Mixed connective tissue diseaseM35.10

Relatively benign, systemic, multi-organ, autoimmune disease with overlapping symptoms of systemic scleroderma, dermatomyositis, and systemic lupus erythematosus, and evidence of antibodies to extractable nuclear antigens (U1nRNP= nuclear ribonucleic proteins). Depending on the author, different diagnostic criteria are described.

Occurs mainly in women, first symptoms mainly between 20-40 years. The disease is also described in children.

Integument: Onset with indurated swellings of the fingers (puffy fingers), dorsum of the hands and feet (88%).

• There is edema and acrosclerosis, Raynaud's phenomenon (84%), frequent esophageal involvement as in systemic scleroderma. Very characteristic are the severe Raynaud's attacks partly with finger necrosis. In addition, there are features of systemic lupus erythematosus.

General internal symptoms: fatigue, fever, arthralgias, myositis, polyserositis, hepatosplenomegaly, lymphadenopathy, pulmonary changes (fibrosis, pulmonary hypertension = life-limiting factor!). Arthralgias or arthritis (96%). Motility disorders of the esophagus (72%). Myositis (72%). Fever episodes & lymphadenopathy. Rarely involvement of kidneys, heart and CNS.

In the presence of the serological criterion (positive U1nRNP-AK ) and 3 of the following 5 clinical criteria (puffy finger, synovitis, confirmed myositis, Raynaud's sndrome, sclerodactyly with or without other scleroderma signs) the diagnosis can be made with a specificity of 83%.

Serum: Mostly high titre antinuclear factors, mottled pattern, (> 1:160).

In 100% of cases also positive detection of U1-RNP antibody, ENA.

Missing detection of autoantibodies against ds-DNA, Smith, Scl-70, PM-Scl, Ro, La and other nuclear antigens. Increase in gamma globulins, positive rheumatoid factors in 60% of cases. General signs of inflammation, leukopenia, neutropenia, anaemia, thrombocytopenia.

Notice! U1-RNP antibodies are not restricted to MCTD but are also observed in SLE and PSS.

Diagnostic criteria:

1. anti-ENA antibodies of specificity U1.nRNP (U1 small nuclear ribonucleoprotein autoantigen) titre: >1:1600

2. characteristic clinical manifestation of at least 2 systemic diseases:

• Lupus erythematosus systemic
• Systemic Scleroderma
• Myositis
• Rheumatoid Arthritis

3. at least 3 of the following main symptoms

• Raynaud phenomenon
• Scleroderma
• swollen hands (puffy hands)
• Proximal muscle weakness (typical symptoms of myositis)
• Synovitis

Diagnosis: All 3 criteria must be met for diagnosis.

There are no systematic reports on the treatment of mixed connective tissue disease. In particular, placebo-controlled studies are lacking.

The method of choice is monotherapeutic (!) immunosuppressive therapy with systemic glucocorticoids, initially in medium dosage, e.g. 1 mg/kg bw prednisolone equivalent p.o. 1 time/day, rapid dose reduction to 7.5 mg prednislolone equivalent/day.

If this therapy fails to lower steroidal medication below Cushing's threshold, combination with azathioprine (e.g., Imurek) 100 mg/day or ciclosporin A (e.g., Sandimmun) initially 5 mg/kg bw/day, later reduction.

Therapy trial with photopheresis is possible.

Some positive experience reports are available on the use of mycophenolate mofetil. Otherwise therapy according to the symptoms in the foreground. See below Lupus erythematosus, systemic and scleroderma.

Clinical follow-up of patients primarily described by Sharp revealed transformation of the clinical picture to progressive systemic scleroderma in nearly all patients.

Other investigators have demonstrated that approximately 10 years after the initial diagnosis of Sharp's syndrome, >40% of patients no longer met the original diagnostic criteria. Diagnoses were: systemic scleroderma, lupus erythematosus or undfíffered collagenosis (see also Alves MR et al. 2020).

The entity of the disease is often disputed. Neither the clinical symptoms nor the detection of U1nRNP-AK are specific for MCTD.

1. Alarcon-Segovia D et al (1989) Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 16: 328-334.
2. Alves MR et al (2020) "Mixed connective tissue disease": a condition in search of an identity. Clin Exp Med 20:159-166.
3. Bodolay E et al (2003) Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol 21: 313-320.
4. Crowson AN et al (2003) Cutaneous vasculitis: a review. J Cutan Pathol 30: 161-173.
5. Haustein U-F (2005) MCTD-mixed connetive tissue disease. JDDG 3: 97-104
6. Maddison PJ (1991) Overlap syndromes and mixed connective tissue disease. Current Opinion in Rheumatology 3: 995-1000.
7. Maverakis E et al (2014) International consensus criteria for the diagnosis of Raynaud's phenomenon. J Autoimmun 48-49:60-5
8. Meurer M et al (1989) The spectrum of antinuclear and anticytoplasmic antibodies in dermatomyositis and polymyositis overlap syndromes. Dermatologist 40: 623-629
9. Michels H (1997) Course of mixed connective tissue disease in children. Ann Med 29: 359-364
10. Mosca M et al (2014) The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun 48-49:50-2
11. Nimelstein SH et al (1980) Mixed connective tissue disease a subsequent evaluation of the original 25 patients. Medicine (Baltimore) 59: 239
12. Pope JE (2002) Scleroderma overlap syndromes. Curr Opin Rheumatol 14: 704-710.
13. Sharp GC et al (1972) Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a speciic antibody to an extractable nuclear antigen (ENA). Am J Med 52: 148-159
14. Sharp GC, Irvin W, Holman H, Tant E (1969) A distinct rheumatic disease syndrome associated to a particular nucleoantigen. Clin Res 17: 359