Introduction

The idiopathic inflammatory myopathies (IIMs), which are collectively also known as myositis, are characterised clinically by muscle weakness, decreased muscle endurance and muscle inflammation. On the basis of different clinical and histopathologic features, three main subsets of myositis have been defined: polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). Considering the aetiology, IIMs are multifactorial disorders. The pathomechanism is not clearly known. In myositis research, the first step forward was the development a system of generally accepted criteria by Bohan and Peter. This system is currently used for diagnosis ( Table 1 ). Furthermore, the group of clinical disease IIMs can be divided into subgroups ( Table 2 ). This clinical classification still creates very heterogeneous groups, although it has some predictive value of prognostic and therapeutic points of view .

We consider ‘definite DM’ the presence of three of diagnostic criteria (DC) 1, 2, 3 and 4 + skin rashes; ‘probable DM’ when the patient has two of DCs 1, 2, 3, 4 + skin rashes; and ‘possible DM’ one of DCs + skin rashes. ‘Definitive PM’ means four of DCs 1, 2, 3, 4; ‘probable PM’ if three of DCs 1, 2, 3, 4; and ‘potential PM’ if two of DCs 1, 2, 3, 4 are present .

The sensitivity and specificity of this system seem controversial in the light of the latest information in myositis research. A combined sensitivity for definite and probable PM and DM was determined to range from 74% to 100% in several studies including more than 800 patients. Besides the specificity and sensitivity, the imprecise definition of individual conditions is the main problem. What does elevated creatine kinase (CK) levels mean? We have no strict judgement about it. Another limitation of Bohan and Peter’s regime is that they did not recognise IBM as a subtype of myositis. A new classification for PM, DM and IBM based on histopathological, immunohistopathological and clinical findings had been suggested. New criteria were tried to be added to this system for facilitating the diagnosis and forming heterogeneous subgroups. Several study groups are working on the establishment of new diagnostic criteria. Spontaneous muscle pain or pain on grasping, arthritis, arthralgia and systemic inflammatory signs as elevated C-reactive protein (CRP) levels and fastened erythrocyte sedimentation rate (ESR) seemed to be among the new diagnostic conditions. However, these parameters are not disease specific. Possibly the autoantibodies will be the key for a new criteria system. Love at al. proposed a new approach to the classification preceding the presence of myositis-specific autoantibodies (MSAs). However, it is difficult to say how long will this quest be .

The classic juvenile DM (JDM) is characterised by classical skin symptoms but the calcification is most frequent in children than in adults. The association with other connective tissue diseases is in fact common, but the malignancy rate in JDM is fortunately very low.

In overlap myositis, the most common ‘second autoimmune diseases’ are systemic sclerosis (SS) and mixed connective tissue disease (MCTD). Rarely, myositis can be associated with systemic lupus erythematosus (SLE), Sjögren’s syndrome and rheumatoid arthritis (RA) as well .

Clinical symptoms

The PM/DM/IBM are rare diseases with an incidence of 0.1–1/100 000/year and a prevalence of 1–6/100 000/year. The male:female ratio is 1:2. DM can occur in children and in adults as well. However, PM is mainly the disease of adults. IBM presents decisively in the sixth or seventh decade, mostly in males. PM and DM are chronic disorders for which the exact time of onset can be difficult to determine.

PM/DM are characterised by progressive weakness of proximal limb muscles, causing difficulties with everyday tasks such as stair climbing, combing and shaving. All the striated muscles are affected, resulting in difficulty in chewing, swallowing, and breathing. In IBM not only proximal but also distal muscle weakness occur. General symptoms include fatigue, malaise and weight loss. Besides the weakness, pain and atrophy can be observed in muscle. Although slow onset of muscle fatigue is the most commonly presenting symptom, the skin or lungs might also be initially affected. During disease progression, symptoms can appear in different organs at different times. Arthralgia and arthritis indicated the involvement of joints. Rarely, signs of myocardial involvement such as myocarditis or arrhythmias are present as well. The multi-organ involvement generally leads to severe complications and poor prognosis.

The skin symptoms of DM are classified into three types, pathognomic (disease specific), characteristic (can occur in other diseases such as SLE and contact dermatitis) and less frequently occurring symptoms. The skin lesions often accompanied by intense itching and photosensitivity are very unpleasant.

Clinical symptoms

The PM/DM/IBM are rare diseases with an incidence of 0.1–1/100 000/year and a prevalence of 1–6/100 000/year. The male:female ratio is 1:2. DM can occur in children and in adults as well. However, PM is mainly the disease of adults. IBM presents decisively in the sixth or seventh decade, mostly in males. PM and DM are chronic disorders for which the exact time of onset can be difficult to determine.

PM/DM are characterised by progressive weakness of proximal limb muscles, causing difficulties with everyday tasks such as stair climbing, combing and shaving. All the striated muscles are affected, resulting in difficulty in chewing, swallowing, and breathing. In IBM not only proximal but also distal muscle weakness occur. General symptoms include fatigue, malaise and weight loss. Besides the weakness, pain and atrophy can be observed in muscle. Although slow onset of muscle fatigue is the most commonly presenting symptom, the skin or lungs might also be initially affected. During disease progression, symptoms can appear in different organs at different times. Arthralgia and arthritis indicated the involvement of joints. Rarely, signs of myocardial involvement such as myocarditis or arrhythmias are present as well. The multi-organ involvement generally leads to severe complications and poor prognosis.

The skin symptoms of DM are classified into three types, pathognomic (disease specific), characteristic (can occur in other diseases such as SLE and contact dermatitis) and less frequently occurring symptoms. The skin lesions often accompanied by intense itching and photosensitivity are very unpleasant.

Environmental factors

The exploration of the IIM’s aetiology today constitutes the main topic of research. Based on recent years’ results we can conclude that environmental factors play a role in the development of this multifactorial disease. Besides the significance of inherited genetic conditions, the role of environmental impacts has more and more evidence. Particularly the aetiological role of infections was mentioned in several studies . Sometimes the presence or former existence of virus is detectable in patients with IIM. The most common virus is Coxsackie B, human T-lymphotropic virus type I (HTLV-1), influenza virus, Echovirus, adenovirus, Toxoplasma , Borellia , hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The light, especially ultraviolet-B (UV-B) wavelengths, can provoke the onset of the disease. Specific processes are still unknown. The UV light increases the synthesis of tumour necrosis factor (TNF) in the skin; this cytokine plays an important role in the pathomechanism . Smoking, whether active or passive, also provokes changes in immunological processes . Drugs such as cloroquine, lovastatine, cimetidine, ethanol, rifampicin, sulphonamide, levodopa and cytotoxic agents can also cause IIM. It is assumed that some of them moderate the immunological mechanisms, while others will help through the changes in metabolic pathways. After stopping the medication, usually myositis disappears .

Pathomechanism

PM, DM and IBM, although immunopathologically distinct, share three dominant histological features: inflammation, fibrosis and loss of muscle fibres. The role of immune system in the pathomechanism of PM and DM like in other autoimmune diseases is confirmed by the presence of cellular and humoral abnormalities and the enhanced autoantibody levels. Progress in molecular immunology and immunogenetics has enhanced our understanding of these cellular processes. Based on the T-cell receptor (TCR) gene rearrangement, the auto-invasive CD8+ T-cells in PM and IBM, but not DM, are specifically selected and clonally expanded in situ by heretofore unknown muscle-specific autoantigens. In endomysial inflammatory infiltrate in PM, the two main cells are macrophages and Tc cells. Macrophages produce pro-inflammatory cytokines (interleukin-1 (IL-1) and TNF-α). The initial step in the development of an abnormal immune response is the activation of Tc cells . At the surface of affected muscle fibres opposite to healthy muscles, the up-regulation of MHC-I and MHC-II expression had been noticed. Besides the TCR–MHC-I connection, the co-operation between the co-stimulatory molecules of immunological synapse is necessary for T-cell activation. On the cell membrane of muscle fibres appears the BB1 molecule (CD80), which is a member of the B7 family. CD28 and CTLA-4 expressed by the Tc cells can be related to this molecule. The co-stimulatory CD40 molecule also appears on the muscle fibres, while its ligand CD40L can be detected on the infiltrating T-cells. The CD40–CD40L interaction stimulates antigen presentation on muscle fibres by inducing the expression of BB1; on the other hand, by helping the IL-6, -8, -15 and chemokines (monocyte chemotactic protein-1 (MCP-1) and regulated upon activation normal T-cell expressed and presumably secreted (RANTES)) production of muscle fibres stimulates the Tc cell adhesion, activation and differentiation. The chemokines participate in the recruitment of additional inflammatory cells, the attraction and activation of Tc cells. In PM, the helper T1 (Th1) and helper T2 (Th2) balance change in favour of the Th1 population .

In DM, the immune processes are directing against the endothelium of intramuscular micro-vessels. Perivascular infiltrates of Th cells, B lymphocytes, macrophages and neutrophils are observed. The peripheral blood Th1–Th2 balance decides for the Th2 cells. The chemokines in DM not only are involved in recruitment of inflammatory cells but, in later stages of the disease, also promote the development of fibrosis . In DM, the CD4+ Th cell-mediated cytokine response and B-cell-induced humoral mechanisms play the main role. Elevated immunoglobulin levels, immunoglobulin G (IgG) and immunoglobulin M (IgM), and complement depositions appeared in the walls of capillaries. The C5b-9 MAC complex is deposited onto the walls of capillaries in muscle and skin. The cell wall lytic effect of MAC explains capillary destruction, muscle ischaemia caused by chronic hypoperfusion and leads to perifascicular atrophy. Lundberg’s latest research showed that in the early stage of myositis there is no inflammatory infiltration in the muscle fibres. The characteristics of this stage are the MHC-I expression of muscle fibres and increased expression of IL-I α on endothelial cells. In the acute phase, T-cells and macrophages infiltrate the affected muscles while on these muscle fibres MHC-I and MHC-II expression can be detected. Meanwhile, forced IL-1α and β, TNF-α, TGF-β, macrophage inflammatory protein-1 alpha (MIP I α) and β, RANTES, MCP-1, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) expression are also present. Increased IL-1α expression on mononuclear cells and growth in IL-1β and TNF-α expression of mononuclear and endothelial cells were observed as well. Enhanced expression of TGF-β was detected on mononuclear cells, endothelial cells and extracellular matrix cells. Increased VCAM-1 and ICAM-1 expression in endothelial cells is able to show that the role of blood vessels needs more attention. In chronic myositis, MHC-I expression and IL-1α and β overexpression can be demonstrated but the presence of inflammatory cell infiltration can not be shown .

The messenger RNA of cytokines is variably expressed, except for a persistent up-regulation of IL-1β in IBM and transforming growth factor β in DM. In IBM, the IL-1, secreted by the chronically activated endomysial inflammatory cells, may participate in the formation of amyloid because it up-regulates β-amyloid precursor protein (b-APP) gene expression and b-APP promoter and co-localises with β-APP within the vacuolated muscle fibres. In DM, transforming growth factor β is overexpressed in the perimysial connective tissue but this can be down-regulated after successful immunotherapy and reduction of inflammation and fibrosis. The degenerating muscle fibres express several anti-apoptotic molecules, such as Bcl-2, and resist apoptosis-mediated cell death. In myositis, several of the identified molecules and adhesion receptors play a role in the process of inflammation, fibrosis and muscle fibre loss, and could be targets for the design of semi-specific therapeutic interventions .

Genetics

The role of genetic factors in the aetiology of myositis was described in several cases, as well as the incidence in certain ethnic groups and a strong human leucocyte antigen (HLA) association of myositis. The first described IIM-associated genetic factors were the HLA-B8 of MHC-I subclass and the HLA-DR3 from MHC-II subclass. Recent studies showed a strong link between the HLA-DRB1*0301 and DQA1*0501 genes of MHC-II subclass. In all familial and sporadic of both the US and European adults and children in the IIM subgroup, an increased incidence has been described. West and Reed also observed an association of HLA-DMA*0103 and DMB*0102 genes of MHC-II subclass in 30 Caucasian JDM patients. Arnett et al. found an increased incidence of HLA-DRB1*0301, HLA-DQA1*0501 and HLA-DQB1*0201 alleles in Caucasian patients. Examining the African-American and Mexican-American population of adult IIMs and JDM, only the HLA-DQA1*0501 allele was found significantly more frequent. Japanese IIM patients demonstrated HLA-DQA1*0102 and HLA-DQA*0103 allele dominance. In this population, HLA-B8 and HLA-DR3 were very rare alleles. Furuya et al. found rare association with HLA-B7 and HLA-B59 in Japanese patients of IIM. Spanish JDM patients also had the HLA-DQA1*0501 association. It is interesting to note that in adult Spanish IIM patients this gene in the association was not observed. In mid-American patients a protective effect of HLA-DQA1*01 gene had been described. An increased incidence of the HLA-DRB1*0803 allele also had been described in IIM patients. The HLA-B7 gene was significantly more frequent in the patients with overlap syndrome. Interestingly, all the HLA-B7-antigen-positive patients suffered from myositis–scleroderma overlap syndrome. The presence of HLA-DRB1*0101 antigen also had been observed in significantly greater proportion in overlap syndromes. There are some genes, such as HLA-DQA1*0501, with positive or protective function considering IIM. The protective effect of the HLA-DRB1*14 gene had been described in Korean patients. However, no genetic risk factors had been determined .