If rituximab will work, seems at least imaginable, but is also questionable with respect to the high drug resistance of your patient. However, from my own clinical experience, it will be worth to identify the vitamin D status due to the large impact of D3 and calcium on immune functions. Long-standing vitamin D3 deficiency leads to deficiency of calcium and phosphate, resulting in altered intracellular calcium handling, with reduced ATP-production and deranged gene expression, chronic endoplasmatic reticulum stress, reduced calcium binding proteins, and most presumably also in altered phosphorylation status of membrane receptors. I have seen a lot of vitamin D-deficient patients who suffered from drug resistance and oversensitivity against drugs and who were able to take profit from treatment with cholecalciferol (10000 IU = 250 mcg/day), combined with multiminerals and sufficient calcium supply (1200 mg in divided doses).

The proposed dosage is not toxic. 25OHD3 levels will help to monitor the treatment regimen.

Best regards

Annedore

A number of people have had experience with using rituximab in ASS, including ourselves, going back to about 2004. You should check the reports on the net but I think they are still case studies rather than any prospective trials of any size. The consensus is, I believe, that rituximab can be helpful, and in some cases is associated with major improvement. That was our view when I retired from practice. Chester Oddis took a particular interest in this and may be a good person to contact.

My only concern is that rituximab does appear to be able to induce a form of pneumonitis itself. And one case of dermatomyositis of ours who I think had Jo-1 antibodies developed a severe adult respiratory distress syndrome after infusion. If I were to use rituximab for this disease I think I would probably use a small dose for the first infusion - maybe 250mg and give the infusion very slowly and carefully. Most rituximab reactions occur with the first infusion so if this was tolerated I would no worry about then giving a full 1gm dose perhaps a week later. (The two week interval often used for rituximab doses in autoimmunity is a historic anomaly based on the interval we set up at UCL in order to be able to give rituximab alongside cyclophosphamide. I know of no practical reason for sticking to the interval, other than that it is now what people have most experience with. )

Both answers are interesting. I would recommend a flow cytometry assesment of B cell in the patient prior to decide the real treatment although I would prefer vitamin D prior to rituximab. Rituximab is quite strong treatment for some patients and failure or adverse reactions are quite common.

good luck

Firstly in case of resistant to treatment, we recommend to evaluate the diagnosis of patient even though Jo-1 positivity. We should make differential diagnosis of steroid myopathy and other muscular pathologies. A newly published study, confirmed the more effectiveness of rituximab in especially SS-A positive Antisynthetase syndrome patients. Concomitant rituximab and cyclophosphamide treatment could increase immunosuppression level. If you define the findings of resistant disease course, therapy planning may be more feasible.

I agree with checking the vitamin D status for sure. Would your patient be responsive to Rituxan? I suppose there is only one way to find out, and I am assuming he/she has an autoimmune inflammatory myopathy, as opposed to some other type of myopathy, as correctly pointed out above,

According to the available evidences, Rituximab can be as a therapeutic option for the condition, especially in the therapy of refractory interstitial lung disease in patients with ASS

I have a similar patient, a 36 year old woman, an anti-synthetase syndrome in a JDM with 18 years of follow-up. Recently gave birth to a healthy child. There was a dramatical - biochemical and clinical- response, after several courses of Rituximab combined with MTX.

Dear all tank you very much for your pertinent answers

Dr Jonathan_Edwards .

Do You mean Chester V. Oddis, M.D. - Department of Medicine - University of Pittsburgh

Office: Arthritis Institute. S705 BST, 3500 Terrace Street. Pittsburgh, PA 15261. Phone: 412-383-8861. Fax: 412-383-8864.

[email protected] ?

Chet Oddis is certainly around Pennsylvania and yes I think Pittsburgh. There cannot be two people with that name!

Serum antibodies to aminoacyl-transfer RNA synthetases are not limited to only John P (Jo-1) who had PM and interstitial lung disease.

If myositis pts are not responding to hard cytotoxic drugs MTX, Az, CP and immune suppressive IVIG one might have to take this as a wake up call.

B cell clones undergo different rates of clonal expansion and thus show variable susceptibility to B cell depletion. Long -lived tissue resident plasma cells (that do not express CD20) resistant to Cyclophosphamide Tx are found in SLE.

Is this also happening in the case of certain pathogenic anti-acyl transfer RNA sythetase AutoAbs in chronic Myositis pts?.

I recommend monitoring Rituximab therapy not only in terms of Flow Cytometry peripheral B cell counts but also precise and accurate

1. clinical diagnosis of the muscle inflammation and pain.

a. define exactly what is the undifferentiated CTD (PM, DM, PM/Scl overlap, IBM, necrotizing Inflammatory myositis that is HMG Co Enzyme A reductase positive) you are talking about here?

b.does pt show involvement of lung and other tissues?

c. What are Creatinine kinase levels- i.e. the fold increase above the normal range (20-220 U /L)

2. laboratory values.

a TITRE of the anti-synthetase AutoAbs (Jo-1, -Anti-PL-7 -Anti-PL-12 -Anti-EJ -Anti-OJ -Anti-KS -Anti-Zo -Anti-Ha-YRS -Anti-SRP) at BASELINE and at 2,4,8,12 week follow up visits post Ritixumab B cell depletion.

b. which AutoAbs increase?

c. which AutoAbs remain unchanged?

d. which AutoAbs show >2 fold decline at each Rituximab FU visits?

e. which AutoAbs show sustained decline and

f. which AutoAbs rebound after cessation of Rituximab.?

For the sake of claritiy- let's consider to strike the term "Anti-Synthetase Syndrome" from the clinical vocabulary. I find the anti-synthetase syndrome a mess and confusion.

Is this an advert for serology kits Simon? Do you have a basis for your recommendation? Having probably done more immunodynamics on patients with autoimmunity treated with rituximab than anyone else (bar Dr Cambridge of course) my impression is that your recommendation would be a waste of money for the clinician looking after the patient rather than doing research. A repeat antibody titre at 3 and 6 months is probably quite enough to see a downswing (the degree of downswing probably tells you very little). How you play things after that has not been established but I would tend to recommend measuring if you think it would alter your interpretation of equivocal clinical indications for intervention further. I think most clinicians appreciate that diagnostic tags are shorthand and that looking after patients involves rather more!

Dear Jonathan Edwards

Thank you very much to your pertinent and helpful answer. My patient received the first infusion with any problem.

Dear Simon Lytton ,

Your comment is very didactic and pertinent

Thank you

In our experience, Rituximab was effective in treating ASS. I agree with previous comments that there are no prospective trials and that data mostly derive from retrospective studies or case series. Rituximab is most often used in refractory cases. In one of our patients, we used Rituximab as primary treatment based on findings of elevated Bcells in FACS analysis and high levels of IL-6. 

The standard interval for RTX 1g two weeks apart worked in our experience but I agree that this is merely convenience and not evidence based.

I might add that we used RTX as primary treatment in ASS instead of other DMARDS. You can check pubmed for studies on RTX in ASS, also the EULAR textbook is quite actual and a good reference.