scleroderma, 34% had arthritis. Higher CCP, ESR and CRP levels were observed in the SSc group with arthritis. 90% had arthralgia and correlation was found between the arthralgia group and presence of IgM RF.^[4]

Nucleolar ANA

Antinuclear antibody testing is a screening test for lupus. It detects antibodies that bond with human antigen such as DNA (i.e. anti-DNA antibody). Antigens on the nucleus are a substrate for antinuclear antibody (ANA). This can be tested by sampling a person’s blood serum and seeing if ANA binds to it. A microscope equipped to detect a glow in the dark (fluorescence) is used and the appearance of a positive ANA is described as a pattern. The most common patterns are homogenous and speckled but one that is strongly associated with scleroderma is a nucleolar pattern.

Monitor

Treatment

Treatment overview

The optimal treatment for systemic sclerosis-associated interstitial lung disease (SSc-ILD) is not known. Based on the best available evidence, we suggest initiating immunosuppressive therapy in patients with symptomatic SSc-ILD and features suggesting a high likelihood of progression. Mycophenolate mofetil is preferred as initial therapy over cyclophosphamide due to a better safety profile and comparable efficacy as described in the following sections. Azathioprine is an alternative that can be considered for patients with contraindications to or intolerance of cyclophosphamide and mycophenolate. Patients can also be offered the opportunity to participate in a clinical trial (clinicaltrials.gov).[1]

Tocilizumab (Actemra)

The role of adjuvant low dose of oral glucocorticoids (equivalent of ≤10 mg/day of prednisone) in combination with cyclophosphamide is unclear. In studies evaluating the efficacy of cyclophosphamide versus placebo in SSc-ILD, many patients also received low dose glucocorticoid. However, evidence in support of this practice is lacking, and we reserve low dose glucocorticoids for patients with other indications for glucocorticoids (eg, arthritis, pruritus). We avoid combining high dose glucocorticoids with cyclophosphamide because of the lack of clinical trial data and the attendant risks of scleroderma renal crisis and opportunistic infection.[1]

Treatment of progressive disease

Rituximab

Rituximab is a monoclonal antibody that targets CD20-positive B lymphocytes, leading to long-lived depletion of circulating B cells in most patients. Based on promising results from small clinical trials and some observational studies, rituximab may be an option for SSc-ILD, although widespread use should await further study, such as a large clinical trial with follow-up for 24 months. 

The potential efficacy of rituximab for SSc-ILD was examined in a small randomized trial that compared rituximab plus "standard therapy" (eg, prednisone, cyclophosphamide and/or mycophenolate) with standard therapy alone. The eight patients in the rituximab group had significantly better forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) at one year than the six patients receiving standard therapy alone. In a follow-up study, the eight patients in the rituximab arm received two additional cycles of rituximab a 12 and 18 months and were reassessed at two years. A significant increase in FVC compared with baseline was noted (median percentage improvement 12.79). DLCO also increased relative to baseline (mean ± SEM: 63.13 ± 7.65 versus 52.25 ± 7.32, respectively, p<0.001). However, observational studies have reported conflicting results. 

Studies suggesting a benefit to rituximab include the following: 

In a systemic review of two trials and several observational studies (575 participants) of patients with SSc-ILD, rituximab resulted in a modest 4.49 percent (95% CI 0.25, 8.73) improvement in FVC at six months and a 7.03 percent (95% CI 4.37, 9.7) improvement in FVC at 12 months.

In a series of 20 patients treated with rituximab (two infusions of 1000 mg, two weeks apart, with repeat treatment in eight patients) and followed for 12 months, a significant increase was noted in FVC compared with baseline, while the DLCO remained stable. The HRCT scores also remained stable. 

A smaller series of eight SSc patients with severe and progressive interstitial lung disease noted an improvement in pulmonary function among seven patients and stability in another over 9 to 12 months of follow-up.

A case-control study of nine SSc-ILD patients from the European Scleroderma Trial and Research (EUSTAR) database found that FVC was stable compared with baseline after rituximab treatment for a median of six (4 to 12) months, whereas matched controls showed a decline in FVC.

Among eight patients with SSc-ILD treated with one or more cycles of rituximab, six remained stable and two experienced disease progression. On the other hand, a series of 15 patients found no improvement in skin disease and no change in pulmonary function tests (PFTs) six months after two doses of rituximab. [1]

Prognosis