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

The useful Sodium Thiosulfate

 

Sodium thiosulfate is not the first drug you think of when asked to reel off a series of medications. Yet, it is a versatile, underappreciated agent that can on occasions be lifesaving.

One of its foremost roles is in cyanide poisoning. When you think of cyanide, you invariably conjure up images of the Agatha Christie type pill in the cup of tea type scenario. Yet, that sort of cyanide, usually KCN, is rarely available, and most cases of cyanide poisoning occur to due to smoke inhalation in people caught in fires, from hydrogen cyanide. Here, the three most useful agents are sodium thiosulfate, sodium nitrite and good, old-fashioned vitamin B12- hydroxocobalamin.

You may have heard of cisplatin induced hearing loss? This is particularly problem in paediatric oncology, where IV cisplatin is given to treat a hepatoblastoma, for example. Yet, by limiting cisplatin infusion time to 6 hours, and giving IV sodium thiosulfate within 6 hours of cisplatin, you can reduce the incidence of cisplatin induced hearing loss in these children.

Sodium thiosulfate is particularly useful where vascular calcification leads to troublesome complications such as skin ulcerations in fatty areas in patients with advanced CKD, known as calciphylaxis, or where a rare autosomal recessive disorder called ACDC exists.

ACDC is admittedly rare. It is an inherited, autosomal recessive disorder where relatively young subjects in their 40s and 50s present with severe limb claudication, ischaemic ulcers, critical limb claudication & joint pains in hands and feet. The hallmark is calcification of arteries such as iliac, femoral and tibial arteries, but sparing the aorta, which is very unlike atherosclerosis, which ACDC is often confused with.

ACDC stands for “arterial calcification with deletion of CD73”. You may remember that CD73 converts cyclic AMP to adenosine. Apparently, this leads to higher levels of tissue non-specific alkaline phosphatase downstream, and ectopic calcification. Apart from arterial calcification, you also get periarticular calcification, which can be a clue.

Again, IV sodium thiosulfate in such subjects can be limb sparing.

Preventing Gentamicin Induced Permanent Deafness in Newborn Children

 You ever heard of a child going deaf after a single dose of Gentamicin? It's more common than you think and it happens regrettably too late to do anything about it, as a single dose of gentamicin can cause permanent deafness in these children.

It happens in 1250 newborns every year in the United Kingdom.

These unfortunate children are 0.2 of the population, who carry a specific mitochondrial DNA mutation.

Remember, mitochondria have a circular DNA comprised of 16,569 base pairs (as opposed to the linear nuclear DNA, which is comprised of 3.3 billion base pairs). The mitochondrial DNA contains 37 genes, which code for 13 proteins, 22 tRNAs, and 2 ribosomal RNAs.

One of those two rRNAs is coded by a mitichondrial gene called MT-RNR1. If a child has a single nucleotide polymorphism, m.1555A>G (which means at the 1555th mitochondrial base pair, adenine has been replaced by guanine), he or she is exquisitely sensitive to the ototoxic effects of Gentamicin, and can develop permanent and catastrophic deafness after a single dose of gentamicin.

This is clearly a problem, as the UK, like many other countries, has guidelines which recommend that the empirical treatment of neonatal sepsis should be with a combination of gentamicin and benzylpenicillin. Moreover, NICE guidance also stipulate that any suspected sepsis must be treated within 1 hour of diagnosis, given its usually severe consequences.

But how do you test for a mitochondrial mutation within 1 hour? Standard genetic tests take hopelessly long.

Well, it seems that the pandemic has tought us a trick or two. At the Manchester Centre for Genomic Medicine, they have developed a point of care test (POCT) using the same technique used for COVID19- PCR amplification- that gives a result within 26 minutes of taking a gum swab from a newborn.

Those testing positive on the POCT are then confirmed with standard (old fashioned) Sanger sequencing and receive Cefotaxime rather than the combination of gentamicin and benzylpenicillin. No deafness!

And how does gentamicin cause deafness in this children? Well, gentamicin kills bacteria by binding to their 16S rRNA and preventing bacterial protein synthesis. In children who have the m1555A>G mutation in their MT-RNR1 mitochondrial gene, the normally eucaryotic 12S rRNA assumes a shape like the bacterial 16S rRNA, and thus binds to gentamicin.

The test has been provisionally approved by NICE, and is currently being piloted prior to a national rollout.

Reference:

AMA Pediatr. 2022;176(5):486-492. doi:10.1001/jamapediatrics.2022.0187

The Man With Recurrent Leg Swelling

 Saw an interesting case last week.

Thirty-two year old Caucasian man, works loading-unloading shlelves in a supermarket. Over several months, has had recurrent episodes of swelling in his right lower foot, extending from shin, across the ankle into the dorsum of foot. During the episodes, which last several hours, the leg feels very swollen, tight and uncomfortable but not much actual pain.

As usual GP thought of gout, checked urate levels- plumb normal. Does a MRI of the ankle after a normal X-ray. That just shows subcut fluid, joint looks fine. Inflammatory markers normal.

Chap comes to Rheumatology clinic. I get a bit more history. Turns out that the episodes always happen after lunch when he goes back to his rather manual role at the supermarket. He usually has various types of sandwich for lunch.

Has he ever had anything else that seemed unusual? Turns out that in the past, on several occasions, when he had a can of Fosters (a type of lager), his throat felt swollen "inside", so that he would struggle to swallow for hours afterwards, although there was no shortness of breath. He now avoids lager.

The penny drops. The guy has a fascinating condition called "Food Dependent, Exercise Induced Anaphylaxis" (FDEIA). Most published cases in the literature have been in conjunction with wheat consumption, followed shortly afterwards by exercise. Except that now we realise that it's not just exercise, but alcohol and NSAIDs that can trigger this after subjects have fed.

Although in most cases, the putative food contains wheat, other allergens that can trigger it are celery, mustard, fenugreek and coriander. Celery and mustard are of course widely added to spice up pizzas and other takeaways and therefore may be hidden.

You might have guessed that the episodes of "swelling" inside the throat and the leg, both represent angioedema, the first mucosal, the second cutaneous.

This is now called augmentation factor anaphylaxis or cofactor associated food allergy. Avoidance works best, but of course, sometimes the specific food trigger can be hidden, and therefore difficult to identify.

Interestingly celery interacts with birch pollen and a couple of other pollen to give rise to what is described as "Pollen Food Allergy". These people with apparent hay fever, get anaphylaxis type episodes every time they ingest celery.

Such people sgould avoid food that contain a very high concentration of fruit pulp such as smoothies, as the latter is apparently rich in something called Lipid Transfer Protein (LTP), which is very allergenic.

They should also consider carrying an EpiPen, just in case...

Mycoplasma hominis & Ureaplasma urealyticum Cause Septic Arthritis in Subjects with Hypogammaglobulinemia

 If you have a subject with hypogamma, either due to CVID or other "constitutional" causes, such XLA, or acquired, due to immunosuppression, usually with Rituximab, who present with a picture of inflammatory arthritis, either monoarthritis or oligoarthritis, suspect infection by either Mycoplasma hominis or Ureaplasma urealyticum, particularly if usual cultures are negative and the usual antibiotics do not work.

Both organisms are overrepresented in subjects with septic arthritis developing against a background of hypogamma, particularly on Rituximab. The most commonly affected joints are hip, knee, shoulder, elbow, ankle and PIP. Prosthetic joint infections, particularly affecting the hip have been reported several times.

These fastidious organisms will not grow on routine cultures. M.hominis may show up on anaerobic culture plates after 5 days, but is best cultured on PPLO (pleuropneumonia like organism) broth or looked for by 16S RNA. Similarly, U.urealyticum is best cultured on Ureaplasma differential agar, Ureaplasma broth, or A7B agar. Fortunately, the last 3 will also grow M.hominis. U.urealyticum can also be identified on 16S RNA analysis.

If a person with hypogamma and putative inflammatory arthritis has proven culture negative on synovial fluid and blood culture, do ask for these special media or 16S RNA to isolate these 2 organisms. 

Ureaplasma requires urea in its culture medium for growth. It produces urease with breaks down urea into ammonia, and can thus change the colour of phenol red to pink. M.hominis metabolises arginine, but not glucose. Ureaplasma ferments neither, but produces a "managanese reaction" in culture.

If the usual antibiotics have not worked, there would be a natural tendency to attribute the inflamed joint(s) to the underlying disorder such as RA or Lupus, or make a new diagnosis of one of the above two, and treat with steroids. This may lead to a worsening of such arthritis, so special caution is warranted in subjects with hypogamma.

A course of doxycycline may be indicated if the usual antibiotics which target cell walls (which these organisms lack) have not worked. Resolution of fever/arthritis with doxycycline supports the likelihood of infection by one of the above two.

Beware Adult Onset CGD in Subjects with Pulmonary or Extrapulmonary Granulomas but Negative AFB & Tuberculous Culture

 Chronic Granulomatous Disease (CGD) is rare and affects 1 in 200,000 live births. While 75% have the X-linked form (and thus presenting in boys) due to a protein subunit of NADPH oxidase called gp91phox, the rest have an autosomal recessive form due to other protein subunits of the same enzyme, namely p22phox, p47phox, and p67 phox. Of these, p47phox is the second commonest and can present during adulthood occasionally. The involved gene is that of NCF-1 (Neutrophil Cytosolic Factor-1). The average age for presentation of the X-linked form is 3 years, and for the autosomal recessive forms, 8 years.

When CGD presents in adulthood, it is often confused with tuberculosis due to a pulmonary involvement (the most commonly affected organ in CGD), and presence of granulomas on biopsy. These granulomas are however, non-necrotising, and obviously without detectable AFB and yield negative cultures for M.tuberculosis. They are therefore sometimes diagnosed as pulmonary sarcoidosis, given the geographical setting and demographics.

Sputum or bronchoscopic washings growing the following 6 genus in a subject with pulmonary granuloma should lead to a suspicion of CGD- Aspergillus, Candida, Staphylococcus, Serratia, Burkholderia or Nocardia.

These patients often have hyperglobulinemia, with raised Ig levels, but this is not invariable. 

CGD can affect other areas, and thus cause abscesses or cellulitis in the skin, gingivitis (but not periodontitis, unlike leucocyte adhesion defects) Crohn's like granulomas in the intestines, and spinal abscesses. Granulomas can cause obstructive lesions in the urogenital & GI tracts. Delayed wound healing is often a notable feature.

Unlike LAD, which can also rarely present in adulthood, the neutrophil count tends to be normal between infectious episodes. Just for context, there are two forms of LAD, including LAD-1, caused by a defect of CD18, which is a part of the heterodimeric beta-integrins, and LAD-2, caused by a defect in fucosylation, and thus an absence of Sialyl Lewis-X , the latter being necessary for neutrophils to roll on endothelial cells prior to adhesion and diapedesis. Subjects with LAD tend to have severe periodontitis and perpetually high neutrophil counts. LAD-2 is associated with developmental abnormalities such as stunted growth.

The most convenient diagnostic test for CGD is flow cytometry with Dihydrorhodamine 123. Absence of fluorescent staining indicates abrogation of oxidative burst in neutrophils, which is characteristic of CGD. An alternative test is the Nitroblue tetrazolium test (NBT).

The only curative treatment is allogeneic BMT. Symptoms can be improved by treatment with gamma-interferon, and prophylactic administration of co-trimoxazole and itraconazole. Infective episodes should be treated with specific antibiotics.

Why Extensive Training May Not Help You Run Faster

Practice makes perfect. Right? Not always, it would seem.

I have often wondered why, despite running daily, I have not been able to improve my times. I would be classed as middle to long distance runner, averaging 6 miles daily during weekdays and 9.5 miles on weekends. In the spring of 2020, I thought I had hit a sweet spot, consistently running the longer weekend distance at between 73 and 75 minutes. At 54.5 years of age, that was a reasonable time.

But things went backwards in the autumn of that year, and this year I have struggled to get below 90 minutes for the 9.5 mile run.  In fact most runs have been in the mid to high 90s, with a few taking longer than 100 minutes.

Is this muscle fatigue, perhaps an inevitable consequence of the exercise addict's need to run daily? Or is it due to glycogen depletion?

The answer, it would seem lies elsewhere.

There are two broad categories of muscle fibres, the red, myoglobin rich, largely aerobic, mitochondria laden "slow" Type I fibre, and the larger, predominantly anaerobic, white, glycogen loaded "fast" Type II fibre, that predominantly use glycogen to generate its ATP. 

Type II fibres are further subdivided into Type IIA & Type IIB.

It seems that the determinant of the type of muscle fibre is the myosin heavy chain (MHC, not to be confused with Major Histcompatibility Complex) isotype. Thus Type I fibres are rich in MHC 1, type IIA in MHC 2A, and Type IIB in MHC 2X, also called MHC 2D.

You may well wonder what happened to MHC 2B and 2C? Well, MHC 2B is found in some ultrafast Type II fibres, mainly in cranial muscles, and MHC 2C is found in regenerating muscle fibres.

Biochemically, type I and type II fibres are distinguished by their ATPase staining and the speed of the sarcoplasmic reticulum (SR) in releasing calcium. Thus, Type I fibres stain for ATPase at low pH, while Type II fibres do so at an alkaline pH. Similarly Type II fibres possess SR that release Ca very quickly, while with Type I fibres, the release of Ca from SR is slower.

The distinction between Type IIA and Type IIB fibres is more than that of semantics. Type IIA has characteristics that are intermediate between Type I and Type IIB. Thus, they are versatile in being able to function as slow muscle fibres that serve sustained activity such as gaze, while, when called upon, they can also serve up the explosive speed of contraction, sustainable only for short periods, that epitomises Type IIB fibres. 

Muscle fibres can be "pure" and contain just MHC1 or 2A or 2X, but they can also be hybrid- ie. contain MHC1 & 2A, or 2A&2X, or all three, ie. MHC1, 2A &2X. 

Using immunohistochemical staining, long distance elite runners have a higher proportion of  MHC1 fibres than non-runners, roughly equivalent amounts of MHC2A, and almost no MHC2X fibres. Similarly, non-runners tend to have more hybrid MHC fibres in general than runners, which suggests that hybrid fibres can change their composition depending on the workload imposed on them.

Type I fibres are high maintenance. They tend to be smaller, have larger blood supply and higher oxygen consumption. Type II fibres are larger, but consume low oxygen, and at least the IIB fibres are relatively less used, "standing by" for the relatively less frequent occasions when explosive power is required.

A muscle fibre owes its "type" or allegiance to the alpha motor neuron that innervates it. Thus a motor unit (comprised of all the muscle fibres innervated by a particular motor neurone) will always innervate the same type of muscle fibres. Thus a motor unit can be classified as Fast twitch (F) or Slow twitch (S). The F units are further classified as Fatigue resistant (FR) or Fast fatiguing (FF). When there is denervation and cross re-enervation, the muscle fibres take on the characteristics of the "new" motor neurone. Thus S units can turn into FR or FF on cross-reinnervation and so on.

It follows from the above that with training, entire motor units change their character (as individual muscle fibres are unable to do so, being dictated by the motor unit they are part of). Thus, with prolonged training, FF units can change into FR and FR into S. Change in the other direction happens with deconditioning.

And herein, I believe lies my predicament. I believe that my FF units have slowly transitioned into FR and FR units into S units. Glycogen depletion would not be germane to this, as it would only affect the FF motor units, which are comprised principally of Type IIB muscle fibres. While the S units and FR units are fatigue resistant and ideal for long distance running, the muscle fibres they innervate are smaller, and lack the speed of FF units.