2024 ACR/ACCP Guidelines on Treatment of SARD-ILDs

The ACR/ACCP committee looked at ILD associated with five common SARD categories:

1. Systemic Sclerosis (SSc)

2. RA

3. IIM (includes anti-synthetase syndromes and Immune mediated necrotising myositis).

4. Sjogren's

5. MCTD

Following is a summary of the recommendations:

For initiation of treatment:

1. MMF as first line choice to commence treatment in all categories. However, this may be tempered by extra-pulonary considerations, for example, rituximab may be preferred in RA with active joint disease.

2. Cyclophosphamide still among first line choices, but Rituximab preferred in all 5 categories due to equivalent results and lower incidence of side effects.

3. Steroids, either short term or long term, to be avoided in SSc.

4. Short term steroids acceptable in other categories, but not long term.

5. Tocilizumab, elevated to one of the first line choices in SSc and MCTD with SSc features.

6. In RA-ILD, Methotrexate, Leflunomide, anti-TNFs and Abatacept should not be used for treatment of ILD. There is discretion to use them for arthritis, but some panelists would withdraw them if incident ILD develops.

7. JAK inhibitors can be used as first line in IIM, and particularly useful in MDA-5 (JAKi include Tofacitinib, Baricitinib and Upadacitinib).

8. Similarly, calcineurin inhibitors, with tacrolimus preferred to ciclosporin, is amongst first line choices for IIM-ILD.

9. Nintedanib is now recommended as a first line choice in  SSc, but not others.

10. Azathioprine remains among first line choices for all categories, but is down in the pecking order for SSc, behind MMF, Rituximab and Tocilizumab.

For progression of ILD despite treatment:

1. If any of the first line Rx above has not been used, it may now be used, with the exception of Azathioprine.

2. Nintedanib can be used for all categories, on the grounds of PPF.

3. Tocilizumab may be used for progressive RA-ILD.

4. IVIG may be used for progressive IIM-ILD.

5. AHST may be considered at this point for SSc-ILD.

6. Pirfenidone may be considered, but only for progressive RA-ILD.

7. Lung transplant can be considered in all categories.

For rapidly progressive ILD (RP-ILD), as seen, for example in MDA-5:

1. IV methylprednisolone, 1g for 3 days, plus at least 2 others from Rituximab, Cyclophosphamide, IVIg, MMF, JAKi and Tacrolimus

2. For non MDA-5 conditions, it is IV methylprednisolone and at least one, or sometimes two of the others.

3. Again, avoid steroids in SSc-ILD.

4. Rituximab and Cyclophosphamide preferred ahead of MMF and calcineurin inhibitors in RP-ILD.

5. Rituximab preferred ahead of Cyclophosphamide in MDA-5 associated RP-ILD.

6. JAKi useful for slowly progressive MDA-5 but not for RP-ILD.

6. Consider early referral for lung transplant in all eligible cases of RP-ILD.

https://acrjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/art.42861?af=R

Myxovirus Resistance Protein A (MxA) & Antibodies to Nuclear Matrix Protein-2 (NXP-2) in Dermatomyositis Sine Dermatitis

 There has long been debate on what is the most sensitive and specific marker that distinguishes Dermatomyositis (DM) from Polymyositis (PM) or Inclusion Body Myositis (IBM), and further whether anti-synthestase syndromes (ASS) should be included under DM. 

Where subjects present with a skin rash and muscle weakness with one of 5 DM specific autoantibodies, i.e. Mi-2, NXP-2, MDA-5, TIF-1gamma or SAE, the diagnosis of DM is straightforward. Given the difficulty in obtaining muscle biopsies within the NHS, particularly in DGHs, most Rheumatologists would settle for a diagnosis of DM in this scenario, particularly if the EMG too is characteristic of a myopathy.

But what if DM presents without a skin rash, as it can in approximately 8% of subjects. The distinction between DM one one hand and PM, IBM and ASS on the other is more than academic, firstly because of a higher association of cancer with the former, and secondly because of increasing reports of efficacy of JAK inhibitors for DM but not the other conditions.

In this situation, two tests can be useful. The first requires a muscle biopsy, and the second is included in the DM specific autoantibody panel.

First, the staining of the sarcoplasm of muscle for Myxovirus Resistance Protein A (MxA) is highly sensitive (76%) and 100% specific for DM. This is a Type I interferon induced protein and therefore an interferon signature. It is not seen in PM, IBM or ASS. Unlike the latter three, DM is an interferonopathy (which is why it responds to JAK inhibitors).

While other interferon signatures such as RIG-1 and ISG-15 are also quite specific for DM, as indeed are muscle biopsy findings of perifascicular atrophy (PFA) and deposition of membrane attack complex on capillaries, none of these are as sensitive as MxA. (While ASS also displays PFA on biopsy, the characteristic necrotic and regenerating fibres in perifascicular fibres sets it apart from the mainly degenerative fibres seen in DM).

The other useful marker of Dermatomyositis sine (without) dermatitis is the muscle specific antibody NXP-2. This is seen in fully 86% of subjects who have DM without skin involvement at presentation, but only in 28% of subjects who have DM with rash. Therefore, a subject presenting with myositis, but no rash and a positive NXP-2 should be treated as DM rather than PM. In a minority of such subjects, a typical rash may appear after many months or even years.

DM sine dermatitis should not be confused with amyopathic DM, which is characterised by rash and lung involvement without muscle involvement. Most such subjects are positive for MDA-5 and have a severe lung phenotype.

References

1. https://jamanetwork.com/journals/jamaneurology/fullarticle/2764337

2. https://pubmed.ncbi.nlm.nih.gov/30267437/