Glossary of terms.

Fascia is not one membrane but a system of layers. Anatomically it splits into the superficial fascia — looser, fused with the subcutaneous tissue — and the deep fascia, strong and elastic, lying directly against the muscle. It is that second layer where the M35.4 disease process sits.

• Mechanical role — it transmits force between muscles and lets tissue layers glide over one another.
• What happens in M35.4 — inflammatory infiltrate and collagen deposition thicken the fascia; biopsy material is described as thickened 2–10× above normal.
• Consequence visible on the skin — a stiffened fascia removes the skin's natural mobility over the muscle; hence peau d'orange and the groove sign.
• Extent — the infiltrate can spread into neighbouring layers: the subcutaneous tissue and the superficial layer of muscle (perimysium).

Pinal-Fernandez 2014 · Lebeaux & Sène 2012

• Positionbetween the dermis and the superficial fascia
• Compositionadipose tissue, connective septa, vessels
• Role in M35.4a layer often co-involved by the inflammatory infiltrate
• In biopsya mandatory component of a full-thickness sample

The subcutaneous tissue is rarely the first site of the disease process, but it almost always takes part in its spread. The inflammatory infiltrate described in the fascia extends into the connective septa running through the fat — and it is that continuity which explains why a needle or punch biopsy, ending in the dermis, never reaches the decisive information.

Collagen is not in itself pathological — it is the scaffold of every connective tissue. In M35.4 the problem is its quantity and architecture: fibroblasts driven by cytokines produce it faster than the tissue can remodel it.

Pinal-Fernandez 2014 · Lebeaux & Sène 2012

The fibroblast is the executor, not the initiator. In the best-accepted hypothesis today it is the eosinophils — interacting with fascial fibroblasts — that induce the release of pro-fibrotic cytokines:

• TGF-βthe key regulator of fibrosis
• IL-1, IL-5, IL-6pro-inflammatory interleukins
• TGF-α, TIMP-1modulators of extracellular matrix metabolism

The result is overproduction of collagen and other matrix proteins. The fascia thickens 2–5 fold, loses elasticity and mechanically restricts limb mobility.

The factor that activates the eosinophils at the very start of this cascade remains unknown — one of the main open questions in M35.4 pathogenesis.

Fibrosis does not appear suddenly — it is the end of a sequence that can be traced step by step:

1. An unidentified trigger leads to activation and degranulation of eosinophils.
2. Eosinophils, interacting with fascial fibroblasts, induce the release of pro-fibrotic cytokines.
3. Fibroblasts overproduce collagen and other matrix proteins — biopsy shows active fibroblasia.
4. Fibrosis matures into its “glassy” form; the fascia loses elasticity and mechanically blocks movement.

At this stage the inflammatory signs — warmth, redness, pain — gradually subside, but the tissues do not return to normal. It is this gap between “it stopped hurting” and “it stopped working” that accounts for permanent contractures.

• Cell typean acidophilic granulocyte, one of the white-cell lines
• Normal in bloodusually < 0.5 × 10⁹/L
• Typical in M35.4often > 1.0 × 10⁹/L, sometimes far higher
• Present in the active phase60–80% of patients

In M35.4 pathogenesis eosinophils are suspected of an initiating role: their activation and degranulation sets off a cascade of pro-fibrotic cytokines acting on fascial fibroblasts. Importantly, the eosinophil count in blood and their presence in tissue are two different things — biopsy finds them in roughly 50–60% of cases, more often in the early phase.

• Definition — an eosinophil count in peripheral blood above 0.5 × 10⁹/L.
• Diagnostic status — one of the Pinal-Fernandez minor criteria; at least two such criteria alongside the major criterion are required for diagnosis.
• Frequency — 60–80% of patients in the active phase. In the remaining 20–40% the result may be normal or only slightly raised.
• Monitoring value — it correlates only partly with disease activity; steroids lower the eosinophil count faster than the fascial process itself recedes.

The first-eosinophilia trap: this result most often steers the work-up towards allergy and parasitic disease — reasonably so, since those are the commonest causes. When eosinophilia accompanies symmetrical hardening of the limbs, however, a systemic connective-tissue disease tends to be considered from the outset.

ESR measures how fast red blood cells settle in a tube over one hour. The more acute-phase proteins circulate, the faster erythrocytes clump and fall. It is an old, cheap and completely non-specific parameter — its strength is that it rises whenever inflammation is present anywhere in the body.

• Typical values in M35.4 — often markedly elevated, in the 50–100 mm/h range.
• What it does not say — it does not indicate where the inflammation is, or of what kind.
• Dynamics — it reacts more slowly than CRP, both as the process builds and as it settles.
• Practical role — cheap and universally available, so it is often the first signal that symptoms are not merely mechanical overload.

Both parameters say the same sentence — “something is going on” — only at different speeds. They are read together because the gap between them can be informative: CRP returns to normal quickly once inflammation settles, while ESR can stay elevated for weeks longer.

• Character — a polyclonal rise, mainly in the IgG class; this is not the monoclonal spike typical of gammopathies.
• Mechanism — it reflects B-lymphocyte activation in response to chronic inflammation.
• Frequency in M35.4 — present in roughly 50–70% of patients.
• How it is detected — by total protein with a proteinogram (serum protein electrophoresis).
• Criterion status — hypergammaglobulinaemia above 1.5 g/L, especially in the IgG class, appears among the Pinal-Fernandez minor criteria.

The efficacy of rituximab — a drug that depletes B lymphocytes — in refractory M35.4 is sometimes read as indirect confirmation that B-cell activation is not merely a passive echo of inflammation. The details of that mechanism remain unknown.

Aldolase is an enzyme present in muscle, but also in the liver and in erythrocytes — so its elevation alone does not prove muscle involvement. In M35.4 its diagnostic value comes from being read alongside CK: the pattern “aldolase raised, CK normal” is more characteristic of fascial involvement than of a primary myopathy.

• Typea glycolytic enzyme, present in muscle among other tissues
• In M35.4may be elevated when muscles are involved
• Frequencyless often than in classic inflammatory myopathies
• Criterion statusmuscle weakness and/or raised aldolase — a minor criterion

A normal CK can be a misleading signal for a patient — “if the muscle enzymes are normal, it can't be serious”. In M35.4 the opposite holds: it is precisely a normal CK alongside a clear loss of range of motion that turns attention to the fascia rather than the muscle itself.

• What the test detects — antibodies directed against components of the cell nucleus, detected by indirect immunofluorescence.
• Typical result in M35.4 — most often negative or low-positive.
• What a high titre means — it points towards systemic sclerosis or lupus rather than eosinophilic fasciitis.
• Limitation — low ANA titres are also found in healthy people; the result is always interpreted together with the clinical picture.

In this work-up ANA is an opening test, not a decisive one: a positive result triggers the specific antibody panel (anti-Scl-70, anti-centromere), and it is that panel which separates the disease entities.

• Antigentopoisomerase I
• Characteristic ofsystemic sclerosis, diffuse form
• Result in M35.4negative
• Companion testanti-centromere — also negative in M35.4

This is a test with inverted logic: its value in M35.4 lies in a negative result. Together with anti-centromere it forms a scleroderma-excluding pair — and since systemic sclerosis is the most important differential diagnosis, that pair is among the most frequently ordered early in the work-up.

This sign is not a change in the skin itself — it is the shadow cast on the skin by the stiffened layer beneath it. The sequence runs like this:

1. The fascia under the skin thickens and loses elasticity.
2. The skin “sticks” to it and loses its natural mobility over the muscle.
3. At hair-follicle and sweat-pore attachments the skin is anchored more firmly than in between them.
4. A pattern of fine dimples appears, resembling an orange peel, clearest when the skin is gently squeezed between the fingers.

The absence of peau d'orange does not exclude the diagnosis — the sign is classic for the intermediate phase and may be missing both very early and in advanced fibrosis.

Of the whole M35.4 clinical picture the groove sign is the most “mechanical”: the superficial vein does not change itself, it is drawn inwards by the thickened fascia surrounding it. The tissue around the vein hardens while the vein stays soft — and that difference draws the groove on the skin.

• Where it is seen most often — on the forearm and the lower leg.
• How it is brought out — in the described examination the limb is raised above heart level and held for some tens of seconds until the veins empty.
• What is then visible — in healthy tissue the skin surface stays smooth; in M35.4 a distinct linear depression appears along the course of the vein.
• Diagnostic value — together with peau d'orange the sign is considered pathognomonic; the presence of a groove sign or peau d'orange appears among the minor criteria.

• How it differs from stiffness — morning stiffness eases once you get moving; a contracture does not ease at all, because the block is mechanical, not muscular.
• Mechanism in M35.4 — fibrosis of the fascia and subcutaneous tissue shortens the distance over which tissues can stretch.
• Most disabling joints — fixed elbow flexion, restricted forearm supination, contractures at the ankle joints.
• Risk factor — the later treatment begins, the more likely the restriction becomes permanent.

The contracture is the M35.4 complication most strongly bound to time. The disease itself carries a good prognosis — but the window in which tissues retain their capacity to recover closes as the inflammatory phase gives way to the fibrotic one.

Myalgia in M35.4 occurs without clinical muscle weakness — and that is what separates it from inflammatory myopathies. The pain most often involves the thighs, upper arms and back; it is usually accompanied by a fall in exercise tolerance out of proportion to the pain itself.

• Definitionjoint pain without visible inflammation
• Joint on examinationunchanged — no swelling, effusion or redness
• In M35.4present in some patients
• Common confusionmistaken for arthritis and for contracture

In M35.4 joint pain and loss of joint mobility can occur together, but they do not share a cause: the pain is arthralgia, the restriction is a consequence of fibrosis in the surrounding tissues. Separating the two matters practically — because they lead to two different conclusions about what is happening in the tissue.

In this phase the affected areas are swollen, warmer to the touch, reddened and painful — and harder in depth than the swelling alone would suggest. Range of motion slowly begins to narrow.

In roughly 30–50% of patients the onset can be linked in time to a specific event. The distribution of reported triggers:

• No identifiable trigger50–70 %
• Exertion / physical work≈ 20 %
• Mechanical trauma≈ 10 %
• Infection (incl. COVID-19)< 10 %
• Drug or vaccinecase reports

Lebeaux & Sène 2012 · Mango 2020

This is the most treacherous feature of the phase: the disappearance of pain and redness can read as improvement, when in fact it marks the process shifting into a form from which tissues do not spontaneously return to normal.

A full-thickness sample is a wedge of tissue spanning every layer — from the surface down to muscle:

1. Epidermis and dermis.
2. Subcutaneous tissue with its vessels and septa.
3. Superficial fascia.
4. Deep fascia — the key layer, lying against the muscle.
5. Superficial layer of muscle.

In this material the pathologist looks for fascial thickening, an inflammatory infiltrate (lymphocytes, plasma cells, macrophages; eosinophils in roughly 50–60% of biopsies) and thickening of the collagen bundles.

A needle or punch biopsy ends in the dermis while the decisive changes lie deeper — a frequent reason for the first “negative” biopsies in patients who do have the disease. The absence of eosinophils in the sample likewise does not exclude it: after prior steroid exposure they vanish from the tissue quickly.

MRI is the best non-invasive method, but it does not replace biopsy. Sensitivity of the individual investigations in detecting M35.4:

• Full-thickness fascial biopsy≈ 95 %
• Contrast MRI (T2 / STIR + gadolinium)≈ 80–90 %
• Peripheral eosinophilia60–80 %
• Hypergammaglobulinaemia50–70 %
• Musculoskeletal ultrasound≈ 25 %

Beyond diagnosis itself, MRI serves two practical roles: it points to the biopsy site with the most pronounced changes, lowering the risk of a false-negative result, and it allows an objective assessment of treatment response on a follow-up scan after 3–6 months.

Pinal-Fernandez 2014 · Kissin 2015 · Daoussis 2022

STIR is a sequence in which the fat signal is suppressed. Once fat stops shining, what stays bright is whatever holds water — and inflammatory oedema is above all water. That is why this sequence is often the most telling one in M35.4.

• What it reveals — a hyperintense, bright fascia across the inflamed area.
• Why fat saturation — the fascia runs between layers of fat; without suppressing its signal the contrast between them would be weaker.
• What it cannot separate — oedema itself is not specific to M35.4; the image is read together with T1 and the post-gadolinium sequence.
• Value in monitoring — the fading of hyperintensity on a follow-up scan is one of the objective signals of treatment response.

• How it works — the contrast reaches areas of increased blood flow and boosts their signal on T1 images.
• What it shows in M35.4 — actively inflamed fascia; enhancement reflects an ongoing process, not the scar left behind by one.
• Why that matters — it separates the phase in which treatment still has inflammation to quiet from established fibrosis.
• Role in the criteria — a characteristic MRI picture including post-gadolinium enhancement appears among the minor criteria.

Gadolinium agents call for caution in people with advanced renal failure — nephrogenic systemic fibrosis (NSF) has been described in that group, an entity whose clinical picture is itself sometimes confused with M35.4. Assessing renal function before the scan is part of standard radiological practice.

• PublisherWorld Health Organization (WHO)
• Revisiontenth
• BlockM30–M36 — systemic connective tissue disorders
• CodeM35.4
• Entry name“Other systemic involvement of connective tissue”

An ICD-10 code is rarely more to a patient than a string of characters on a discharge letter, but in system terms it does three jobs: it identifies the entity in medical records, it governs eligibility for benefits, and in public statistics it is the only trace by which a rare disease can be counted at all.

The difference is larger than it looks. In ICD-10 eosinophilic fasciitis has no name of its own — it shares a collective entry with other systemic connective tissue diseases. In ICD-11 it receives its own code and its own name, which for a rare disease translates directly into visibility in statistics and registries.

The examination consists of viewing the small vessels of the nailfold under a microscope. It is non-invasive, takes a quarter of an hour and needs no preparation — yet it is among the most decisive tests in separating the scleroderma-like diseases.

• Picture in systemic sclerosis — pathological: dilated, tortuous capillaries with dropout in the vascular pattern.
• Picture in M35.4 — normal.
• Why it works — scleroderma is a vascular disease as much as a connective tissue one; M35.4 remains a fascial process and leaves the digital microcirculation unchanged.
• Practical value — a normal result alongside hardened limbs shifts the reasoning away from scleroderma and towards M35.4.

Glucocorticoids open the sequence of four treatment lines described in the literature. Each line has its own time horizon after which a clinician judges efficacy:

• I. Glucocorticoids (0.5–1 mg/kg)1–4 wks.
• II. Methotrexate3–6 mo.
• III. Biologics3–9 mo.
• IV. Experimental therapiesindividual

The first line doubles as a diagnostic test: a very good response to steroids is among the features separating M35.4 from systemic sclerosis, which responds poorly to them.

Lebeaux & Sène 2012 · Mazori 2017 · Mango 2020

Dosage is determined exclusively by the treating physician individually for each patient, depending on clinical picture, body weight, comorbidities, and other factors. The values cited below come from the scientific literature and do not constitute an indication for self-dosing.

The prednisone schedule described in the literature has three phases:

1. Induction — 0.5–1 mg/kg body weight per day, held for 6–8 weeks until the inflammation settles.
2. Reduction — once parameters and skin tension normalise, the dose is lowered gradually, in reported schemes by 10–20% every 2–4 weeks.
3. Maintenance and withdrawal — a band of 5–10 mg per day before therapy ends entirely; withdrawal in under nine months is described as an exception rather than the rule.

A relapse at any stage turns the dose back upwards. The shape and pace of the whole schedule are strongly individualised — the description above sets out a typical course from the literature, not a plan applicable to any particular patient.

Lebeaux & Sène 2012 · Jinnin 2018

Dosage is determined exclusively by the treating physician individually for each patient, depending on clinical picture, body weight, comorbidities, and other factors. The values cited below come from the scientific literature and do not constitute an indication for self-dosing.

• Mechanismfolic acid antagonist, an immunosuppressant
• Treatment linesecond
• Reported dose15–25 mg weekly, preferably subcutaneously
• Full effectafter 3–6 months

The role of methotrexate in M35.4 is to enable a reduction of the steroid dose and to hold remission. The literature describes the accompanying monitoring:

• Full blood count every 4–6 weeks.
• Liver function tests — AST, ALT, GGT.
• Renal function — creatinine, eGFR.
• Folic acid supplementation, customarily 5 mg once weekly, on a different day from MTX.

Methotrexate dominates second-line practice mainly because of availability and clinicians' familiarity with it, not because of a proven advantage over the alternatives — the question of the “ideal” second-line treatment remains open.

Dosage is determined exclusively by the treating physician individually for each patient, depending on clinical picture, body weight, comorbidities, and other factors. The values cited below come from the scientific literature and do not constitute an indication for self-dosing.

Mycophenolate mofetil inhibits purine synthesis, on which T and B lymphocytes depend more heavily than the body's other cells. Hence its relatively selective immunosuppressive action.

• Position in the sequence — an alternative to methotrexate in the second line; in some accounts it appears only among fourth-line therapies.
• Reported dose — 1.5–3 g per day.
• Assessment horizon — 3–6 months, as with methotrexate.
• When it is considered — when methotrexate is not tolerated or does not hold remission.

What is known about MMF in M35.4 rests on single case reports and small series. No randomised controlled trial has compared it directly with methotrexate in this disease.

Dosage is determined exclusively by the treating physician individually for each patient, depending on clinical picture, body weight, comorbidities, and other factors. The values cited below come from the scientific literature and do not constitute an indication for self-dosing.

• Molecular target — the CD20 antigen on the surface of B lymphocytes; the antibody leads to their depletion.
• Position in the sequence — third line, in cases refractory to steroids and methotrexate.
• Route — intravenous, in cycles.
• Horizon for judging effect — 3–9 months.
• Organisational condition — the decision to start it is described as requiring a reference centre.

The efficacy of rituximab matters beyond therapy itself: if removing B lymphocytes improves the disease picture, then alongside eosinophils they too must play a part in pathogenesis. The details of that mechanism remain unknown and belong to the open research questions.

IL-6 is a pro-fibrotic cytokine strongly involved in M35.4 pathogenesis — hence the interest in a drug that neutralises it. Among the research directions under study, tocilizumab today has the broadest base of reported patients:

• Tocilizumab (anti-IL-6)≈ 30–50 reported
• JAK inhibitors≈ 15–30
• Anti-IL-5≈ 5–15
• Sirolimus / mTORcase reports

“The broadest base” here means a few dozen reported patients. None of these directions has yet entered a prospective trial — the whole field rests on case series, not on controlled comparisons.

case series 2018–2025

IVIG is a product of human origin — a pool of IgG antibodies from thousands of donors. In autoimmune disease it is used not to make up a deficiency but to exploit its modulating effect on the immune system.

• Origina pool of IgG from plasma donors
• Actionimmunomodulating, not substitutive
• Position in the sequencefourth line — experimental therapies
• Routeintravenous

In M35.4, IVIG is described as adjunctive therapy in cases refractory to all earlier lines, alongside mycophenolate, cyclophosphamide and — in extreme situations — autologous stem cell transplantation. Decisions at this level are described as taken only in clinical centres.

Methotrexate works as a folic acid antagonist — and part of its side effects arises from exactly that antagonism. Supplementation is the way to separate the therapeutic effect from that toxicity. The customarily reported dose is 5 mg once a week, given on a different day from MTX.

Dosage is determined exclusively by the treating physician individually for each patient, depending on clinical picture, body weight, comorbidities, and other factors. The values cited below come from the scientific literature and do not constitute an indication for self-dosing.

The term does not describe a chemical class but a function a drug performs within a regimen. The same methotrexate is an immunosuppressant from the mechanistic angle and a steroid-sparing agent from the angle of the role it plays alongside prednisone.

• Aim — to limit the long-term side effects of steroid therapy by lowering the steroid dose.
• Condition — the added drug has to hold disease control at the lower dose; otherwise the reduction ends in relapse.
• Typical representative in M35.4 — methotrexate; mycophenolate mofetil is described in the same role.
• Timing consequence — steroid-sparing drugs act more slowly than steroids, so reduction begins only after their build-up period.

• Compositionpsoralen (a photosensitiser) + UVA light
• Orderoral psoralen, then irradiation
• Role in M35.4adjunctive treatment in refractory forms
• Availabilityused in some centres

PUVA is the exception in this list: it is the only method mentioned that does not act systemically through the blood but locally on the skin and the tissues just beneath it. Psoralen is inactive on its own — only UVA irradiation switches it on, which keeps the effect confined to the irradiated area.

The prognosis in M35.4 is generally good but calls for nuance. Four figures worth holding together — the situation after 2–3 years of treatment:

• Full remission within 2–3 years50–70 %
• Relapse after treatment withdrawal30–70 %
• Partial remission, persisting skin changes20–30 %
• Spontaneous remission without treatmentrare

The strongest predictor of a good response remains a short time from first symptoms to starting corticosteroids. Relapses usually respond well to restarting therapy; the spread in their reported frequency stems from differences in withdrawal schemes between centres.

Lakhanpal 1988 · Wright 2016 · Mango 2020

The checklist a rheumatologist runs through when hesitating between EF and systemic sclerosis:

No single feature settles the question, but four or five concordant rows make the diagnosis close to binary in clinical practice. Historically EF was for years taken to be a variant of scleroderma; it was Shulman's 1974 description that first set it apart as a separate entity.

Lebeaux & Sène 2012 · Mazori 2017 · Onajin 2022

• Extent — scleroderma limited to the skin, without internal organ involvement.
• Depth of the process — histologically it begins in the dermis; M35.4 begins in the fascia.
• Relation to M35.4 — not merely a differential diagnosis: the two entities can coexist in the same patient.
• Pansclerotic form — cited in the literature as particularly hard to distinguish from EF.
• Prognostic significance — the presence of morphea is among the features linked in some series to a risk of M35.4 relapse.

Morphea is the exception in this category: the other entries are diseases that must be told apart from M35.4. This one must be told apart and simultaneously allowed for as a companion.

In M35.4 diagnostics Raynaud's phenomenon matters through its absence. It is one of those history items where the answer “no” carries more information than the answer “yes”.

• Mechanismepisodic spasm of small finger arteries
• Triggercold or stress
• Appearanceblanching, then bluish discolouration of the digits
• In systemic sclerosispresent in about 90% of patients
• In M35.4absent

Together with acrosclerosis, a normal capillaroscopy and the lack of organ involvement, it forms the set of four “absences” on which the clinical separation of M35.4 from scleroderma rests.

Sparing of the digits is regular enough in M35.4 to have become part of the distribution of changes across the body — and that distribution is itself the most useful differentiating pattern at the bedside:

• Forearms and lower legs (bilateral)≈ 90 %
• Upper arms and thighs≈ 60–70 %
• Trunk≈ 20–30 %
• Neck, face< 10 %
• Digits, hands, feetspared

Why the autoimmune process “does not reach” the digits remains unexplained. The fascia of the hands and feet has a different architecture and blood supply, but the mechanism of this sparing belongs to the open questions of pathogenesis.

Lakhanpal 1988 · Bischoff & Derk 2008 · Mango 2020

GVHD is not an autoimmune disease in the classic sense: it is the transplanted immune cells of the donor recognising the recipient's tissues as foreign. The chronic form of that reaction can produce skin and fascial changes close to those of M35.4.

• Context — a complication after allogeneic haematopoietic cell transplantation.
• Frequency as an M35.4 mimic — very rare; described as sporadic.
• What settles it — the clinical context: a past transplant is information nothing else in the picture can replace.
• The reverse direction — transplantation is also listed among possible triggers of M35.4 itself, precisely as a manifestation of chronic GVHD.

NSF holds a peculiar place in this work-up: it is at once a differential diagnosis for M35.4 and a possible complication of the very investigation — contrast MRI — that belongs to the M35.4 diagnostic standard. This is why assessing renal function before contrast is part of routine radiological practice.

EMS belongs to the group of scleroderma-like diseases whose history has a start date and an end date. That is exceptional — most entities in this category have no epidemiological “founding event”.

1. 1974 Shulman describes eosinophilic fasciitis as a distinct syndrome.
2. 1981 Spain: the toxic oil syndrome epidemic — the first modern precedent of a mass scleroderma-like illness.
3. 1989 USA: the EMS epidemic linked to contaminated L-tryptophan supplements.
4. Today sporadic cases; the entity remains in the M35.4 differential.

The mimicry of M35.4 in EMS rests on two elements at once: eosinophilia and muscle pain. That is exactly why the pairing “eosinophilia + myalgia” does not on its own establish M35.4 and needs the clinical picture and biopsy alongside it.

• PlaceSpain
• Year1981
• Causeconsumption of contaminated cooking oil
• Clinical pictureclose to M35.4
• Status todayhistorical

TOS is kept in this glossary for cognitive rather than practical reasons. Nobody today separates M35.4 from toxic oil syndrome at the bedside. The entity does show something that matters for understanding the whole category, though: a scleroderma-like picture with eosinophilia can arise from a purely external agent, without any primary autoimmune predisposition.

• Nature of the disease — suppression of the production of all blood-cell lines in the marrow.
• Relation to M35.4 — not a differential diagnosis in the ordinary sense, but a described, rare coexistence.
• Prognostic weight — the individual deaths reported in connection with M35.4 involved complications of coexisting haematological states, mainly aplastic anaemia.
• Practical consequence — patients with M35.4 are advised to have blood counts monitored in long-term follow-up.

Mortality attributable directly to M35.4 itself is low. This glossary entry exists precisely because the most serious events described in this disease did not arise from the disease itself, but from what can accompany it.