54 year old female patient with raynaud syndrome for 3 years has sudden onset of hand and feet inflamatory arthralgia with swelling of the hands and feet, proxymal myalgia, normal muscular testing, high esr and pcr, low ck 19 ( normal values 34-145), low ldh 116( normal values 135-250) low tgo 11 (normal values 13-40), low iron 21 ( normal values 50-170), negativ ana, negative myositis panel, ena shows low positive pm- scl antibody. The chest ct is normal. She has treatment with prednisone 10mg per day and methotrexate 10mg per week . What is the differential diagnosis? What is the cause for the low ck and ldh?
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PM-Scl antibody overlap syndrome myositis scleroderma
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PM-Scl antibody overlap syndrome Raynaud arthritis low CK LDH differential diagnosis
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PM-Scl antibody clinical features arthritis myalgia low creatine kinase
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scleromyositis PM-Scl overlap syndrome clinical manifestations
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inflammatory myopathy normal CK amyopathic seronegative myositis
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PMID: 35220464
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low CK LDH in inflammatory myopathy causes muscle enzyme dilution mechanism
I now have enough information to provide a thorough, well-referenced answer. Let me compile everything.
Differential Diagnosis and Clinical Analysis
This is a clinically rich case. The key features to synthesize are:
- 54-year-old woman
- 3 years of Raynaud phenomenon (secondary, given what follows)
- Acute onset inflammatory polyarthralgia with hand/foot swelling
- Proximal myalgia with normal muscle strength testing
- High ESR and CRP
- Subnormal CK (19), LDH (116), AST/TGO (11), and iron (21)
- Negative ANA, negative myositis panel (standard)
- ENA: low-positive anti-PM-Scl antibody
- Normal chest CT
- On prednisone 10 mg/day + methotrexate 10 mg/week
1. Most Likely Diagnosis: PM/Scl Overlap Syndrome (Scleromyositis)
The anti-PM-Scl antibody is the central diagnostic clue. This antibody targets the PM/Scl complex (a nucleolar exosome component) and defines a distinct overlap syndrome sitting between systemic sclerosis (SSc) and inflammatory myopathy (polymyositis/dermatomyositis) - sometimes called scleromyositis.
From the Firestein & Kelley Textbook of Rheumatology: "Among patients with inflammatory myositis overlap syndromes, those with antibodies to the PM/SCL antigen are more likely to exhibit clinical features of limited or SSc, ILD, and calcinosis" (Firestein & Kelley's, p. 1925).
Key features of PM/Scl overlap syndrome that fit this patient:
- Raynaud phenomenon - typically the first and most common manifestation (>80% of anti-PM-Scl patients)
- Inflammatory arthritis / arthralgia
- Proximal myalgia (myositis may be subclinical or mild, especially early)
- Normal or mildly elevated CK (about 1/3 of DM patients have normal CK; even more so in overlap syndromes)
- Low-positive antibody titers are consistent with early or mild disease
- Negative standard ANA is possible because anti-PM-Scl has a nucleolar pattern that may not be captured by standard HEp-2 cell substrates, or the titer is below the threshold
- Normal chest CT: ILD is a well-known complication but may not be present at this early stage
The 2022 systematic review by Júnior et al. (PMID 35220464) confirmed that in myositis-SSc overlap, anti-PM/Scl is among the antibodies most correlated with this entity, and Raynaud's phenomenon with joint involvement are hallmark features.
2. Differential Diagnosis (Ranked by Clinical Fit)
a) PM/Scl Overlap Syndrome (Scleromyositis) - Most likely
As above. The antibody is the anchor. Subclinical/early myositis with myalgia but preserved strength is a recognized presentation. The "low-positive" titer is consistent with early-stage disease. Notably, anti-PM-Scl-75 (one of the two epitopes) associates more with digital ulcers and muscle atrophy, while anti-PM-Scl-100 associates with higher CK elevations - a low titer anti-PM-Scl-75 pattern fits the profile here.
b) Undifferentiated Connective Tissue Disease (UCTD) evolving into overlap
Per the textbook (Henry's Clinical Diagnosis), UCTD patients have early CTD features without meeting full criteria for a defined disease. In UCTD, "synthetase and PM/Scl antibodies predict differentiation into a myositis overlap syndrome." This patient may be in a transitional phase from UCTD (3 years of Raynaud alone) now developing overlap features. UCTD and early PM/Scl overlap are not mutually exclusive - they represent a continuum.
c) Polymyalgia Rheumatica (PMR) - secondary differential
PMR typically presents in patients >50 years with proximal myalgia, very high ESR/CRP, normal muscle strength, and normal CK. This fits several features here. However:
- PMR does not explain the Raynaud phenomenon (3 years preceding)
- PMR does not explain the anti-PM-Scl positivity
- Hand/foot swelling can occur in atypical PMR but is more typical of the overlap syndromes
- PMR would not have a detectable myositis-associated antibody
PMR remains a co-diagnosis to consider (or a "PMR-like phenotype" within the overlap syndrome), since the myalgia and high inflammatory markers respond to low-dose prednisone (10 mg) - which is the standard PMR dose.
d) Early/Limited Systemic Sclerosis (SSc sine scleroderma)
Anti-PM-Scl can occur in 4-8% of SSc patients. The absence of skin thickening, normal chest CT, and negative Scl-70/anti-centromere make full SSc less likely currently, but early lcSSc is possible.
e) Mixed Connective Tissue Disease (MCTD)
MCTD (Sharp syndrome) combines features of SLE, SSc, and myositis with anti-U1-RNP antibodies. This patient lacks anti-U1-RNP and the ANA is negative, making MCTD less likely - though the clinical phenotype overlaps considerably.
f) RS3PE Syndrome (Remitting Seronegative Symmetric Synovitis with Pitting Edema)
RS3PE presents with sudden onset of symmetrical pitting edema of hands and feet with synovitis, elevated ESR, in older patients. It is typically seronegative and responds dramatically to low-dose prednisone. Some features here fit (hand/foot swelling, elevated ESR, prednisone response), but anti-PM-Scl positivity and Raynaud point away from a pure RS3PE diagnosis. RS3PE can be paraneoplastic - worth excluding.
g) Antisynthetase Syndrome (negative myositis panel notwithstanding)
Antisynthetase syndrome (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, etc.) features: myositis, arthritis, Raynaud, mechanic's hands, ILD. The negative myositis panel argues against this, but panels vary - some centers do not include all synthetases. If the panel did not include anti-OJ, anti-KS, or anti-MDA5, these remain possible. The normal chest CT makes ILD-associated antisynthetase less likely at this stage.
3. Why Are CK, LDH, AST (TGO), and Iron Low?
This is a particularly interesting finding. Low (below-normal) muscle enzymes and hepatic enzymes in a patient with apparent myalgia can have several explanations:
a) Muscle Mass Reduction ("Enzyme Source Depletion")
The most clinically important explanation for persistently low CK and LDH in a myopathy context is reduced muscle mass. As the Myositis Association literature notes: "In advanced disease, serum muscle enzyme levels can be persistently low in the setting of major muscle weakness." If there is subclinical ongoing muscle atrophy or cachexia from the chronic inflammatory state, there is simply less muscle tissue to release CK and LDH - so absolute levels fall below normal even during active inflammation.
b) Circulating Autoantibody-Mediated Inhibition of CK/LDH
As noted in the Open Rheumatology Journal study on laboratory abnormalities in PM/DM: "Patients with DM more frequently have circulating inhibitors or autoantibodies to CK or to other enzymes and these autoantibodies may result in lower serum enzyme levels." This is a recognized phenomenon in inflammatory myopathies, particularly in DM and overlap syndromes, where anti-enzyme antibodies (not the same as myositis-specific antibodies) can bind to and inactivate or accelerate clearance of CK in the circulation - leading to paradoxically low enzyme levels despite active muscle disease.
c) Amyopathic / Hypomyopathic Presentation
In the context of the PM/Scl overlap syndrome, true muscle inflammation may be mild or subclinical. Per the Tietz Textbook of Laboratory Medicine: "A third of DM patients have normal creatine kinase concentrations." In overlap syndromes with anti-PM-Scl, the myositis component is often milder than in classic PM. Normal or subnormal CK simply reflects the absence of significant muscle fiber necrosis at this time point. The myalgia is real but may be driven more by periarticular/fascial inflammation than by myofiber breakdown.
d) Effect of Treatment
This patient is on prednisone 10 mg/day. Corticosteroids reduce inflammation and muscle enzyme release. If treatment was started before the enzymes were first checked, the CK and LDH could have already been suppressed from a previously elevated state. (Note: paradoxically, high-dose steroids over time can also cause steroid myopathy, but this typically produces normal or low CK with proximal weakness - and is a competing explanation.)
e) Low Serum Iron (21, normal 50-170)
Iron deficiency in this context is almost certainly a consequence of chronic inflammatory disease (anemia of chronic disease/inflammation). The cytokines IL-6, TNF-alpha, and others produced in active autoimmune disease upregulate hepcidin, which sequesters iron in macrophages and reduces intestinal absorption. The result is functional iron deficiency. The same inflammatory state that raises ESR and CRP drives the low iron. This is consistent with the overall clinical picture of active systemic inflammation.
f) Low AST/TGO (11, normal 13-40)
AST (TGO) is the liver enzyme most closely tied to muscle metabolism. Its sub-normal level is consistent with the same muscle mass depletion/autoantibody inhibition mechanism as CK and LDH - and also with the possibility that the patient has a low lean body mass or is nutritionally compromised. In some cases, low-normal AST also reflects vitamin B6 (pyridoxine) deficiency, as pyridoxal phosphate is an obligate cofactor for transaminases. Methotrexate can impair folate/B vitamin metabolism and potentially reduce transaminase activity.
4. Summary Table
| Feature | PM/Scl Overlap | PMR | UCTD | Antisynthetase |
|---|---|---|---|---|
| Raynaud | +++ | - | ++ | ++ |
| Arthralgia/arthritis | ++ | + | ++ | +++ |
| Proximal myalgia, normal strength | ++ | +++ | + | + |
| Elevated ESR/CRP | ++ | +++ | + | ++ |
| Low/normal CK | ++ | +++ | ++ | - (usually elevated) |
| Anti-PM-Scl | +++ (defining) | - | - | - |
| ILD (CT normal now) | future risk | - | low | common |
| Prednisone response | ++ | +++ | ++ | ++ |
5. Recommended Next Steps
Given the current working diagnosis of PM/Scl overlap syndrome / early scleromyositis:
- Nailfold capillaroscopy - will likely show SSc-pattern abnormalities (dilated/dropout capillaries) supporting secondary Raynaud
- Muscle MRI (thigh/shoulder) - detect subclinical muscle edema/inflammation (more sensitive than CK)
- Muscle biopsy (if clinically justified) - to confirm inflammatory myopathy even with low CK
- Repeat HRCT chest in 12 months - PM/Scl is an ILD risk factor; serial monitoring is warranted even with a normal baseline
- Anti-PM-Scl confirmation and titer (PM-Scl-75 vs PM-Scl-100 subtype) by a reference laboratory - some standard ENA panels have variable sensitivity
- Iron studies (ferritin, transferrin saturation, hepcidin if available) - to characterize anemia of chronic disease vs. true iron deficiency
- Pulmonary function tests (PFT with DLCO) - DLCO reduction may precede CT changes in ILD
- Consider increasing methotrexate dose (up to 15-25 mg/week) or adding hydroxychloroquine; the current regimen is appropriate but may need optimization as the disease declares itself
Sources: Firestein & Kelley's Textbook of Rheumatology (p. 1925-1926); Tietz Textbook of Laboratory Medicine, 7th Ed. (pp. 3405-3422); Júnior et al., Clin Rheumatol 2022 - PMID 35220464 (systematic review of myositis-SSc overlap); musculoskeletalkey.com on overlap syndromes and treatment-resistant inflammatory myopathy.
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